Next-generation sequencing identifies pathogenic and modifier mutations in a consanguineous Chinese family with hypertrophic cardiomyopathy

Abstract

Supplemental Digital Content is available in the text

Clinical Interpretation of Sequence Variants

“…For recessive disorders, incidental carriers can harbor pathogenic variants unrelated to the disease phenotype. Zhang et al, 2017). Because approximately 15-50% of familial HCM patients harboring two heterozygous variants has been observed and speculated to result in a more severe phenotype of HCM (Emrahi, Tabrizi, Gharehsouran, Ardebili, & Estiar, 2016;Zhao et al, 2017), BP5 should not be applied in this case.…”

Exome sequencing identifies a FHOD3 p.S527del mutation in a Chinese family with hypertrophic cardiomyopathy

“…To investigate the cause of the clinical heterogeneity of the family, we performed additional analyses on the filtered exome sequencing data of the seven patients. A list of genes associated with cardiac hypertrophy or heart development was identified using the following criteria: (i) genes and closely related genes known to cause or contribute to cardiomyopathy and channelopathy (see Supporting information, Table S1); (ii) genes involved in heart development and morphogenesis (GO:0007507: heart development; GO:0003007: heart morphogenesis); and (iii) five polymorphisms involved in the renin–angiotensin–aldosterone system (RAAS). The five polymorphisms involved in RAAS were previously studied as disease modifiers in HCM, including rs4646994 in the angiotensin converting enzyme gene ( ACE ); rs5186 in the angiotensin II receptor type 1 gene ( AGTR1 ); rs1800875 in the cardiac chymase A gene ( CMA1 ); rs699 in the gene encoding angiotensinogen ( AGT ); and rs1799998 in the aldolase synthase gene ( CYP11B2 ).…”

“…Moreover, FHOD3 was associated with cardiomyopathy and was predicted to be deleterious. Sanger sequencing validated that the T A B L E 2 Clinical characteristcs of affected family members following criteria: (i) genes and closely related genes known to cause or contribute to cardiomyopathy and channelopathy 17,18 (see Supporting information, Table S1); (ii) genes involved in heart development and morphogenesis (GO:0007507: heart development;…”

Exploring the Continuum of Hypertrophic Cardiomyopathy—From DNA to Clinical Expression

“…In addition to RAAS, other plausible modifiers of HCM expression have been proposed: ankyrin-2 (ANK2) [36], integrin alpha 8 (ITGA8), ankyrin repeat protein (CARP) [61], voltage-dependent l-type calcium channel subunit beta-2 (CACNB2) [62], ryanodine receptor 2 (RYR2) [63], sodium channel α-subunit gene ( SCN5A ) [63], Muscle ring-finger protein-1 (MURF1), and Muscle ring-finger protein-2 (MURF2) [64]. For instance, it has been shown that ANK2 rare variants were associated with severe LVH, while patients harboring SCN5A rare variants were more likely to have LVOT obstruction and LA enlargement [36].…”