Genetic basis of familial dilated cardiomyopathy patients undergoing heart transplantation

https://doi.org/10.1016/j.healun.2015.12.014Get rights and content

Background

Dilated cardiomyopathy (DCM) is the most frequent cause of heart transplantation (HTx). The genetic basis of DCM among patients undergoing HTx has been poorly characterized. We sought to determine the genetic basis of familial DCM HTx and to establish the yield of modern next generation sequencing (NGS) technologies in this setting.

Methods

Fifty-two heart-transplanted patients due to familial DCM underwent NGS genetic evaluation with a panel of 126 genes related to cardiac conditions (59 associated with DCM). Genetic variants were initially classified as pathogenic mutations or as variants of uncertain significance (VUS). Final pathogenicity status was determined by familial cosegregation studies.

Results

Initially, 24 pathogenic mutations were found in 21 patients (40%); 25 patients (48%) carried 19 VUS and 6 (12%) did not show any genetic variant. Familial evaluation of 220 relatives from 36 of the 46 families with genetic variants confirmed pathogenicity in 14 patients and allowed reclassification of VUS as pathogenic in 17 patients, and as non-pathogenic in 3 cases. At the end of the study, the DCM-causing mutation was identified in 38 patients (73%) and 5 patients (10%) harbored only VUS. No genetic variants were identified in 9 cases (17%).

Conclusions

The genetic spectrum of familial DCM patients undergoing HTx is heterogeneous and involves multiple genes. NGS technology plus detailed familial studies allow identification of causative mutations in the vast majority of familial DCM cases. Detailed familial studies remain critical to determine the pathogenicity of underlying genetic defects in a substantial number of cases.

Section snippets

Study population

This study was approved by the ethics committee of the participant centers and complied with the Declaration of Helsinki.

A total of 52 non-related patients with HTx due to familial DCM at 3 Spanish heart transplant centers (Hospital Universitario Puerta de Hierro, Hospital Universitario 12 de Octubre and Hospital Universitario Virgen de la Arrixaca) were included in the study.

DCM was defined as familial if 1 or more relative(s) (in addition to the proband) had DCM during life or at post-mortem

Results

The study cohort comprised 52 patients (mean age at first evaluation 39.9 ± 14.3 years, range 11 to 64 years; 92% males). Clinical and familial characteristics are presented in Table S2 in Supplementary material 1 (available online at www.jhltonline.org). Fifty-one patients (98%) had known family history of DCM and 20 (38%) had family history of SCD (7 of those in a relative <35 years of age). Pedigrees of the 52 families are provided (see Supplementary material 2 available online at //www.jhltonline.org

Discussion

In this study we have examined, for the first time, the genetic basis of familial DCM in individuals with HTx. This work is also the first to address the yield of modern NGS technology plus detailed familial studies in this setting. Our findings show that the genetic spectrum of familial DCM patients undergoing HTx is heterogeneous and that several genes are involved in the pathogenesis of the disease. We also found that current NGS genetic studies, when combined with detailed familial

Disclosure statement

I.G.-D. is an employee of Health In Code; L.M. is shareholder of Health In Code; and S.C., L.P.-B., E.L.-P. and P.G.-P. share a patent on diagnostic testing. The other authors have no conflicts of interest to disclose. The authors gratefully acknowledge SecuGen for help with the haplotype analysis and Kenneth McCreath for English editing. This study was supported by the Instituto de Salud Carlos III (Grants PI11/0699, RD012/0042/0015, RD012/0042/0049, RD012/0042/0066 and RD12/0042/0069) and the

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