<p>3-Methylcrotonyl-CoA Carboxylase Deficiency (MCCD) is an autosomal recessive disorder of leucine catabolism, which has a highly variable clinical phenotype, ranging from acute metabolic acidosis to non-specific 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.</p> <p>We performed exome sequencing on DNA from 107 healthy controls and 33 cases. 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. We determined that individuals with non-specific clinical phenotypes are highly inbred compared to cases that are asymptomatic and healthy controls. For five of these individuals we discovered a homozygous damaging mutation in a disease gene that is likely to underlie their non-specific clinical phenotypes previously attributed to MCCD.</p>

Consanguinity and Rare Mutations Outside of MCCC Genes Underlie Non-Specific Phenotypes of MCC Deficiency