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Deletions of specific exons of FHOD3 detected by next‐generation sequencing are associated with hypertrophic cardiomyopathy
Author(s) -
Ochoa Juan P.,
Lopes Luis R.,
PerezBarbeito Marlene,
CazónVarela Laura,
TorreCarpente Maria M.,
SonichevaPaterson Natalia,
De UñaIglesias David,
Quinn Ellen,
KuzminaKrutetskaya Svetlana,
Garrote José A.,
Elliott Perry M.,
Monserrat Lorenzo
Publication year - 2020
Publication title -
clinical genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.543
H-Index - 102
eISSN - 1399-0004
pISSN - 0009-9163
DOI - 10.1111/cge.13759
Subject(s) - proband , hypertrophic cardiomyopathy , genetics , copy number variation , exon , biology , gene , dna sequencing , phenotype , clinical significance , computational biology , genome , mutation , medicine , biochemistry
Abstract Despite new strategies, such as evaluating deep intronic variants and new genes in whole‐genome‐sequencing studies, the diagnostic yield of genetic testing in hypertrophic cardiomyopathy (HCM) is still around 50%. FHOD3 has emerged as a novel disease‐causing gene for this phenotype, but the relevance and clinical implication of copy‐number variations (CNVs) have not been determined. In this study, CNVs were evaluated using a comparative depth‐of‐coverage strategy by next‐generation sequencing (NGS) in 5493 HCM probands and 2973 disease‐controls. We detected three symmetrical deletions in FHOD3 that involved exons 15 and 16 in three HCM families (no CNVs were detected in the control group). These exons are part of the diaphanous inhibitory domain of FHOD3 protein, considered a cluster of mutations for HCM. The clinical characteristics of the affected carriers were consistent with those reported in FHOD3 in previous studies. This study highlights the importance of performing CNV analysis systematically in NGS genetic testing panels for HCM, and reinforces the relevance of the FHOD3 gene in the disease.