Although the optimal approach is debated, systematic genetic screening for hypertrophic cardiomyopathy (HCM) is recommended. The performance of this approach was tested in GEREMY, a HCM prospective ob Show more
Although the optimal approach is debated, systematic genetic screening for hypertrophic cardiomyopathy (HCM) is recommended. The performance of this approach was tested in GEREMY, a HCM prospective observational French register. Screening was based on a 12-gene panel, including the Fabry disease (GLA) and the transthyretin (TTR) genes. In case of a negative result and according to the clinical profile, 17-80 gene panels of were used. A 748 adult cohort was examined: 68.9 % male, 54.6 ± 18.1 years, 27.5 % with a HCM family history, maximal wall thickness 19.1 ± 4.8 mm. Pathogenic or likely pathogenic variants were identified in 296 (39.6 %) patients, localized 1) in sarcomeric genes in 233, most frequently MYBPC3 (150) and MYH7 (42), with 24 identified only by large panels, with multiple variants in 8 patients and 2) in non-sarcomeric genes in 63, identified only with large panels in 26, predominantly TTR (26) and GLA(9), representing 8.8 % and 3.0 % of positive studies, respectively. Performance was 57.1 % before 40 years and 68.6 % in case of FH (vs otherwise 28.7 % and 26.1 % respectively, p < 0.001). In patients with a negative study, 148 had variants of unknown significance and 95 had senile or AL amyloidosis. Systematic genetic screening with a limited panel showed good performance, with diagnosis of Fabry disease (∼1 %) and hereditary TTR amyloidosis (∼3.5 %). Larger targeted panels were conclusive in 35.3 % of patients, of which 12 % had a negative initial approach. Show less
Cardiac myosin binding protein C (MyBP-C) is a sarcomeric protein belonging to the intracellular immunoglobulin superfamily. Its function is uncertain, but for a decade evidence has existed for both s Show more
Cardiac myosin binding protein C (MyBP-C) is a sarcomeric protein belonging to the intracellular immunoglobulin superfamily. Its function is uncertain, but for a decade evidence has existed for both structural and regulatory roles. The gene encoding cardiac MyBP-C (MYBPC3) in humans is located on chromosome 11p11.2, and mutations have been identified in this gene in unrelated families with familial hypertrophic cardiomyopathy (FHC). Detailed characterization of the MYBPC3 gene is essential for studies on gene regulation, analysis of the role of MyBP-C in cardiac contraction through the use of recombinant DNA technology, and mutational analyses of FHC. The organization of human MYBPC3 and screening for mutations in a panel of French families with FHC were established using polymerase chain reaction, single-strand conformation polymorphism, and sequencing. The MYBPC3 gene comprises > 21,000 base pairs and contains 35 exons. Two exons are unusually small in size, 3 bp each. We found six new mutations associated with FHC in seven unrelated French families. Four of these mutations are predicted to produce truncated cardiac MyBP-C polypeptides. The two others should each produce two aberrant proteins, one truncated and one mutated. The present study provides the first organization and sequence for an MyBP-C gene. The mutations reported here and previously in MYBPC3 result in aberrant transcripts that are predicted to encode significantly truncated cardiac MyBP-C polypeptides. This spectrum of mutations differs from the ones previously observed in other disease genes causing FHC. Our data strengthen the functional importance of MyBP-C in the regulation of cardiac work and provide the basis for further studies. Show less