MYBPC3 is the most frequently mutated gene in hypertrophic cardiomyopathy (HCM). Several loss-of-function founder variants have been reported in MYBPC3 from various geographic regions, altogether sugg Show more
MYBPC3 is the most frequently mutated gene in hypertrophic cardiomyopathy (HCM). Several loss-of-function founder variants have been reported in MYBPC3 from various geographic regions, altogether suggestive of a modest or absent effect of these variants on reproductive fitness. One of them, a MYBPC3 splice variant, NM₀₀₀₂₅₆.3:c.3330+2T > G, was first described in homozygous state in newborns presenting with a severe, recessive form of HCM among the Amish population and was later associated with adult-onset dominant HCM in heterozygous carriers. We here report this splice variant in heterozygous state in eight unrelated Swiss families with HCM, making it the most prevalent cardiomyopathy variant in western Switzerland. This variant was identified in patients using targeted (n = 5) or full-genome sequencing (n = 3). Given the prevalence of this variant in the Old Order Amish, Mennonites and Swiss populations, and given that both Amish and Mennonites founders originated from the Bern Canton in Switzerland, the MYBPC3, NM₀₀₀₂₅₆.3:c.3330+2T > G variant appears to be of Swiss origin. Neighboring regions that hosted the first Amish settlements (Alsace, South Germany) should be on the lookout for that variant. The existence of MYBPC3 founder variants in different populations suggests that individuals with early-onset clinical disease may be the tip of the iceberg of a much larger number of asymptomatic carriers. Alternatively, reproductive fitness could even be slightly increased in some variant carriers to compensate for the reduction of fitness in the more severely affected ones, but this remains to be investigated. Show less
Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease (1/500) and the most common cause of sudden cardiac death in young people. Pathogenic mutation detection of HCM is having Show more
Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease (1/500) and the most common cause of sudden cardiac death in young people. Pathogenic mutation detection of HCM is having a growing impact on the medical management of patients and their families. However, the remarkable genetic and allelic heterogeneity makes molecular analysis by conventional methods very time-consuming, expensive and difficult to realise in a routine diagnostic molecular laboratory. The authors used their custom DNA resequencing array which interrogates all possible single-nucleotide variants on both strands of all exons (n=160), splice sites and 5'-untranslated region of 12 HCM genes (27 000 nucleotides). The results for 122 unrelated patients with HCM are presented. Thirty-three known or novel potentially pathogenic heterozygous single-nucleotide variants were identified in 38 patients (31%) in genes MYH7, MYBPC3, TNNT2, TNNI3, TPM1, MYL3 and ACTC1. Although next-generation sequencing will replace all large-scale sequencing platforms for inherited cardiac disorders in the near future, this HCM resequencing array is currently the most rapid, cost-effective and reasonably efficient technology for first-tier mutation screening of HCM in clinical practice. Because of its design, the array is also an appropriate tool for initial screening of other inherited forms of cardiomyopathy. Show less