Genetic Basis of Childhood Cardiomyopathy

Abstract

Background: The causes of cardiomyopathy in children are less well described than in adults. We evaluated the clinical diagnoses and genetic causes of childhood cardiomyopathy and outcomes of cascade genetic testing in family members. Methods: We recruited children from a pediatric cardiology service or genetic heart diseases clinic. We performed Sanger, gene panel, exome or genome sequencing and classified variants for pathogenicity using American College of Molecular Genetics and Genomics guidelines. Results: Cardiomyopathy was diagnosed in 221 unrelated children aged ≤18 years. Children mostly had hypertrophic cardiomyopathy (n=98, 44%) or dilated cardiomyopathy (n=89, 40%). The highest genetic testing diagnostic yields were in restrictive cardiomyopathy (n=16, 80%) and hypertrophic cardiomyopathy (n=65, 66%), and lowest in dilated cardiomyopathy (n=26, 29%) and left ventricular noncompaction (n=3, 25%). Pathogenic variants were primarily found in genes encoding sarcomere proteins, with TNNT2 and TNNI3 variants associated with more severe clinical outcomes. Ten children (4.5%) had multiple pathogenic variants. Genetic test results prompted review of clinical diagnosis in 14 families with syndromic, mitochondrial or metabolic gene variants. Cascade genetic testing in 127 families confirmed 24 de novo variants, recessive inheritance in 8 families, and supported reclassification of 12 variants. Conclusions: Genetic testing of children with cardiomyopathy supports a precise clinical diagnosis, which may inform prognosis.

Uncovering the Dual Role of Mitochondrial and Nuclear DNA Variants in Pediatric Cardiomyopathies

“…While this could be due to asymptomatic patients receiving a diagnosis only during routine check-ups or other illnesses, socioeconomic factors that affect the access of young children/families to healthcare services in the country should not be ignored. Moreover, one another comprehensive study revealed positive association between cardiomyopathy subtype and age at diagnosis(Bagnall et al, 2022). Similarly, the diagnosis of HCM was made at later ages compared to other subtypes, while in cases of DCM, it was made before the age of 3 in our study.…”

Genetic Screening Reveals Heterogeneous Clinical Phenotypes in Patients with Dilated Cardiomyopathy and Troponin T2 Variants

“…Autosomal dominant variants in TNNT2 are a well-established genetic cause for dilated, hypertrophic, restrictive, or non-compaction CM [6]. However, the clinical phenotype of TNNT2-associated CM shows high variability, as illustrated by an overview of clinically reported variants in TNNT2 [Supplementary Table S1].…”

“…For all three variants, the affected amino acid residue is evolutionarily well conserved (Supplementary Table S3). Overall, not only does the cardiac phenotype of TNNT2-associated CM vary [6,[8][9][10], but the age at disease onset also shows a large range. Furthermore, the differences observed even in carriers of identical genetic variants suggest the influence of modifiers that promote the onset and development of a specific phenotype.…”

“…TNNT2 binds to tropomyosin and helps position it on actin, and together with the rest of the troponin complex, modulates contraction [5]. Variants in TNNT2 can lead to different CM phenotypes, such as HCM [6,7], RCM [8], and DCM [6,9,10]. In one study, the age of onset for DCM caused by a TNNT2 variant was 16-45 years in 4 families (13 patients) [10].…”

The Genetic Basis of Primary Cardiomyopathies in Childhood: Implications for Clinical Genetic Testing

“…In this issue, Bagnall et al 10 describe the outcomes of clinical genetic testing in a cohort of 221 unrelated children and young adults (≤18 years of age) with primary cardiomyopathy (HCM n=98, DCM n=89, RCM n=20, left ventricular noncompaction cardiomyopathy n=12, ACM n=2). Children with cardiomyopathy due to metabolic, mitochondrial, or overt syndromic causes were excluded.…”