Submission Details

PPP1R13L was evaluated for autosomal recessive arrhythmogenic cardiomyopathy with variable ectodermal abnormalities. Naturally occurring biallelic loss-of-function variants in the PPP1R13L gene have been found to cause progressive, early onset dilated cardiomyopathy-like phenotype in both mice (PMID: 15661756) and Poll Hereford cattle (PMID: 19016676) with ectodermal features such as abnormal coat in mice and wooly haircoat in cattle. Both variants were predicted to cause loss-of-function, the first being a 14bp deletion variant that includes the splice donor site of exon 8 and leads to intron retention and a premature stop codon and the second a 7bp duplication (c.956_962dup7, (p.Ser322GlnfsX4)) causing a translational frameshift that is predicted to undergo nonsense mediated mRNA decay. In mice, Western blot analysis confirmed that the identified in the mutant mice caused complete loss of expression as no 98 kD protein band was detected in the mutant mouse hearts, unlike in normal hearts. Biallelic homozygous and compound heterozygous variants in PPP1R13L have also been found in at least 14 individuals in the literature, most commonly associated with severe, progressive pediatric-onset dilated cardiomyopathy with or without ectodermal features. In a study of a large multi-generational consanguineous family (PMID: 28069640), five infants were affected with early onset DCM with a homozygous truncating variant (c.2241C > G, (p.Tyr747X)) that showed no protein expression in patient-derived fibroblasts. The patients showed mild skin, teeth, and hair abnormalities. All passed away before the age of 3. Another study (PMID: 32666529) described a total of seven affected children with DCM from five families with biallelic PPP1R13L variants. All of the children had pediatric onset dilated cardiomyopathy between ages 3 months to 9 years, three of them died from heart failure and two needed heart transplantation. The variants in this study included frameshift, nonsense and missense variants. A case study (PMID: 35924320) described a 2-year-old patient with heart failure and runs of ventricular tachycardia with multiple acute exacerbation of heart failure during viral illnesses that led to the implantation of a LVAD. The patient had bifid notched central incisors, a high anterior hairline and wiry coarse hair. Trio whole exome sequencing found a homozygous pathogenic variant in PPP1R13L (c.1068dup (p.Ser357LeufsX49)). In another study of a multi-generational consanguineous family (PMID: 37698259), a total of five patients were diagnosed with severe, rapidly progressive DCM by age three. Four died by age five. Whole exome sequencing identified homozygous PPP1R13L variants (c.988_989insC (p.Arg330ProfsX76) in all three tested affected individuals and none of the unaffected siblings were found to be homozygous. Western blot analysis showed the absence of the PPP1R13L protein in patient fibroblasts. Changes in inflammatory signals in patient-derived and PPP1R13L knockout tissues of both mice and human have been seen, suggesting that impaired inflammatory response may be part of the underlying molecular pathology (PMID: 28069640). In summary, PPP1R13L is definitively associated with AR arrhythmogenic cardiomyopathy with variable ectodermal abnormalities. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on 10/18/2024 (SOP Version 10).