Long-read sequencing identified a novel nonsense and a de novo missense of PPA2 in trans in a Chinese patient with autosomal recessive infantile sudden cardiac failure.

Background and aims Biallelic missense variants in PPA2 gene cause infantile sudden cardiac failure (SCFI; OMIM #617222) characterized by sudden cardiac failure, sudden cardiac death in infants. Here, we present an unusual survivor with one inherited plus one de novo variant in PPA2. Since next-generation sequencing (NGS) fails to resolve variant phasing, which require long-read sequencing to clarify the diagnosis. Materials and methods Whole exome and Sanger sequencing were initially performed to identify the causative variants. PCR-based short tandem repeats (STRs) analysis and long-read single molecule real-time (SMRT) sequencing were further implemented for paternity testing and variant phasing. Pathogenicity evaluation of the biallelic variants in PPA2 was conducted according to the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) guidelines based on VarSome. Results Whole exome and Sanger sequencing revealed two variants in PPA2, with one novel nonsense variant (c.524C>G; p.Ser175*) inherited from the mother and one de novo missense variant (c.379C>T; p.Arg127Cys). PCR-based STRs analysis verified the paternity. And long-read SMRT sequencing phased the two variants in trans and identified the paternal origin of the de novo variant. The genetic diagnosis clarified the genetic etiology of the proband and assisted in patient management and counseling. Conclusion We identified a rare combination of one inherited plus one de novo variant of PPA2 in a patient with autosomal recessive SCFI, which expanded the mutation spectrum of PPA2 and demonstrated the power of target long-read sequencing to make up the diagnostic gap of prevailing NGS.