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Genet Med. 2015 Aug;17(8):660-7. doi: 10.1038/gim.2014.157. Epub 2014 Nov 6.

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

Author information

1
Department of Pediatrics, Rady Children's Hospital, University of California, San Diego, La Jolla, California, USA.
2
1] Department of Pediatrics, Rady Children's Hospital, University of California, San Diego, La Jolla, California, USA [2] Clinical and Translational Research Institute, University of California, San Diego, La Jolla, California, USA.
3
1] Division of Metabolic Diseases and Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland [2] Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
4
Department of Clinical Medicine, University of Tromsø, Tromsø, Norway.
5
1] Department of Pediatrics, Rady Children's Hospital, University of California, San Diego, La Jolla, California, USA [2] Clinical and Translational Research Institute, University of California, San Diego, La Jolla, California, USA [3] Institute for Genomic Medicine, University of California, San Diego, La Jolla, California, USA.

Abstract

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.Genet Med 17 8, 660-667.

PMID:
25356967
PMCID:
PMC4422778
DOI:
10.1038/gim.2014.157
[Indexed for MEDLINE]
Free PMC Article

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