Sudden unexpected death in asymptomatic infants due to PPA2 variants

Colin K.L. Phoon, Matthew Halvorsen, David B. Goldstein, Rachel Rabin, Frank Cecchin, Laura Crandall, Orrin Devinsky

Research output: Contribution to journalArticlepeer-review

14 Scopus citations


Background: Sudden death in children is a tragic event that often remains unexplained after comprehensive investigation. We report two asymptomatic siblings who died unexpectedly at approximately 1 year of age found to have biallelic (compound heterozygous) variants in PPA2. Methods: The index case, parents, and sister were enrolled in the Sudden Unexplained Death in Childhood Registry and Research Collaborative, which included next-generation genetic screening. Prior published cases of PPA2 variants, along with the known biology of PPA2, were also summarized. Results: Whole exome sequencing in both siblings revealed biallelic rare missense variants in PPA2: c.182C > T (p.Ser61Phe) and c.380G > T (p.Arg127Leu). PPA2 encodes a mitochondrially located inorganic pyrophosphatase implicated in progressive and lethal cardiomyopathies. As a regulator and supplier of inorganic phosphate, PPA2 is central to phosphate metabolism. Biological roles include the following: mtDNA maintenance; oxidative phosphorylation and generation of ATP; reactive oxygen species homeostasis; mitochondrial membrane potential regulation; and possibly, retrograde signaling between mitochondria and nucleus. Conclusions: Two healthy and asymptomatic sisters died unexpectedly at ages 12 and 10 months, and were diagnosed by molecular autopsy to carry biallelic variants in PPA2. Our cases add additional details to those reported thus far, and broaden the spectrum of clinical and molecular features of PPA2 variants.

Original languageEnglish
Article numbere1008
JournalMolecular genetics & genomic medicine
Issue number1
StatePublished - 1 Jan 2020
Externally publishedYes


  • PPA2
  • cardiomyopathy
  • mitochondrial disease
  • myocarditis
  • sudden death


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