Molecular analysis of dilated and left ventricular noncompaction cardiomyopathies in Egyptian children

Abstract

Background: Paediatric cardiomyopathy is a progressive, often lethal disorder and the most common cause of heart failure in children. Despite its severe outcomes, the genetic aetiology is still poorly characterised. High-throughput sequencing offers a great opportunity for a better understanding of the genetic causes of cardiomyopathy. Aim: The current study aimed to elucidate the genetic background of cardiomyopathy in Egyptian children. Methods: This hospital-based study involved 68 patients; 58 idiopathic primary dilated cardiomyopathy and 10 left ventricular noncompaction cardiomyopathy. Cardiomyopathy-associated genes were investigated using targeted next-generation sequencing. Results: Consanguinity was positive in 53 and 70% of dilated cardiomyopathy and left ventricular noncompaction cardiomyopathy patients, respectively. Positive family history of cardiomyopathy was present in 28% of dilated cardiomyopathy and 10% of the left ventricular noncompaction cardiomyopathy patients. In 25 patients, 29 rare variants were detected; 2 likely pathogenic variants in TNNI3 and TTN and 27 variants of uncertain significance explaining 2.9% of patients. Conclusions: The low genetic detection rate suggests that novel genes or variants might underlie paediatric cardiomyopathy in Egypt, especially with the high burden of consanguinity. Being the first national and regional report, our study could be a reference for future genetic testing in Egyptian cardiomyopathy children. Genome-wide tests (whole exome/genome sequencing) might be more suitable than the targeted sequencing to investigate the primary cardiomyopathy patients. Molecular characterisation of cardiomyopathies in different ethnicities will allow for global comparative studies that could result in understanding the pathophysiology and heterogeneity of cardiomyopathies.

Homozygous TNNI3 Mutations and Severe Early Onset Dilated Cardiomyopathy: Patient Report and Review of the Literature

“…The authors also demonstrated the histopathological effects of the reported mutations by determining the absence of TNNI3 mRNA and protein in heart biopsies of both patients, and the parallel increase in the fetal isoform TNNI1. The correlation with LVNC has been corroborated by Mehaney et al [ 34 ], who reported the case of a 7-year-old male patient who was diagnosed at the age of 6 months with an overlapping phenotype of LVNC and DCM, and presented with a homozygous c.258del (p.Leu88Trpfs*27) mutation. The two distinct case series published in 2021 by Seidel et al [ 35 ] and Pezzoli et al [ 36 ] further consolidated the p.Arg69Alafs* and c.24+2T>A mutations as recurrent causes of early onset autosomal recessive DCM in four unrelated patients; notably, Seidel’s study was performed on a selected cohort of myocarditis patients, as was the case of Belkaya’s.…”

Exploring the complex spectrum of dominance and recessiveness in genetic cardiomyopathies

“… 10 , 67 ) 3 3 PTV/missense Exome (3 trio) – Embryonic lethality JPH2 Junctional membrane complex DCM 6 (refs. 7 , 8 , 10 , 68 – 70 ) 7 7 PTV/missense Exome (2 trio, 2 proband). Panel (1 trio, 2 proband) – Embryonic lethality KLHL24 E3 ubiquitin ligase substrate adapter HCM 3 (refs.…”

Analysis of the disease burden of cardiomyopathy in children aged 0–14 years in China from 1990 to 2019

“…The results suggested that the overall burden of cardiomyopathy in children aged 0-14 years in China presented a downward trend during the period of 1990-2019, which was mainly due to the continuous progress of basic, translational, and clinical researches related to cardiomyopathy. Genomics technology has promoted the continuous development of precision medicine, and more and more unexplained cardiomyopathy has been unveiled (20)(21)(22)(23)(24). In this context, medical personnel and scientific researches have gained a deeper understanding on the causes of pediatric cardiomyopathy, and the diagnosis and treatment strategies for pediatric cardiomyopathy have also been continuously developed and improved.…”