Recurrent and founder mutations in the Netherlands: cardiac Troponin I (TNNI3) gene mutations as a cause of severe forms of hypertrophic and restrictive cardiomyopathy*

Abstract

Background About 2-7% of familial cardiomyopathy cases are caused by a mutation in the gene encoding cardiac troponin I (TNNI3). The related clinical phenotype is usually severe with early onset. Here we report on all currently known mutations in the Dutch population and compared these with those described in literature.Methods TheTNNI3 gene was screened for mutations in all coding exons and flanking intronic sequences in a large cohort of cardiomyopathy patients. All Dutch index cases carrying a TNNI3 mutation that are described in this study underwent extensive cardiological evaluation and were listed by their postal codes. Results In 30 families, 14 different mutations were identified. Three TNNI3 mutations were found relatively frequently in both familial and non-familial cases of hypertrophic cardiomyopathy (HCM) or restrictive cardiomyopathy (RCM). Haplotype analysis showed that p. Arg145Trp and p.Ser166Phe are founder mutations in the Netherlands, while p.Glu209Ala is not. The majority of Dutch TNNI3 mutations were associated with a HCM phenotype. Mean age at diagnosis was 36.5 years. Mutations causing RCM occurred less frequently, but were identified in very young children with a poor prognosis. Conclusion In line with previously published data, we found TNNI3 mutations to be rare and associated with early onset and severe clinical presentation.

Mutations inFLNCare Associated with Familial Restrictive Cardiomyopathy

“…Currently, about 30% of the reported RCM cases are presumed to have a familial etiology [Denfield and Webber, ]. However, RCM mutations have been identified in very few cases, primarily in genes encoding proteins localized to the sarcomere or Z‐band TNNI3 [Mogensen et al., ; van den Wijngaard et al., ], TNNT2 [Peddy et al., ], DES [Hager et al., ; Pruszczyk et al., ] , MYH7 [Karam et al., ], ACTC1 [Kaski et al., ] , MYPN [Purevjav et al., ], TTN [Peled et al., ], and BAG3 [Konersman et al., ]. The large number of cases lacking a molecular‐level etiology suggests that additional genes remain to be identified.…”

“…Putative disease‐causing variants were confirmed by Sanger sequencing and cosegregation studies were undertaken using all available family members. Variants were also checked for their frequency in the Exome Aggregation Consortium (ExAC: http://exac.broadinstitute.org, September 2015).The potential effect of protein coding variants was evaluated using prediction software including Polyphen‐2 [Pfeffer et al., ], PROVEAN [Plodinec et al., ], SNPs&GO [Kushwaha et al., ], Align‐GVGD [Keren and Popp, ], Mutation Assessor [Elliott et al., ], Mutation Taster [van Spaendonck‐Zwarts et al., ], and CADD [Kircher et al., ]. Variants have been classified according to the American College of Medical Genetics and Genomics (ACMG) standards and guidelines for the interpretation of sequence variants [Richards et al., ].…”

Proteasome dysfunction in cardiomyopathies

“…The R145W mutation in TnI causes restrictive cardiomyopathy and has been associated with sudden cardiac death (van den Wijngaard et al . ). This mutation increases the Ca 2+ sensitivity of force and ATPase activity (Gomes et al .…”

Fragmented QRS Predicts Heart Failure Progression in Patients With Hypertrophic Cardiomyopathy

“…TNNI3 mutation could be a risk factor for early onset and severe clinical presentation in patients with HCM. 37 The results might be also influenced by this specific distribution of sarcomere gene mutations.…”