Sudden unexpected death in asymptomatic infants due to PPA2 variants.
PPA2
cardiomyopathy
mitochondrial disease
myocarditis
sudden death
Journal
Molecular genetics & genomic medicine
ISSN: 2324-9269
Titre abrégé: Mol Genet Genomic Med
Pays: United States
ID NLM: 101603758
Informations de publication
Date de publication:
01 2020
01 2020
Historique:
received:
13
07
2019
revised:
04
09
2019
accepted:
05
09
2019
pubmed:
11
11
2019
medline:
30
3
2021
entrez:
10
11
2019
Statut:
ppublish
Résumé
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. 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. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 31705601
doi: 10.1002/mgg3.1008
pmc: PMC6978244
doi:
Substances chimiques
Mitochondrial Proteins
0
Inorganic Pyrophosphatase
EC 3.6.1.1
PPA2 protein, human
EC 3.6.1.1
Types de publication
Case Reports
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1008Informations de copyright
© 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.
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