Exome sequencing identifies ACSF3 as a cause of combined malonic and methylmalonic aciduria

Jennifer L. Sloan, Jennifer J. Johnston, Irini Manoli, Randy J. Chandler, Caitlin Krause, Nuria Carrillo-Carrasco, Suma D. Chandrasekaran, Justin R. Sysol, Kevin O'Brien, Natalie S. Hauser, Julie C. Sapp, Heidi M. Dorward, Marjan Huizing, Bruce A. Barshop, Susan A. Berry, Philip M. James, Neena L. Champaigne, Pascale De Lonlay, Vassilli Valayannopoulos, Michael D. GeschwindDimitar K. Gavrilov, William L. Nyhan, Leslie G. Biesecker, Charles P. Venditti

Research output: Contribution to journalArticlepeer-review

81 Scopus citations


We used exome sequencing to identify the genetic basis of combined malonic and methylmalonic aciduria (CMAMMA). We sequenced the exome of an individual with CMAMMA and followed up with sequencing of eight additional affected individuals (cases). This included one individual who was identified and diagnosed by searching an exome database. We identify mutations in ACSF3, encoding a putative methylmalonyl-CoA and malonyl-CoA synthetase as a cause of CMAMMA. We also examined a canine model of CMAMMA, which showed pathogenic mutations in a predicted ACSF3 ortholog. ACSF3 mutant alleles occur with a minor allele frequency of 0.0058 in 1/41,000 control individuals, predicting a CMAMMA population incidence of 1/41:30,000. ACSF3 deficiency is the first human disorder identified as caused by mutations in a gene encoding a member of the acyl-CoA synthetase family, a diverse group of evolutionarily conserved proteins, and may emerge as one of the more common human metabolic disorders.

Original languageEnglish (US)
Pages (from-to)883-886
Number of pages4
JournalNature Genetics
Issue number9
StatePublished - Sep 2011
Externally publishedYes

ASJC Scopus subject areas

  • Genetics


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