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    "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Bi-allelic pathogenic variants in the cystic fibrosis transmembrane conductance regulator &#40;<span class="elsevierStyleItalic">CFTR</span>&#41; gene are the cause of cystic fibrosis &#40;CF&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">1</span></a> More than 2000 specific variants have been reported to date&#46; Most of these alterations are detected in exons and exon-intron boundaries &#40;splicing variants&#41;&#46; Changes in the promoter region&#44; full or partial gene deletions&#44; and more recently&#44; deep intronic splicing variants &#40;DISV&#41; account for the remaining cases&#46; DISV are alterations in the DNA sequence of intronic regions that generate cryptic splicing sites that favour the transcription of intronic sequences &#40;pseudoexons&#41; in mRNA molecules&#46; These pseudoexons serve as templates for the synthesis of dysfunctional proteins&#44; such as the CFTR protein in the case of CF&#44; or create premature stop codons in the pre-mRNA molecules that result in nonsense mediated decay&#46; These pathogenic variants could account for a majority of the 2&#8211;5&#37; of remaining unknown variants in both cystic fibrosis &#40;CF&#41; and CFTR-related disorders &#40;CFTR-RD&#41; patients&#46; The study of intronic sequences requires complex and expensive technology&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">2</span></a> We implemented next-generation sequencing &#40;NGS&#41; to study CF patients in our Genetic Laboratory in 2014 and were able to identify DISV in the second allele of four historical clinical CF cases that have been followed-up in our CF Unit during the last decades&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">In order to assess the role of DISV on CF diagnosis&#44; we present 4 cases of patients with clinical suspicion of CF but with incomplete genotype&#44; in whom we detected DISV by NGS technologies&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">3</span></a> We used the <span class="elsevierStyleItalic">CFTR</span> MASTR&#8482; Dx kit &#40;Multiplicom&#44; Niel&#44; Belgium&#41; directed to the 27 <span class="elsevierStyleItalic">CFTR</span> coding exons&#44; selected intronic regions or variants and part of the <span class="elsevierStyleItalic">CFTR</span> promoter region&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">4</span></a> Cases 1&#8211;3 were diagnosed as CF during childhood by clinical manifestations and positive sweat test&#46; However&#44; only one mutated allele was detected in each patient during infancy&#46; Case 4 was followed&#8211;up in our Unit since the age of 19&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">The clinical and demographic characteristics of the patients are shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0020" class="elsevierStylePara elsevierViewall">The deep intronic variant c&#46;1680-883A&#62;G &#40;rs1554388867&#44; Legacy name c&#46;1811&#43;1637A&#62;G&#44; intron 12&#41; was detected in cases 1&#8211;3&#44; and the variant c&#46;870-1113&#95;870-1110del &#40;rs397508809&#44; Legacy name c&#46;1002-1110&#95;1113del&#44; intron 7&#41; in case 4&#46; In the first three cases&#44; CF was diagnosed during childhood owing to clinically compatible symptoms and positive sweat tests&#46; The fourth case was initially classified as CFTR-RD at 19 years of age because of clinically compatible symptoms&#44; an inconclusive sweat test &#40;&#60;60<span class="elsevierStyleHsp" style=""></span>mmol&#47;L<span class="elsevierStyleHsp" style=""></span>Cl<span class="elsevierStyleSup">&#8722;</span>&#41;&#44; and the detection of a single variant in the genetic analysis&#46; CF was confirmed genetically 20 years later following the detection of a DISV in the second allele&#46; This patient presented a severe phenotype with altered lung function&#44; low body mass index &#40;BMI&#41;&#44; great extent of bronchiectasis&#44; and a significant delay in diagnosis that could have negatively affected disease progression&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">The deep intronic variant c&#46;870-1113&#95;870-1110del&#44; which was found in case 4&#44; is located in intron 7 of the <span class="elsevierStyleItalic">CFTR</span> gene and alters the mRNA splicing process creating a pseudoexon with a 101 nucleotide sequence between exons 6b and 7&#46; This variant was initially identified in one patient with a clinically compatible phenotype and a negative sweat test&#44; and in three Italian patients with a classic CF phenotype&#46;<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">5&#44;6</span></a> Moreover&#44; 17 patients with CF from other studies have also been diagnosed with this pathogenic variant&#46;<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">7&#8211;9</span></a> The patients have been reported as manifesting a wide spectrum of phenotypes including severe disease&#44; delayed diagnoses&#44; higher frequencies of diffuse bronchiectasis&#44; with or without colonisation by <span class="elsevierStyleItalic">Pseudomonas aeruginosa</span>&#44; pancreatic sufficiency &#40;PS&#41; that may progress to pancreatic insufficiency &#40;PI&#41; &#40;as in our case 4 patient at 32 years old&#41;&#44; and positive or inconclusive sweat tests&#46; The variability of the phenotype has been related to levels of aberrant mRNA&#44; which is affected by the expression of splicing factor SRp75&#46; Decreasing levels of this factor have been shown to correct abnormal splicing of the variant&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">7</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">The deep intronic variant c&#46;1680-883A&#62;G is a more recently described variant located in intron 12<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">10</span></a> that results in aberrantly spliced transcripts due to the inclusion of a pseudo-exon&#46; Only three cases with this splicing intronic variant have been referenced in the literature and included in the CFTR-France Database&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">11</span></a> These three reported patients were diagnosed during childhood &#40;2 months&#44; 5 months&#44; and 3 years&#41; and were compound heterozygous with a positive sweat test&#44; with or without PI&#44; with respiratory symptoms at diagnosis&#44; and without further follow-up data&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">11</span></a> Our three patients with this intronic variant &#40;cases 1&#8211;3&#41; now aged 49&#44; 19 and 22 years respectively&#44; are the only ones with available long-term follow up and progression data&#46; They were diagnosed during childhood with positive sweat tests&#44; are compound heterozygous for severe pathogenic variants and have PI&#44; bilateral bronchiectasis&#44; bronchial colonisation by <span class="elsevierStyleItalic">Staphylococcus aureus</span>&#44; <span class="elsevierStyleItalic">Achromobacter</span> sp&#46; or <span class="elsevierStyleItalic">Pseudomonas aeruginosa</span>&#44; sinusitis and&#47;or nasal polyposis&#44; and preserved lung function&#44; except for case 3&#44; who had very impaired lung function and required a lung transplant at the age of 21&#46; Our data support the involvement of this variant with a severe CF phenotype&#44; in similar manner to c&#46;1680-877G&#62;T and c&#46;1680-886A&#62;G variants&#44;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">12</span></a> and shows the long-term evolution of these patients when they are subjected to careful follow-up measures &#40;case 3 was referred to our Cystic Fibrosis Unit just for lung transplant&#41;&#46; Bonini et al&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">10</span></a> developed oligonucleotides that can correct aberrant splicing with the use of target site blocker treatment &#40;TSB&#41;&#44; opening the alternative of a tailored therapy for the causative defect&#46; The use of other techniques capable of correcting aberrant splicing caused by other deep intronic variants have also been described recently&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">13&#8211;16</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">In conclusion&#44; in CF cases with only one pathogenic variant detected&#44; it is important to sequence the entire <span class="elsevierStyleItalic">CFTR</span> gene regions to confirm genetic diagnosis for management of the patient and to provide adequate genetic counselling&#46; The increasing number of DISV reported<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">10&#44;17&#44;18</span></a> will provide a better understanding of their pathogenic role in altering mRNA transcription using current technologies&#44; such as NGS and new genome editing tools&#46; This is essential in the present era for designing specific therapeutic approaches to correct the altered CFTR and move towards personalised medicine<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">19</span></a> or 4P medicine &#40;&#8216;personalised&#8217;&#44; &#8216;predictive&#8217;&#44; &#8216;preventive&#8217; and &#8216;participatory&#8217;&#41;&#46;</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Funding</span><p id="par0040" class="elsevierStylePara elsevierViewall">This work has been partially supported by a grant of <span class="elsevierStyleGrantSponsor" id="gs1">Fundaci&#243;n Mutua Madrile&#241;a&#46; XIV Convocatoria de Ayudas a la Investigaci&#243;n en Salud&#46; 2017</span>&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Conflicts of interest</span><p id="par0045" class="elsevierStylePara elsevierViewall">The authors have no conflict of interest to disclose&#46;</p></span></span>"
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          "leyenda" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Abbreviations</span>&#46; CF&#58; cystic fibrosis&#59; NPD&#58; nasal potential difference&#59; ND&#58; not done&#59; FVC&#58; forced vital capacity&#59; FEV1&#58; forced expiratory volume in the first second&#59; BMI&#58; body mass index&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Case 1&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Case 2&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Case 3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Case 4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Deep intronic splicing variant&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">c&#46;1680-883A&#62;G&#40;Intron 12&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">c&#46;1680-883A&#62;G&#40;Intron 12&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">c&#46;1680-883A&#62;G&#40;Intron 12&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">c&#46;870-1113&#95;870-1110del&#40;Intron 7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Variant second allele<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> &#40;Legacy name&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">c&#46;254G&#62;T&#40;G85V&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">c&#46;3909C&#62;G&#40;N1303K&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">c&#46;3909C&#62;G&#40;N1303K&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">c&#46;1521&#95;1523delCTT&#40;delF508&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Gender&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Female&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Male&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Female&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Female&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Age at diagnosis of CF&#44; years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">39&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Age at deep intronic splicing variant detection&#44; years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">41&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">18&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">21&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">39&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Current age&#44; yearsSymptoms at diagnosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">49Repeated episodes of bronchitis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">19Repeated episodes of pneumonia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">22Repeated episodes of pneumonia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">43Repeated episodes of bronchitis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Sweat test&#44; mmol&#47;L &#91;Cl<span class="elsevierStyleSup">&#8722;</span>&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">83&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">101&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">116&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">50&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NPD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Positive&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Bronchial colonisation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Staphylococcus aureus</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Achromobacter</span> sp&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Achromobacter</span> sp&#46;&#44; <span class="elsevierStyleItalic">Pseudomonas aeruginosa</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Staphylococcus aureus</span>&#44; <span class="elsevierStyleItalic">Haemophilus influenzae</span>&#44; <span class="elsevierStyleItalic">Achromobacter</span> sp&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Bronchiectasis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Upper lobes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Diffuse&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Diffuse&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Diffuse&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Sinusitis and&#47;or nasal polyposis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">FVC&#44; predicted percentage&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">81&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">93&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">41&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">56&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">FEV1&#44; predicted percentage&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">87&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">83&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">20&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">44&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">O<span class="elsevierStyleInf">2</span> saturation&#44; &#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">98&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">98&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">94&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">98&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">BMI&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">37&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">20&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">17&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">19&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pancreatic insufficiency&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No<span class="elsevierStyleHsp" style=""></span>&#8594;<span class="elsevierStyleHsp" style=""></span>Yes<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pancreatitis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Haemoptysis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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                0 => "xTab2647761.png"
              ]
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              "identificador" => "tblfn0005"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Variant cDNA name&#46;</p>"
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            1 => array:3 [
              "identificador" => "tblfn0010"
              "etiqueta" => "b"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0010">At 32 years old&#46;</p>"
            ]
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        "descripcion" => array:1 [
          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Clinical characteristics&#46;</p>"
        ]
      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0015"
          "bibliografiaReferencia" => array:19 [
            0 => array:3 [
              "identificador" => "bib0100"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Consensus on the use and interpretation of cystic fibrosis mutation analysis in clinical practice"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "C&#46; Castellani"
                            1 => "H&#46; Cuppens"
                            2 => "M&#46; Macek Jr&#46;"
                            3 => "J&#46;J&#46; Cassiman"
                            4 => "E&#46; Kerem"
                            5 => "P&#46; Durie"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jcf.2008.03.009"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Cyst Fibros"
                        "fecha" => "2008"
                        "volumen" => "7"
                        "paginaInicial" => "179"
                        "paginaFinal" => "196"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18456578"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
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                ]
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            1 => array:3 [
              "identificador" => "bib0105"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Best practice guidelines for molecular genetic diagnosis of cystic fibrosis and CFTR-related disorders &#8211; updated European recommendations"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "E&#46; Dequeker"
                            1 => "M&#46; Stuhrmann"
                            2 => "M&#46;A&#46; Morris"
                            3 => "T&#46; Casals"
                            4 => "C&#46; Castellani"
                            5 => "M&#46; Claustres"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/ejhg.2008.136"
                      "Revista" => array:6 [
                        "tituloSerie" => "Eur J Hum Genet"
                        "fecha" => "2009"
                        "volumen" => "17"
                        "paginaInicial" => "51"
                        "paginaFinal" => "65"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18685558"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib0110"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Applicability and efficiency of NGS in routine diagnosis&#58; in-depth performance analysis of a complete workflow for CFTR mutation analysis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "A&#46; Pagin"
                            1 => "A&#46; Devos"
                            2 => "M&#46; Figeac"
                            3 => "M&#46; Truant"
                            4 => "C&#46; Willoquaux"
                            5 => "F&#46; Broly"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1371/journal.pone.0149426"
                      "Revista" => array:4 [
                        "tituloSerie" => "PLOS ONE"
                        "fecha" => "2016"
                        "volumen" => "11"
                        "paginaInicial" => "e0149426"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            3 => array:3 [
              "identificador" => "bib0115"
              "etiqueta" => "4"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Multicenter validation study for the certification of a CFTR gene scanning method using next generation sequencing technology"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
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Scientific Letter
Long-term Follow-up in Adult Patients with Cystic Fibrosis and Deep Intronic Splicing Variants
Seguimiento a largo plazo en pacientes adultos con fibrosis quística y variantes de splicing en regiones profundas de los intrones
Antonio Álvareza,d,e,
Corresponding author
aalvarez@vhebron.net

Corresponding author.
, Karina Loora,d,e, Paula Fernández-Alvarezb,e, Silvia Gartnerc,e, Eva Polverinoa,d,e, Mario Culebrasa,d,e, David Clofenta,d,e, Elena García Arumíb,e, Eduardo F. Tizzanob,e,1, Javier de Graciaa,d,e,1
a Department of Respiratory Medicine – Adult Cystic Fibrosis Unit, Vall d’Hebron Barcelona Hospital Campus, Universitat Autònoma de Barcelona, Passeig Vall d’Hebron 119-129, 08035 Barcelona, Spain
b Department of Clinical and Molecular Genetics, Vall d’Hebron Barcelona Hospital Campus, Universitat Autònoma de Barcelona, Passeig Vall d’Hebron 119-129, 08035 Barcelona, Spain
c Department of Pediatrics – Pediatric Cystic Fibrosis Unit, Vall d’Hebron Barcelona Hospital Campus, Universitat Autònoma de Barcelona, Passeig Vall d’Hebron 119-129, 08035 Barcelona, Spain
d CIBER Enfermedades Respiratorias (Ciberes), Passeig Vall d’Hebron 119-129, 08035 Barcelona, Spain
e Vall d’Hebron Institut de Recerca (VHIR), Passeig Vall d’Hebron 119-129, 08035 Barcelona, Spain
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            "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">&#40;A&#41; Axial CT image of the chest with intravenous contrast medium&#44; showing a paraaortic mass in the anterior mediastinum &#40;asterisk&#41;&#46; The straight arrow shows the theoretical path of the biopsy needle in a left parasternal approach between the left inner mammary vessels &#40;circle&#41; and the left edge of the sternum&#46; Note that the aortic arch &#40;Ao&#41; is in the theoretical path of the biopsy needle&#46; The curved arrow shows that the left lung parenchyma would be punctured using this access&#46; &#40;B&#41; Axial CT image of the chest with intravenous contrast medium in which the straight arrow shows the theoretical path of the biopsy needle using a right parasternal medial approach to the right internal mammary vessels &#40;circle&#41;&#46; Note that the aortic arch &#40;Ao&#41; is not in the theoretical path of the biopsy needle&#44; but that this approach also punctures the left pulmonary parenchyma &#40;curved arrow&#41;&#46; &#40;C&#41; Axial CT image of the chest with intravenous contrast medium in which the straight arrow shows the theoretical path of the biopsy needle using a right parasternal lateral approach to the right internal mammary vessels &#40;circle&#41;&#46; Note that the aortic arch &#40;Ao&#41; is also not in the theoretical path of the biopsy needle&#44; but that this approach punctures the right pulmonary parenchyma &#40;curved arrow&#41;&#46; &#40;D&#41; Axial CT image of the chest obtained during the biopsy procedure using the CPLA&#44; with the patient in the semi-right lateral decubitus position&#44; showing an intramuscular needle &#40;arrows&#41; between the right internal mammary vessels &#40;circle&#41; and the right sternum margin for local instillation of saline &#40;hydrodissection&#41;&#46; &#40;E&#41; Axial CT image of the chest obtained during the biopsy procedure using the CPLA with the patient in the semi-right lateral decubitus position&#46; After expanding the anterior mediastinum using hydrodissection &#40;white arrows&#41;&#44; the biopsy needle is inserted &#40;black arrows&#41; into the chest wall&#46; Note that the biopsy needle is directed into the space between the right internal mammary vessels &#40;circle&#41; and the right edge of the sternum&#46; &#40;F&#41; Axial CT image of the chest obtained during the biopsy procedure by CPLA&#44; with the patient in the semi-right lateral decubitus position&#44; where the biopsy needle &#40;arrows&#41; has been advanced to the paraaortic mass &#40;black asterisk&#41; through the space between the right edge of the sternum and the right internal mammary vessels &#40;circle&#41;&#46; Note the presence of a &#8220;salinoma&#8221; &#40;white asterisk&#41; in the anterior mediastinum and the parallel trajectory of the biopsy needle to the aortic arch avoiding any possibility of damaging the aorta &#40;Ao&#41;&#46;</p>"
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such as the CFTR protein in the case of CF&#44; or create premature stop codons in the pre-mRNA molecules that result in nonsense mediated decay&#46; These pathogenic variants could account for a majority of the 2&#8211;5&#37; of remaining unknown variants in both cystic fibrosis &#40;CF&#41; and CFTR-related disorders &#40;CFTR-RD&#41; patients&#46; The study of intronic sequences requires complex and expensive technology&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">2</span></a> We implemented next-generation sequencing &#40;NGS&#41; to study CF patients in our Genetic Laboratory in 2014 and were able to identify DISV in the second allele of four historical clinical CF cases that have been followed-up in our CF Unit during the last decades&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">In order to assess the role of DISV on CF diagnosis&#44; we present 4 cases of patients with clinical suspicion of CF but with incomplete genotype&#44; in whom we detected DISV by NGS technologies&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">3</span></a> We used the <span class="elsevierStyleItalic">CFTR</span> MASTR&#8482; Dx kit &#40;Multiplicom&#44; Niel&#44; Belgium&#41; directed to the 27 <span class="elsevierStyleItalic">CFTR</span> coding exons&#44; selected intronic regions or variants and part of the <span class="elsevierStyleItalic">CFTR</span> promoter region&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">4</span></a> Cases 1&#8211;3 were diagnosed as CF during childhood by clinical manifestations and positive sweat test&#46; However&#44; only one mutated allele was detected in each patient during infancy&#46; Case 4 was followed&#8211;up in our Unit since the age of 19&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">The clinical and demographic characteristics of the patients are shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0020" class="elsevierStylePara elsevierViewall">The deep intronic variant c&#46;1680-883A&#62;G &#40;rs1554388867&#44; Legacy name c&#46;1811&#43;1637A&#62;G&#44; intron 12&#41; was detected in cases 1&#8211;3&#44; and the variant c&#46;870-1113&#95;870-1110del &#40;rs397508809&#44; Legacy name c&#46;1002-1110&#95;1113del&#44; intron 7&#41; in case 4&#46; In the first three cases&#44; CF was diagnosed during childhood owing to clinically compatible symptoms and positive sweat tests&#46; The fourth case was initially classified as CFTR-RD at 19 years of age because of clinically compatible symptoms&#44; an inconclusive sweat test &#40;&#60;60<span class="elsevierStyleHsp" style=""></span>mmol&#47;L<span class="elsevierStyleHsp" style=""></span>Cl<span class="elsevierStyleSup">&#8722;</span>&#41;&#44; and the detection of a single variant in the genetic analysis&#46; CF was confirmed genetically 20 years later following the detection of a DISV in the second allele&#46; This patient presented a severe phenotype with altered lung function&#44; low body mass index &#40;BMI&#41;&#44; great extent of bronchiectasis&#44; and a significant delay in diagnosis that could have negatively affected disease progression&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">The deep intronic variant c&#46;870-1113&#95;870-1110del&#44; which was found in case 4&#44; is located in intron 7 of the <span class="elsevierStyleItalic">CFTR</span> gene and alters the mRNA splicing process creating a pseudoexon with a 101 nucleotide sequence between exons 6b and 7&#46; This variant was initially identified in one patient with a clinically compatible phenotype and a negative sweat test&#44; and in three Italian patients with a classic CF phenotype&#46;<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">5&#44;6</span></a> Moreover&#44; 17 patients with CF from other studies have also been diagnosed with this pathogenic variant&#46;<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">7&#8211;9</span></a> The patients have been reported as manifesting a wide spectrum of phenotypes including severe disease&#44; delayed diagnoses&#44; higher frequencies of diffuse bronchiectasis&#44; with or without colonisation by <span class="elsevierStyleItalic">Pseudomonas aeruginosa</span>&#44; pancreatic sufficiency &#40;PS&#41; that may progress to pancreatic insufficiency &#40;PI&#41; &#40;as in our case 4 patient at 32 years old&#41;&#44; and positive or inconclusive sweat tests&#46; The variability of the phenotype has been related to levels of aberrant mRNA&#44; which is affected by the expression of splicing factor SRp75&#46; Decreasing levels of this factor have been shown to correct abnormal splicing of the variant&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">7</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">The deep intronic variant c&#46;1680-883A&#62;G is a more recently described variant located in intron 12<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">10</span></a> that results in aberrantly spliced transcripts due to the inclusion of a pseudo-exon&#46; Only three cases with this splicing intronic variant have been referenced in the literature and included in the CFTR-France Database&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">11</span></a> These three reported patients were diagnosed during childhood &#40;2 months&#44; 5 months&#44; and 3 years&#41; and were compound heterozygous with a positive sweat test&#44; with or without PI&#44; with respiratory symptoms at diagnosis&#44; and without further follow-up data&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">11</span></a> Our three patients with this intronic variant &#40;cases 1&#8211;3&#41; now aged 49&#44; 19 and 22 years respectively&#44; are the only ones with available long-term follow up and progression data&#46; They were diagnosed during childhood with positive sweat tests&#44; are compound heterozygous for severe pathogenic variants and have PI&#44; bilateral bronchiectasis&#44; bronchial colonisation by <span class="elsevierStyleItalic">Staphylococcus aureus</span>&#44; <span class="elsevierStyleItalic">Achromobacter</span> sp&#46; or <span class="elsevierStyleItalic">Pseudomonas aeruginosa</span>&#44; sinusitis and&#47;or nasal polyposis&#44; and preserved lung function&#44; except for case 3&#44; who had very impaired lung function and required a lung transplant at the age of 21&#46; Our data support the involvement of this variant with a severe CF phenotype&#44; in similar manner to c&#46;1680-877G&#62;T and c&#46;1680-886A&#62;G variants&#44;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">12</span></a> and shows the long-term evolution of these patients when they are subjected to careful follow-up measures &#40;case 3 was referred to our Cystic Fibrosis Unit just for lung transplant&#41;&#46; Bonini et al&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">10</span></a> developed oligonucleotides that can correct aberrant splicing with the use of target site blocker treatment &#40;TSB&#41;&#44; opening the alternative of a tailored therapy for the causative defect&#46; The use of other techniques capable of correcting aberrant splicing caused by other deep intronic variants have also been described recently&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">13&#8211;16</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">In conclusion&#44; in CF cases with only one pathogenic variant detected&#44; it is important to sequence the entire <span class="elsevierStyleItalic">CFTR</span> gene regions to confirm genetic diagnosis for management of the patient and to provide adequate genetic counselling&#46; The increasing number of DISV reported<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">10&#44;17&#44;18</span></a> will provide a better understanding of their pathogenic role in altering mRNA transcription using current technologies&#44; such as NGS and new genome editing tools&#46; This is essential in the present era for designing specific therapeutic approaches to correct the altered CFTR and move towards personalised medicine<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">19</span></a> or 4P medicine &#40;&#8216;personalised&#8217;&#44; &#8216;predictive&#8217;&#44; &#8216;preventive&#8217; and &#8216;participatory&#8217;&#41;&#46;</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Funding</span><p id="par0040" class="elsevierStylePara elsevierViewall">This work has been partially supported by a grant of <span class="elsevierStyleGrantSponsor" id="gs1">Fundaci&#243;n Mutua Madrile&#241;a&#46; XIV Convocatoria de Ayudas a la Investigaci&#243;n en Salud&#46; 2017</span>&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Conflicts of interest</span><p id="par0045" class="elsevierStylePara elsevierViewall">The authors have no conflict of interest to disclose&#46;</p></span></span>"
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          "leyenda" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Abbreviations</span>&#46; CF&#58; cystic fibrosis&#59; NPD&#58; nasal potential difference&#59; ND&#58; not done&#59; FVC&#58; forced vital capacity&#59; FEV1&#58; forced expiratory volume in the first second&#59; BMI&#58; body mass index&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Case 1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Case 2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Case 3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Case 4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Deep intronic splicing variant&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">c&#46;1680-883A&#62;G&#40;Intron 12&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">c&#46;1680-883A&#62;G&#40;Intron 12&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">c&#46;1680-883A&#62;G&#40;Intron 12&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">c&#46;870-1113&#95;870-1110del&#40;Intron 7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Variant second allele<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> &#40;Legacy name&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">c&#46;254G&#62;T&#40;G85V&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">c&#46;3909C&#62;G&#40;N1303K&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">c&#46;3909C&#62;G&#40;N1303K&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">c&#46;1521&#95;1523delCTT&#40;delF508&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Gender&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Female&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Male&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Female&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Female&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Age at diagnosis of CF&#44; years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">39&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Age at deep intronic splicing variant detection&#44; years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">41&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">18&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">21&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">39&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Current age&#44; yearsSymptoms at diagnosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">49Repeated episodes of bronchitis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">19Repeated episodes of pneumonia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">22Repeated episodes of pneumonia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">43Repeated episodes of bronchitis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Sweat test&#44; mmol&#47;L &#91;Cl<span class="elsevierStyleSup">&#8722;</span>&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">83&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">101&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">116&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">50&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NPD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Positive&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Bronchial colonisation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Staphylococcus aureus</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Achromobacter</span> sp&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Achromobacter</span> sp&#46;&#44; <span class="elsevierStyleItalic">Pseudomonas aeruginosa</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Staphylococcus aureus</span>&#44; <span class="elsevierStyleItalic">Haemophilus influenzae</span>&#44; <span class="elsevierStyleItalic">Achromobacter</span> sp&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Bronchiectasis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Upper lobes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Diffuse&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Diffuse&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Diffuse&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Sinusitis and&#47;or nasal polyposis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">FVC&#44; predicted percentage&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">81&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">93&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">41&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">56&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">FEV1&#44; predicted percentage&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">87&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">83&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">20&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">44&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">O<span class="elsevierStyleInf">2</span> saturation&#44; &#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">98&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">98&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">94&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">98&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">BMI&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">37&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">20&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">17&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">19&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pancreatic insufficiency&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No<span class="elsevierStyleHsp" style=""></span>&#8594;<span class="elsevierStyleHsp" style=""></span>Yes<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pancreatitis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Haemoptysis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab2647761.png"
              ]
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              "identificador" => "tblfn0005"
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              "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Variant cDNA name&#46;</p>"
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            1 => array:3 [
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              "etiqueta" => "b"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0010">At 32 years old&#46;</p>"
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        "descripcion" => array:1 [
          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Clinical characteristics&#46;</p>"
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      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0015"
          "bibliografiaReferencia" => array:19 [
            0 => array:3 [
              "identificador" => "bib0100"
              "etiqueta" => "1"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Consensus on the use and interpretation of cystic fibrosis mutation analysis in clinical practice"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "C&#46; Castellani"
                            1 => "H&#46; Cuppens"
                            2 => "M&#46; Macek Jr&#46;"
                            3 => "J&#46;J&#46; Cassiman"
                            4 => "E&#46; Kerem"
                            5 => "P&#46; Durie"
                          ]
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                    ]
                  ]
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                    0 => array:2 [
                      "doi" => "10.1016/j.jcf.2008.03.009"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Cyst Fibros"
                        "fecha" => "2008"
                        "volumen" => "7"
                        "paginaInicial" => "179"
                        "paginaFinal" => "196"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18456578"
                            "web" => "Medline"
                          ]
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            1 => array:3 [
              "identificador" => "bib0105"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Best practice guidelines for molecular genetic diagnosis of cystic fibrosis and CFTR-related disorders &#8211; updated European recommendations"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "E&#46; Dequeker"
                            1 => "M&#46; Stuhrmann"
                            2 => "M&#46;A&#46; Morris"
                            3 => "T&#46; Casals"
                            4 => "C&#46; Castellani"
                            5 => "M&#46; Claustres"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/ejhg.2008.136"
                      "Revista" => array:6 [
                        "tituloSerie" => "Eur J Hum Genet"
                        "fecha" => "2009"
                        "volumen" => "17"
                        "paginaInicial" => "51"
                        "paginaFinal" => "65"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18685558"
                            "web" => "Medline"
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              "identificador" => "bib0110"
              "etiqueta" => "3"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Applicability and efficiency of NGS in routine diagnosis&#58; in-depth performance analysis of a complete workflow for CFTR mutation analysis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "A&#46; Pagin"
                            1 => "A&#46; Devos"
                            2 => "M&#46; Figeac"
                            3 => "M&#46; Truant"
                            4 => "C&#46; Willoquaux"
                            5 => "F&#46; Broly"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1371/journal.pone.0149426"
                      "Revista" => array:4 [
                        "tituloSerie" => "PLOS ONE"
                        "fecha" => "2016"
                        "volumen" => "11"
                        "paginaInicial" => "e0149426"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            3 => array:3 [
              "identificador" => "bib0115"
              "etiqueta" => "4"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Multicenter validation study for the certification of a CFTR gene scanning method using next generation sequencing technology"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "A&#46; Bergougnoux"
                            1 => "V&#46; D&#8217;Argenio"
                            2 => "S&#46; Sollfrank"
                            3 => "F&#46; Verneau"
                            4 => "A&#46; Telese"
                            5 => "I&#46; Postiglioni"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1515/cclm-2017-0553"
                      "Revista" => array:6 [
                        "tituloSerie" => "Clin Chem Lab Med"
                        "fecha" => "2018"
                        "volumen" => "56"
                        "paginaInicial" => "1046"
                        "paginaFinal" => "1053"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/29427548"
                            "web" => "Medline"
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            4 => array:3 [
              "identificador" => "bib0120"
              "etiqueta" => "5"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "A new cryptic CFTR exon in mild CF"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "C&#46; Costa"
                            1 => "V&#46; Pruli&#232;re Escabasse"
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ISSN: 15792129
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