Hypertrophic cardiomyopathy (HCM) is a primary cardiac muscle disease defined by left ventricular hypertrophy (LVH), in the absence of abnormal loading conditions. Clinical presentation of the disease shows great variability, ranging from little or no cardiovascular symptoms to heart failure (HF) and sudden cardiac death (SCD). Screening of patients with HCM of unknown aetiology reveals a high prevalence (1-12%) of Fabry disease (FD).
Our aim is to demonstrate a confusing case of 4 relatives with HCM phenotype, who were suspected having FD after genetic variant of unknown significance (GVUS) in a-galactosidase A (GLA) gene was identified in 2 of 3 alive patients. As the cause of HCM remains uncertain, it is recommended to perform a sequencing of sarcomere protein genes.
A GVUS in GLA gene c.937G>T (p.Asp313Tyr) was identified in 2 of 4 patients with HCM phenotype. Since clinical features and histological findings consistent with FD were absent, the cause of HCM was still uncertain after evaluation of patients’ medical history, physical, laboratory, instrumental examination and histological data, next generation sequencing of sarcomere proteins’ genes was performed to three relatives (I-1, II-3, and III-1). Coding sequences of the genes associated with HCM (ACTC1, ACTN2, BRAF, CAV3, CSRP3, GAA, GLA, HRAS, KRAS, MAP2K1, MAP2K2, MYBPC3, MYH6, MYH7, MYL2, MYL3, MYLK2, MYOZ2, NEXN, NRAS, PLN, PRKAG2, PTPN11, RAF1, SOS1, TCAP, TNNC1, TNNI3, TNNT2, and TPM1) were analysed.
We report a case of four patients from one family with HCM phenotype, progressive HF and SCD of the proband‘s (I-1) older daughter (II-1). Since classical clinical features consistent with FD were absent, renal and endomyocardial biopsies were performed for proband and her daughter (II-3). Histological analysis of proband's renal tissue revealed minimal histological changes which could be consistent with FD. Histological examination of proband’s daughter’s myocardium showed no histological changes. Next generation sequencing of sarcomere proteins’ genes revealed two heterozygous pathological variants in all patients: PLN gene c.26_29dupGCTC (p.Ala11Leufs*10) and MYBPC3 gene c.3530_3531insG (p.Phe1177Leufs*31).
Data of the current case suggests that GLA gene variant c.937G>T p.(Asp313Tyr) is not necessarily associated with FD. Two novel heterozygous pathogenic variants in sarcomeric protein genes which have not been previously reported in the literature – PLN gene c.26_29dupGCTC p.(Ala11Leufs*10) and MYBPC3 gene c.3530_3531insG (p.Phe1177Leufs*31) – determine the development of HCM phenotype. Multiple mutations are related to an earlier presentation of HCM with more severe phenotype and higher risk of sudden cardiac death. Multiple variants in sarcomeric protein genes should be recommended as an additional biomarker in the assessment of SCD.