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. Geschwind; Dimitar K. Gavrilov; William L. Nyhan; Leslie G. Biesecker; Charles P. Venditti

doi:10.1038/ng.908

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. Geschwind

Dimitar K. Gavrilov, William L. Nyhan, Leslie G. Biesecker, Charles P. Venditti

Pediatric Genetics & Metabolism

Research output: Contribution to journal › Article › peer-review

95 Scopus citations

Abstract

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 language	English (US)
Pages (from-to)	883-886
Number of pages	4
Journal	Nature Genetics
Volume	43
Issue number	9
DOIs	https://doi.org/10.1038/ng.908
State	Published - Sep 2011

Bibliographical note

Funding Information:
We thank the subjects and families for participating, E. Ostrander for the gift of unrelated Labrador DNA samples, K.M. Gibson and R. Wander for performing the malonyl-CoA decarboxylase assay on fibroblasts from subjects 2 and 9, J. Teer for bioinformatics assistance, S. Suchy for subject referral, M. Podell and W. Gahl for helpful discussions, R. Fisher, I. Bernardini, A. Gropman, L. Hecht, F. Facio, C. Gitiaux, C. Ottolenghi, D. Rabier and G. Touati for laboratory assistance and clinical care, and M. Oglesbee and A. Genders for searching for dogs related to the affected Labrador retriever. J.L.S., J.J.J., I.M., R.J.C., N.C.-C., S.D.C., J.R.S., H.M.D., M.H., K.O., N.S.H., J.C.S., C.K., L.G.B. and C.P.V. were supported by the Intramural Research Program of the NHGRI, NIH. M.D.G. was supported by NIA K23 AG021989 and R01-AG031189.

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Sloan, J. L., Johnston, J. J., Manoli, I., Chandler, R. J., Krause, C., Carrillo-Carrasco, N., Chandrasekaran, S. D., Sysol, J. R., O'Brien, K., Hauser, N. S., Sapp, J. C., Dorward, H. M., Huizing, M., Barshop, B. A., Berry, S. A., James, P. M., Champaigne, N. L., De Lonlay, P., Valayannopoulos, V., ... Venditti, C. P. (2011). Exome sequencing identifies ACSF3 as a cause of combined malonic and methylmalonic aciduria. Nature Genetics, 43(9), 883-886. https://doi.org/10.1038/ng.908

Sloan, JL, Johnston, JJ, Manoli, I, Chandler, RJ, Krause, C, Carrillo-Carrasco, N, Chandrasekaran, SD, Sysol, JR, O'Brien, K, Hauser, NS, Sapp, JC, Dorward, HM, Huizing, M, Barshop, BA, Berry, SA, James, PM, Champaigne, NL, De Lonlay, P, Valayannopoulos, V, Geschwind, MD, Gavrilov, DK, Nyhan, WL, Biesecker, LG & Venditti, CP 2011, 'Exome sequencing identifies ACSF3 as a cause of combined malonic and methylmalonic aciduria', Nature Genetics, vol. 43, no. 9, pp. 883-886. https://doi.org/10.1038/ng.908

@article{c4193238e4a645efb1eff3639b7d4ba2,

title = "Exome sequencing identifies ACSF3 as a cause of combined malonic and methylmalonic aciduria",

abstract = "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.",

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

note = "Funding Information: We thank the subjects and families for participating, E. Ostrander for the gift of unrelated Labrador DNA samples, K.M. Gibson and R. Wander for performing the malonyl-CoA decarboxylase assay on fibroblasts from subjects 2 and 9, J. Teer for bioinformatics assistance, S. Suchy for subject referral, M. Podell and W. Gahl for helpful discussions, R. Fisher, I. Bernardini, A. Gropman, L. Hecht, F. Facio, C. Gitiaux, C. Ottolenghi, D. Rabier and G. Touati for laboratory assistance and clinical care, and M. Oglesbee and A. Genders for searching for dogs related to the affected Labrador retriever. J.L.S., J.J.J., I.M., R.J.C., N.C.-C., S.D.C., J.R.S., H.M.D., M.H., K.O., N.S.H., J.C.S., C.K., L.G.B. and C.P.V. were supported by the Intramural Research Program of the NHGRI, NIH. M.D.G. was supported by NIA K23 AG021989 and R01-AG031189.",

year = "2011",

month = sep,

doi = "10.1038/ng.908",

language = "English (US)",

volume = "43",

pages = "883--886",

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T1 - Exome sequencing identifies ACSF3 as a cause of combined malonic and methylmalonic aciduria

AU - Sloan, Jennifer L.

AU - Johnston, Jennifer J.

AU - Manoli, Irini

AU - Chandler, Randy J.

AU - Krause, Caitlin

AU - Carrillo-Carrasco, Nuria

AU - Chandrasekaran, Suma D.

AU - Sysol, Justin R.

AU - O'Brien, Kevin

AU - Hauser, Natalie S.

AU - Sapp, Julie C.

AU - Dorward, Heidi M.

AU - Huizing, Marjan

AU - Barshop, Bruce A.

AU - Berry, Susan A.

AU - James, Philip M.

AU - Champaigne, Neena L.

AU - De Lonlay, Pascale

AU - Valayannopoulos, Vassilli

AU - Geschwind, Michael D.

AU - Gavrilov, Dimitar K.

AU - Nyhan, William L.

AU - Biesecker, Leslie G.

AU - Venditti, Charles P.

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

Abstract

Bibliographical note

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