Phenotypic diversity identified by cardiac magnetic resonance in a large hypertrophic cardiomyopathy family with a single MYH7 mutation

Abstract

Limited data is available on phenotypic variations with the same genotype in hypertrophic cardiomyopathy (HCM). The present study aims to explore the relationship between genotype and phenotype characterized by cardiovascular magnetic resonance (CMR) in a large Chinese family. A proband diagnosed with HCM from a multigenerational family underwent next-generation sequencing based on a custom sureSelect panel, including 117 candidate pathogenic genes associated with cardiomyopathies. All genetic results were confirmed by the Sanger sequencing method. All confirmed mutation carriers underwent CMR exam and myocardial tissue characterization using T1 mapping and late gadolinium enhancement (LGE) on a 3T scanner (Siemens Trio, Gemany). After clinical and genetic screening of 36 (including the proband) members of a large Chinese family, nineteen family members are determined to carry the single p.T1377M (c.4130C>T) mutation in the MYH7 gene. Of these 19 mutation carriers, eight are diagnosed with HCM, one was considered as borderline affected and ten are not clinically or phenotypically affected. Different HCM phenotypes are present in the nine affected individuals in this family. In addition, we have found different tissue characteristics assessed by T1 mapping and LGE in these individuals. We describe a family that demonstrates the diverse HCM phenotypes associated with a single MYH7 mutation.

Figure 1

Pedigree of the family. Squares represent male relatives; circles represent female relatives; filled symbols indicate HCM patients; slants indicate dead members; arrow represent proband; symbol with dots represent mutation carrier with negative phenotype; ? represent that the subject died before our investigation so that we cannot get clinical data and confirm their phenotype; SCD: Sudden cardiac death: G+: positive genotype; P+: positive phenotype; P−: negative phenotype. IV5 was considered as borderline affected with a maximal LV thickness of 13.2 mm.

Figure 2

Cardiac morphologies evaluated by CMR; II1 had sigmoid septum (black arrow of II1-C points to basal septal hypertrophy) without LVOT obstruction; II5 had the neutral septum (II5-C: white arrow)with RV involvement (II5-C: black arrow); II7 had neutral septum(II7-B: black arrow) with no RV involvement; III1 had sigmoid septum with LVOT obstruction (III1-B:black arrow); III2 had sigmoid septum without LVOT obstruction; III6 had sigmoid septum without LVOT obstruction; III7 had reversed curvature of the septum; III9 had reversed curvature of the septum; IV5 had symmetric LV hypertrophy; Black arrows of II1-D, II5-D, II7-D, III1-D, III6-D, III7-D, and III9-D point to LGE in the myocardium.

Figure 3

(A) Mutation in MYH7 gene for the proband III1, his other 7 family members with positive phenotype and one borderline affected subject (p.T1377M, c.4130C > T). (B) Mutation in MYH7 gene for other 10 family members of the proband with negative phenotype (p.T1377M, c.4130C > 44T).