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,
, 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
Corresponding author
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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Martínez, Marta G. Fuentes, Marta Paz, Israel Rodríguez, Nuria M. Novoa, Marcelo F. Jiménez" "autores" => array:7 [ 0 => array:2 [ "nombre" => "María Teresa" "apellidos" => "Gómez-Hernández" ] 1 => array:2 [ "nombre" => "Ernest J." "apellidos" => "Martínez" ] 2 => array:2 [ "nombre" => "Marta G." "apellidos" => "Fuentes" ] 3 => array:2 [ "nombre" => "Marta" "apellidos" => "Paz" ] 4 => array:2 [ "nombre" => "Israel" "apellidos" => "Rodríguez" ] 5 => array:2 [ "nombre" => "Nuria M." "apellidos" => "Novoa" ] 6 => array:2 [ "nombre" => "Marcelo F." "apellidos" => "Jiménez" ] ] ] ] ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0300289620305184?idApp=UINPBA00003Z" "url" => "/03002896/0000005700000007/v2_202107030624/S0300289620305184/v2_202107030624/es/main.assets" ] "itemAnterior" => array:19 [ "pii" => "S0300289620303070" "issn" => "03002896" "doi" => "10.1016/j.arbres.2020.08.022" "estado" => "S300" "fechaPublicacion" => "2021-07-01" "aid" => "2626" "copyright" => "SEPAR" "documento" => "simple-article" "crossmark" => 1 "subdocumento" => "crp" "cita" => "Arch Bronconeumol. 2021;57:499-501" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "es" => array:11 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Carta Científica</span>" "titulo" => "Biopsia percutánea de masa mediastínica paraaórtica mediante abordaje paraesternal contralateral: un nuevo acceso alternativo seguro" "tienePdf" => "es" "tieneTextoCompleto" => "es" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "499" "paginaFinal" => "501" ] ] "titulosAlternativos" => array:1 [ "en" => array:1 [ "titulo" => "Percutaneous Biopsy of a Paraaortic Mediastinal Mass Using a Contralateral Parasternal Approach: A New Alternative Safe Access" ] ] "contieneTextoCompleto" => array:1 [ "es" => true ] "contienePdf" => array:1 [ "es" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figura 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1072 "Ancho" => 1500 "Tamanyo" => 158445 ] ] "descripcion" => array:1 [ "es" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">A) Imagen axial de TC de tórax con contraste intravenoso en la que se observa una masa paraaórtica en mediastino anterior (asterisco). La flecha recta describe el trayecto teórico de la aguja de biopsia en un abordaje paraesternal izquierdo entre los vasos mamarios internos izquierdos (círculo) y el borde izquierdo del esternón. Nótese que el cayado aórtico (Ao) se encuentra en el trayecto teórico de la aguja de biopsia. La flecha curva indica que en este acceso se punciona el parénquima pulmonar izquierdo. B) Imagen axial de TC de tórax con contraste intravenoso en la que la flecha recta describe el trayecto teórico de la aguja de biopsia en un abordaje paraesternal derecho medial a los vasos mamarios internos derechos (círculo). Nótese que el cayado aórtico (Ao) no se encuentra en el trayecto teórico de la aguja de biopsia, pero que con este abordaje se punciona también el parénquima pulmonar izquierdo (flecha curva). C) Imagen axial de TC de tórax con contraste intravenoso en la que la flecha recta describe el trayecto teórico de la aguja de biopsia en un abordaje paraesternal derecho lateral a los vasos mamarios internos derechos (círculo). Nótese que el cayado aórtico (Ao) tampoco se encuentra en el trayecto teórico de la aguja de biopsia, pero que con este abordaje se punciona el parénquima pulmonar derecho (flecha curva). D) Imagen axial de TC de tórax obtenida durante el procedimiento de biopsia mediante APEC, con la paciente en posición de semidecúbito lateral derecho, en la que se visualiza una aguja intramuscular (flechas) entre los vasos mamarios internos derechos (círculo) y el margen derecho del esternón para la instilación local de suero salino (hidrodisección). E) Imagen axial de TC de tórax obtenida durante el procedimiento de biopsia mediante APEC, con la paciente en posición de semidecúbito lateral derecho, en la que una vez expandido el mediastino anterior mediante la técnica de hidrodisección (flechas blancas) se introduce la aguja de biopsia (flechas negras) en la pared torácica. Nótese que la aguja de biopsia se dirige hacia el espacio existente entre los vasos mamarios internos derechos (círculo) y el borde derecho del esternón. F) Imagen axial de TC de tórax obtenida durante el procedimiento de biopsia mediante APEC, con la paciente en posición de semidecúbito lateral derecho, en la que se ha progresado la aguja de biopsia (flechas) hasta la masa paraaórtica (asterisco negro) a través del espacio entre el borde derecho del esternón y los vasos mamarios internos derechos (círculo). Nótese la presencia del «salinoma» (asterisco blanco) en el mediastino anterior y la imposibilidad de lesionar la aorta (Ao) debido a la trayectoria paralela de la aguja de biopsia al cayado aórtico.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Luis Gorospe, Ana María Ayala-Carbonero, Adela Montelongo-Martín, Rosa Mariela Mirambeaux-Villalona, Paola Arrieta, Gemma María Muñoz-Molina, Sara Fra-Fernández, Amparo Benito-Berlinches, Blanca Lumbreras-Fernández, Javier Alarcón-Rodríguez" "autores" => array:10 [ 0 => array:2 [ "nombre" => "Luis" "apellidos" => "Gorospe" ] 1 => array:2 [ "nombre" => "Ana María" "apellidos" => "Ayala-Carbonero" ] 2 => array:2 [ "nombre" => "Adela" "apellidos" => "Montelongo-Martín" ] 3 => array:2 [ "nombre" => "Rosa Mariela" "apellidos" => "Mirambeaux-Villalona" ] 4 => array:2 [ "nombre" => "Paola" "apellidos" => "Arrieta" ] 5 => array:2 [ "nombre" => "Gemma María" "apellidos" => "Muñoz-Molina" ] 6 => array:2 [ "nombre" => "Sara" "apellidos" => "Fra-Fernández" ] 7 => array:2 [ "nombre" => "Amparo" "apellidos" => "Benito-Berlinches" ] 8 => array:2 [ "nombre" => "Blanca" "apellidos" => "Lumbreras-Fernández" ] 9 => array:2 [ "nombre" => "Javier" "apellidos" => "Alarcón-Rodríguez" ] ] ] ] ] "idiomaDefecto" => "es" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "S1579212921001701" "doi" => "10.1016/j.arbr.2021.05.010" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1579212921001701?idApp=UINPBA00003Z" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0300289620303070?idApp=UINPBA00003Z" "url" => "/03002896/0000005700000007/v2_202107030624/S0300289620303070/v2_202107030624/es/main.assets" ] "en" => array:15 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Scientific Letter</span>" "titulo" => "Long-term Follow-up in Adult Patients with Cystic Fibrosis and Deep Intronic Splicing Variants" "tieneTextoCompleto" => true "saludo" => "<span class="elsevierStyleItalic">Dear Editor</span>," "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "501" "paginaFinal" => "503" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Antonio Álvarez, Karina Loor, Paula Fernández-Alvarez, Silvia Gartner, Eva Polverino, Mario Culebras, David Clofent, Elena García Arumí, Eduardo F. 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"apellidos" => "Tizzano" "referencia" => array:3 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">e</span>" "identificador" => "aff0025" ] 2 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">1</span>" "identificador" => "fn0005" ] ] ] 9 => array:3 [ "nombre" => "Javier" "apellidos" => "de Gracia" "referencia" => array:4 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">d</span>" "identificador" => "aff0020" ] 2 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">e</span>" "identificador" => "aff0025" ] 3 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">1</span>" "identificador" => "fn0005" ] ] ] ] "afiliaciones" => array:5 [ 0 => array:3 [ "entidad" => "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" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "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" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "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" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "CIBER Enfermedades Respiratorias (Ciberes), Passeig Vall d’Hebron 119-129, 08035 Barcelona, Spain" "etiqueta" => "d" "identificador" => "aff0020" ] 4 => array:3 [ "entidad" => "Vall d’Hebron Institut de Recerca (VHIR), Passeig Vall d’Hebron 119-129, 08035 Barcelona, Spain" "etiqueta" => "e" "identificador" => "aff0025" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Seguimiento a largo plazo en pacientes adultos con fibrosis quística y variantes de splicing en regiones profundas de los intrones" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Bi-allelic pathogenic variants in the cystic fibrosis transmembrane conductance regulator (<span class="elsevierStyleItalic">CFTR</span>) gene are the cause of cystic fibrosis (CF).<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">1</span></a> More than 2000 specific variants have been reported to date. Most of these alterations are detected in exons and exon-intron boundaries (splicing variants). Changes in the promoter region, full or partial gene deletions, and more recently, deep intronic splicing variants (DISV) account for the remaining cases. DISV are alterations in the DNA sequence of intronic regions that generate cryptic splicing sites that favour the transcription of intronic sequences (pseudoexons) in mRNA molecules. These pseudoexons serve as templates for the synthesis of dysfunctional proteins, such as the CFTR protein in the case of CF, or create premature stop codons in the pre-mRNA molecules that result in nonsense mediated decay. These pathogenic variants could account for a majority of the 2–5% of remaining unknown variants in both cystic fibrosis (CF) and CFTR-related disorders (CFTR-RD) patients. The study of intronic sequences requires complex and expensive technology.<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">2</span></a> We implemented next-generation sequencing (NGS) 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.</p><p id="par0010" class="elsevierStylePara elsevierViewall">In order to assess the role of DISV on CF diagnosis, we present 4 cases of patients with clinical suspicion of CF but with incomplete genotype, in whom we detected DISV by NGS technologies.<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">3</span></a> We used the <span class="elsevierStyleItalic">CFTR</span> MASTR™ Dx kit (Multiplicom, Niel, Belgium) directed to the 27 <span class="elsevierStyleItalic">CFTR</span> coding exons, selected intronic regions or variants and part of the <span class="elsevierStyleItalic">CFTR</span> promoter region.<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">4</span></a> Cases 1–3 were diagnosed as CF during childhood by clinical manifestations and positive sweat test. However, only one mutated allele was detected in each patient during infancy. Case 4 was followed–up in our Unit since the age of 19.</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>.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0020" class="elsevierStylePara elsevierViewall">The deep intronic variant c.1680-883A>G (rs1554388867, Legacy name c.1811+1637A>G, intron 12) was detected in cases 1–3, and the variant c.870-1113_870-1110del (rs397508809, Legacy name c.1002-1110_1113del, intron 7) in case 4. In the first three cases, CF was diagnosed during childhood owing to clinically compatible symptoms and positive sweat tests. The fourth case was initially classified as CFTR-RD at 19 years of age because of clinically compatible symptoms, an inconclusive sweat test (<60<span class="elsevierStyleHsp" style=""></span>mmol/L<span class="elsevierStyleHsp" style=""></span>Cl<span class="elsevierStyleSup">−</span>), and the detection of a single variant in the genetic analysis. CF was confirmed genetically 20 years later following the detection of a DISV in the second allele. This patient presented a severe phenotype with altered lung function, low body mass index (BMI), great extent of bronchiectasis, and a significant delay in diagnosis that could have negatively affected disease progression.</p><p id="par0025" class="elsevierStylePara elsevierViewall">The deep intronic variant c.870-1113_870-1110del, which was found in case 4, 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. This variant was initially identified in one patient with a clinically compatible phenotype and a negative sweat test, and in three Italian patients with a classic CF phenotype.<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">5,6</span></a> Moreover, 17 patients with CF from other studies have also been diagnosed with this pathogenic variant.<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">7–9</span></a> The patients have been reported as manifesting a wide spectrum of phenotypes including severe disease, delayed diagnoses, higher frequencies of diffuse bronchiectasis, with or without colonisation by <span class="elsevierStyleItalic">Pseudomonas aeruginosa</span>, pancreatic sufficiency (PS) that may progress to pancreatic insufficiency (PI) (as in our case 4 patient at 32 years old), and positive or inconclusive sweat tests. The variability of the phenotype has been related to levels of aberrant mRNA, which is affected by the expression of splicing factor SRp75. Decreasing levels of this factor have been shown to correct abnormal splicing of the variant.<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">7</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">The deep intronic variant c.1680-883A>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. Only three cases with this splicing intronic variant have been referenced in the literature and included in the CFTR-France Database.<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">11</span></a> These three reported patients were diagnosed during childhood (2 months, 5 months, and 3 years) and were compound heterozygous with a positive sweat test, with or without PI, with respiratory symptoms at diagnosis, and without further follow-up data.<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">11</span></a> Our three patients with this intronic variant (cases 1–3) now aged 49, 19 and 22 years respectively, are the only ones with available long-term follow up and progression data. They were diagnosed during childhood with positive sweat tests, are compound heterozygous for severe pathogenic variants and have PI, bilateral bronchiectasis, bronchial colonisation by <span class="elsevierStyleItalic">Staphylococcus aureus</span>, <span class="elsevierStyleItalic">Achromobacter</span> sp. or <span class="elsevierStyleItalic">Pseudomonas aeruginosa</span>, sinusitis and/or nasal polyposis, and preserved lung function, except for case 3, who had very impaired lung function and required a lung transplant at the age of 21. Our data support the involvement of this variant with a severe CF phenotype, in similar manner to c.1680-877G>T and c.1680-886A>G variants,<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 (case 3 was referred to our Cystic Fibrosis Unit just for lung transplant). Bonini et al.<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 (TSB), opening the alternative of a tailored therapy for the causative defect. The use of other techniques capable of correcting aberrant splicing caused by other deep intronic variants have also been described recently.<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">13–16</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">In conclusion, in CF cases with only one pathogenic variant detected, 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. The increasing number of DISV reported<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">10,17,18</span></a> will provide a better understanding of their pathogenic role in altering mRNA transcription using current technologies, such as NGS and new genome editing tools. 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 (‘personalised’, ‘predictive’, ‘preventive’ and ‘participatory’).</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">Fundación Mutua Madrileña. XIV Convocatoria de Ayudas a la Investigación en Salud. 2017</span>.</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.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Funding" ] 1 => array:2 [ "identificador" => "sec0010" "titulo" => "Conflicts of interest" ] 2 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:3 [ "etiqueta" => "1" "nota" => "<p class="elsevierStyleNotepara" id="npar0015">Senior authors from Clinical and Molecular Genetics and Respiratory Departments.</p>" "identificador" => "fn0005" ] ] "multimedia" => array:1 [ 0 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Abbreviations</span>. CF: cystic fibrosis; NPD: nasal potential difference; ND: not done; FVC: forced vital capacity; FEV1: forced expiratory volume in the first second; BMI: body mass index.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <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"> \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 1 \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 \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 \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 \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 \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.1680-883A>G(Intron 12) \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.1680-883A>G(Intron 12) \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.1680-883A>G(Intron 12) \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.870-1113_870-1110del(Intron 7) \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> (Legacy name) \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.254G>T(G85V) \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.3909C>G(N1303K) \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.3909C>G(N1303K) \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.1521_1523delCTT(delF508) \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 \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 \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 \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 \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 \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, years \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 \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 \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 \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 \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, years \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 \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 \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 \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 \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, yearsSymptoms at diagnosis \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 \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 \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 \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 \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, mmol/L [Cl<span class="elsevierStyleSup">−</span>] \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 \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 \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 \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 \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 \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 \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 \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 \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 \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 \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> \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. \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., <span class="elsevierStyleItalic">Pseudomonas aeruginosa</span> \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>, <span class="elsevierStyleItalic">Haemophilus influenzae</span>, <span class="elsevierStyleItalic">Achromobacter</span> sp. \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 \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 \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 \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 \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 \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/or nasal polyposis \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 \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 \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 \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 \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, predicted percentage \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 \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 \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 \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 \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, predicted percentage \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 \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 \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 \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 \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, % \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 \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 \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 \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 \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 \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">37.2 \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">20.8 \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 \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">19.6 \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 \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 \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 \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 \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>→<span class="elsevierStyleHsp" style=""></span>Yes<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a> \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 \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 \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 \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 \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 \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 \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 \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 \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 \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 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2648545.png" ] ] ] "notaPie" => array:2 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Variant cDNA name.</p>" ] 1 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "b" "nota" => "<p class="elsevierStyleNotepara" id="npar0010">At 32 years old.</p>" ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Clinical characteristics.</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. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 8 | 5 | 13 |
| 2024 October | 53 | 17 | 70 |
| 2024 September | 63 | 13 | 76 |
| 2024 August | 82 | 42 | 124 |
| 2024 July | 56 | 19 | 75 |
| 2024 June | 68 | 18 | 86 |
| 2024 May | 95 | 29 | 124 |
| 2024 April | 50 | 19 | 69 |
| 2024 March | 47 | 19 | 66 |
| 2024 February | 42 | 32 | 74 |
| 2024 January | 45 | 26 | 71 |
| 2023 December | 34 | 21 | 55 |
| 2023 November | 49 | 40 | 89 |
| 2023 October | 43 | 29 | 72 |
| 2023 September | 41 | 27 | 68 |
| 2023 August | 42 | 31 | 73 |
| 2023 July | 43 | 23 | 66 |
| 2023 June | 35 | 14 | 49 |
| 2023 May | 36 | 20 | 56 |
| 2023 April | 38 | 31 | 69 |
| 2023 March | 65 | 42 | 107 |
| 2023 February | 49 | 21 | 70 |
| 2023 January | 42 | 38 | 80 |
| 2022 December | 71 | 33 | 104 |
| 2022 November | 94 | 23 | 117 |
| 2022 October | 72 | 37 | 109 |
| 2022 September | 59 | 23 | 82 |
| 2022 August | 53 | 45 | 98 |
| 2022 July | 49 | 45 | 94 |
| 2022 June | 46 | 39 | 85 |
| 2022 May | 44 | 36 | 80 |
| 2022 April | 62 | 35 | 97 |
| 2022 March | 53 | 44 | 97 |
| 2022 February | 27 | 20 | 47 |
| 2022 January | 2 | 0 | 2 |
| 2021 December | 0 | 4 | 4 |
| 2021 September | 2 | 2 | 4 |
| 2021 August | 188 | 4 | 192 |
| 2021 July | 17 | 11 | 28 |
| 2021 June | 1 | 2 | 3 |
| 2021 April | 15 | 4 | 19 |
| 2021 January | 2 | 2 | 4 |
| 2020 December | 1 | 4 | 5 |
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