Biallelic variants in PPP1R13L cause paediatric dilated cardiomyopathy

Abstract

Childhood dilated cardiomyopathy (DCM) is a leading cause of heart failure requiring cardiac transplantation and approximately 5% of cases result in sudden death. Knowledge of the underlying genetic cause can aid prognostication and clinical management and enables accurate recurrence risk counselling for the family. Here we used genomic sequencing to identify the causative genetic variant(s) in families with children affected by severe DCM. In an international collaborative effort facilitated by GeneMatcher, biallelic variants in PPP1R13L were identified in seven children with severe DCM from five unrelated families following exome or genome sequencing and inheritance-based variant filtering. PPP1R13L encodes inhibitor of apoptosisstimulating protein of p53 protein (iASPP). In addition to roles in apoptosis, iASPP acts as a regulator of desmosomes and has been implicated in inflammatory pathways. DCM presented early (mean: 2 years 10 months; range: 3 months-9 years) and was progressive, resulting in death (n = 3) or transplant (n = 3), with one child currently awaiting transplant. Genomic sequencing technologies are valuable for the H.K Robinson and E. Zaklyazminskaya contributed equally to this work.

Novel homozygous stop-gain pathogenic variant of PPP1R13L gene leads to arrhythmogenic cardiomyopathy

“…With the aid of this tool, we identified a novel PPP1R13L stop-gain variant (c.580C > T: p.Gln194Ter) in an autosomal recessive ACM pedigree. In recent years, PPP1R13L variants have been identified in patients with cardio-cutaneous syndrome [ 15 , 20 ], cattle woolly haircoat syndrome [ 14 ], DCM [ 20 ], and ACM [ 13 ] (Table 1 ). The location of all reported variants was shown in Fig.…”

Modern genomic techniques in the identification of genetic causes of cardiomyopathy

“…Few WGS cardiomyopathy studies were found in the literature, presumably due to cost and the current bioinformatic burden relating to data storage and analysis. Two novel cardiomyopathy genes, MYBPHL and PPP1R13L , have been identified through WGS in familial DCM,34 35 but pathogenic variation in these genes has not been described in cardiomyopathy since their original report.…”

Novel PPP1R13L variant expands the phenotype of a rare cardiocutaneous syndrome

“…Affected individuals develop severe dilated cardiomyopathy (DCM) leading to death or cardiac transplant in childhood, and cutaneous manifestations including wooly or wiry hair, wedged teeth, xerotic skin, dystrophic nails, cleft palate, and corneal abnormalities. 1,2…”

“…4 Loss of function is the underlying mechanism of mutations in this gene, with the majority of reported disease-causing variants being truncating (nonsense, frameshift, and splicing variants). 1 Both parents are heterozygous for the variant, which contains a duplica- iASPP regulates desmosomes, which are proteins that anchor together cells subject to physical stress such as skin and myocytes. 1 Other cardiocutaneous conditions (such as Naxos and Carvajal syndromes) share similar desmosomal defects and present with structurally abnormal, arrhythmogenic myocardium and cutaneous features resembling ectodermal dysplasia.…”

“…1 Both parents are heterozygous for the variant, which contains a duplica- iASPP regulates desmosomes, which are proteins that anchor together cells subject to physical stress such as skin and myocytes. 1 Other cardiocutaneous conditions (such as Naxos and Carvajal syndromes) share similar desmosomal defects and present with structurally abnormal, arrhythmogenic myocardium and cutaneous features resembling ectodermal dysplasia. 1 iASPP also downregulates the proinflammatory mediator nuclear factor kappa-B (NF-κB).…”