Abstract
Background and objectives: Dilated cardiomyopathy (DCM) is a rare cardiac disease characterised by left ventricular enlargement, reduced left ventricular contractility, and impaired systolic function. Childhood DCM is clinically and genetically heterogenous and associated with mutations in over 100 genes. The aim of this study was to identify novel variations associated with infantile DCM. Materials and Methods: Targeted next generation sequencing (NGS) of 181 cardiomyopathy-related genes was performed in three unrelated consanguineous families from Saudi Arabia. Variants were confirmed and their frequency established in 50 known DCM cases and 80 clinically annotated healthy controls. Results: The three index cases presented between 7 and 10 months of age with severe DCM. In Family A, there was digenic inheritance of two heterozygous variants: a novel variant in LAMA4 (c.3925G > A, p.Asp1309Asn) and a known DCM mutation in MYH7 (c.2770G > A; p.Glu924Lys). The LAMA4 p.Asp1309Asn variant was predicted to be likely pathogenic according to international guidelines. The other two families had no identifiable potentially deleterious variants. Conclusions: Inheritance of two genetic variants may have a synergistic or dose effect to cause severe DCM. We report of a novel p.Asp1309Asn variation associated with DCM. Targeted NGS is useful in the molecular diagnosis of DCM and to guide whole-family management and counselling.
Highlights
Cardiomyopathy is classified by the European Society of Cardiology into four main classes: dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), restrictive cardiomyopathy (RCM), and arrhythmogenic right ventricular cardiomyopathy (ARVC) [1]
DCM is a rare cardiac disease characterised by left ventricular (LV) enlargement, reduced LV contractility, and impaired systolic function, which can lead to sudden death [2]
We identified digenic MYH7 and LAMA4 variants in an affected DCM individual
Summary
Cardiomyopathy is classified by the European Society of Cardiology into four main classes: dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), restrictive cardiomyopathy (RCM), and arrhythmogenic right ventricular cardiomyopathy (ARVC) [1]. DCM is a rare cardiac disease characterised by LV enlargement, reduced LV contractility, and impaired systolic function, which can lead to sudden death [2]. Familial DCM is present in Medicina 2019, 55, 17; doi:10.3390/medicina55010017 www.mdpi.com/journal/medicina. The familial pattern of DCM is complicated by incomplete penetrance, high variability in age of onset and disease progression, and high genetic heterogeneity [7]. Dilated cardiomyopathy (DCM) is a rare cardiac disease characterised by left ventricular enlargement, reduced left ventricular contractility, and impaired systolic function. Childhood DCM is clinically and genetically heterogenous and associated with mutations in over 100 genes. Variants were confirmed and their frequency established in 50 known DCM cases and 80 clinically annotated healthy controls.
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