Categorized Genetic Analysis in Childhood-Onset Cardiomyopathy

Abstract

Background - Childhood-onset cardiomyopathy (CMP) is a heterogenous group of conditions the etiology of which is largely unknown. The influence of consanguinity on the genetics of CMP has not been addressed at a large scale. Methods - To unravel the genetic etiology of childhood-onset CMP in a consanguineous population a categorized approach was adopted. Cases with childhood-onset CMP were consecutively recruited. Based on the likelihood of founder mutation and on the clinical diagnosis, genetic test was categorized to either: (i) Targeted Genetic Test (TGT) with: targeted mutation test, single gene test, or multi-gene panel for Noonan syndrome, or (ii) Untargeted genetic test with whole exome sequencing (WES) or whole genome sequencing (WGS). Several bioinformatics tools were used to filter the variants. Results - 205 unrelated probands with various forms of CMP were evaluated. The median age of presentation was 10 months. In 30.2% (n=62), TGT had a yield of 82.7% compared to 33.6% for WES/WGS (n=143) giving an overall yield of 53.7%. Strikingly, 96.4% of the variants were homozygous, 9% of which were found in 4 dominant genes. Homozygous variants were also detected in 7 novel candidates ( ACACB , AASDH , CASZ1 , FLII , RHBDF1 , RPL3L , ULK1 ). Conclusions - Our work demonstrates the impact of consanguinity on the genetics of childhood-onset CMP, the value of adopting a categorized population-sensitive genetic approach, and the opportunity of uncovering novel genes. Our data suggest that if a founder mutation is not suspected, adopting WES/WGS as a first-line test should be considered.

Further Evidence of Autosomal Recessive Inheritance of RPL3L Pathogenic Variants with Rapidly Progressive Neonatal Dilated Cardiomyopathy

“…WES in parent-offspring trios provides an efficient means to discover the genetic basis of DCM and ultimately enhances the yield of molecular diagnostics, as demonstrated in our case, which supports the previous findings reported by prior studies [ 9 , 10 , 11 ]. Pathogenic variants of the RPL3L sequence associated with neonatal DCM in both siblings in our report were determined by the criteria laid out by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology [ 12 ].…”

“…The reason for the high diagnostic product by NGS is that commercially available genetic panel tests would not test some of the newly reported gene variants. Al-Hassnan et al have indicated that when there is a strong suspicion of a genetic etiology in a family with cardiac disease, NGS such as WES/WGS should be considered a first-line test [ 10 ]. We report autosomal recessively inherited compound heterozygous variants of RPL3L (ribosomal protein L3-like) in two affected siblings using WES.…”

“…We report autosomal recessively inherited compound heterozygous variants of RPL3L (ribosomal protein L3-like) in two affected siblings using WES. RPL3L variants were considered a variant of uncertain significance before 2020 because of a sporadic allele frequency distribution of <1 in 1000 in the general population and not predicted to be damaging, even though encoded proteins were highly expressed in heart muscles [ 10 ]. Our two cases represent only the second to previously reported five infants from three independent families presenting with severe familial neonatal DCM due to pathogenic RPL3L variants [ 11 ].…”

Compound Heterozygous Missense Variants in RPL3L Genes Associated with Severe Forms of Dilated Cardiomyopathy: A Case Report and Literature Review

“…Genetic testing in individuals with DCM with a positive family history of cardiomyopathy identifies causative mutations in only approximately 25% [ 7 ]. Currently, if there is no family history and no known genetic mutation is suspected, using WES as a first-line genetic test to identify the underlying etiology for DCM is recommended [ 8 ]. In contrast to other types of genetic testing, WES sequences thousands of genes simultaneously rather than analyzing one or a few genes.…”

Identification of a Novel de Novo Variant in the CASZ1 Causing a Rare Type of Dilated Cardiomyopathy

“…The second describes p.Ala1152Thr and p.Thr618Ile variants in a patient with multiple congenital anomalies without intellectual disability, including hyperextensible skin, thoracolumbar scoliosis, and myopathy. Both studies did not prove the causality and pathogenicity of the identified variants; the mutations and the gene were classified as candidates [ 13 , 14 ].…”