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Consanguinity and rare mutations outside of MCCC genes underlie nonspecific phenotypes of MCCD

PURPOSE: 3-Methylcrotonyl-CoA carboxylase deficiency (MCCD) is an autosomal recessive disorder of leucine catabolism that has a highly variable clinical phenotype, ranging from acute metabolic acidosis to nonspecific symptoms such as developmental delay, failure to thrive, hemiparesis, muscular hypo...

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Autores principales: Shepard, Peter J., Barshop, Bruce A., Baumgartner, Matthias R., Hansen, John-Bjarne, Jepsen, Kristen, Smith, Erin N., Frazer, Kelly A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4422778/
https://www.ncbi.nlm.nih.gov/pubmed/25356967
http://dx.doi.org/10.1038/gim.2014.157
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author Shepard, Peter J.
Barshop, Bruce A.
Baumgartner, Matthias R.
Hansen, John-Bjarne
Jepsen, Kristen
Smith, Erin N.
Frazer, Kelly A.
author_facet Shepard, Peter J.
Barshop, Bruce A.
Baumgartner, Matthias R.
Hansen, John-Bjarne
Jepsen, Kristen
Smith, Erin N.
Frazer, Kelly A.
author_sort Shepard, Peter J.
collection PubMed
description PURPOSE: 3-Methylcrotonyl-CoA carboxylase deficiency (MCCD) is an autosomal recessive disorder of leucine catabolism that has a highly variable clinical phenotype, ranging from acute metabolic acidosis to nonspecific symptoms such as developmental delay, failure to thrive, hemiparesis, muscular hypotonia, and multiple sclerosis. Implementation of newborn screening for MCCD has resulted in broadening the range of phenotypic expression to include asymptomatic adults. The purpose of this study was to identify factors underlying the varying phenotypes of MCCD. METHODS: We performed exome sequencing on DNA from 33 cases and 108 healthy controls. We examined these data for associations between either MCC mutational status, genetic ancestry, or consanguinity and the absence or presence/specificity of clinical symptoms in MCCD cases. RESULTS: We determined that individuals with nonspecific clinical phenotypes are highly inbred compared with cases that are asymptomatic and healthy controls. For 5 of these 10 individuals, we discovered a homozygous damaging mutation in a disease gene that is likely to underlie their nonspecific clinical phenotypes previously attributed to MCCD. CONCLUSION: Our study shows that nonspecific phenotypes attributed to MCCD are associated with consanguinity and are likely not due to mutations in the MCC enzyme but result from rare homozygous mutations in other disease genes.
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spelling pubmed-44227782015-08-05 Consanguinity and rare mutations outside of MCCC genes underlie nonspecific phenotypes of MCCD Shepard, Peter J. Barshop, Bruce A. Baumgartner, Matthias R. Hansen, John-Bjarne Jepsen, Kristen Smith, Erin N. Frazer, Kelly A. Genet Med Article PURPOSE: 3-Methylcrotonyl-CoA carboxylase deficiency (MCCD) is an autosomal recessive disorder of leucine catabolism that has a highly variable clinical phenotype, ranging from acute metabolic acidosis to nonspecific symptoms such as developmental delay, failure to thrive, hemiparesis, muscular hypotonia, and multiple sclerosis. Implementation of newborn screening for MCCD has resulted in broadening the range of phenotypic expression to include asymptomatic adults. The purpose of this study was to identify factors underlying the varying phenotypes of MCCD. METHODS: We performed exome sequencing on DNA from 33 cases and 108 healthy controls. We examined these data for associations between either MCC mutational status, genetic ancestry, or consanguinity and the absence or presence/specificity of clinical symptoms in MCCD cases. RESULTS: We determined that individuals with nonspecific clinical phenotypes are highly inbred compared with cases that are asymptomatic and healthy controls. For 5 of these 10 individuals, we discovered a homozygous damaging mutation in a disease gene that is likely to underlie their nonspecific clinical phenotypes previously attributed to MCCD. CONCLUSION: Our study shows that nonspecific phenotypes attributed to MCCD are associated with consanguinity and are likely not due to mutations in the MCC enzyme but result from rare homozygous mutations in other disease genes. 2014-11-06 2015-08 /pmc/articles/PMC4422778/ /pubmed/25356967 http://dx.doi.org/10.1038/gim.2014.157 Text en This work is licensed under a Creative Commons Attribution 3.0 Unported License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/3.0/
spellingShingle Article
Shepard, Peter J.
Barshop, Bruce A.
Baumgartner, Matthias R.
Hansen, John-Bjarne
Jepsen, Kristen
Smith, Erin N.
Frazer, Kelly A.
Consanguinity and rare mutations outside of MCCC genes underlie nonspecific phenotypes of MCCD
title Consanguinity and rare mutations outside of MCCC genes underlie nonspecific phenotypes of MCCD
title_full Consanguinity and rare mutations outside of MCCC genes underlie nonspecific phenotypes of MCCD
title_fullStr Consanguinity and rare mutations outside of MCCC genes underlie nonspecific phenotypes of MCCD
title_full_unstemmed Consanguinity and rare mutations outside of MCCC genes underlie nonspecific phenotypes of MCCD
title_short Consanguinity and rare mutations outside of MCCC genes underlie nonspecific phenotypes of MCCD
title_sort consanguinity and rare mutations outside of mccc genes underlie nonspecific phenotypes of mccd
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4422778/
https://www.ncbi.nlm.nih.gov/pubmed/25356967
http://dx.doi.org/10.1038/gim.2014.157
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