Investigating the Distinctive Clinical and Genetic Landscape of PPA2 Deficiency

BACKGROUND: PPA2 encodes for inorganic pyrophosphatase 2, a mitochondrial enzyme that hydrolyzes inorganic pyrophosphates into orthophosphate. Biallelic loss-of-function variants cause PPA2 deficiency, an emerging recessive cardiac condition that causes heart failure and sudden cardiac death in infants and young people. METHODS: Using published case reports and large-scale genomics resources, we defined the clinical and molecular spectrum of this disease, classified variants using a customized American College of Medical Genetics and Genomics pipeline, assessed genotype-phenotype correlations, calculated predicted prevalence using the gnomAD GenIE tool, and investigated monoallelic associations in the UK Biobank. RESULTS: A total of 63 cases from 37 families were identified from 12 publications. The natural history of this disease is characterized by clinical heterogeneity and high mortality (79% by 20 years of age), typically presenting as a highly arrhythmogenic cardiomyopathy with 2 distinct risk periods: in infancy, where viral infections can lead to heart failure, and in adolescence, where minimal alcohol exposure can trigger sudden cardiac death. The disease is genetically heterogeneous, with 29 distinct variants described (18 of which were classified as [likely] pathogenic), usually in compound heterozygosity. As complete gene knockout appears to be incompatible with life, PPA2 deficiency is caused by biallelic variants within a particular loss-of-function window, with deficiency mitigated by hypomorphic effects, variants in nonconstitutive exons, and particular compound heterozygous combinations. The spectrum of phenotypic effect extends to monoallelic carriers of pathogenic variants, which demonstrate an apparent mitohormesis-like compensatory protection from heart failure. The disease has an estimated prevalence of at least 1/135 000 in European ancestry populations. CONCLUSIONS: PPA2 deficiency is a genetically complex and clinically severe disease. Given the potential for effective life-saving interventions, PPA2 may warrant inclusion in emerging newborn genomic screening programs.