Abstract
Maple syrup urine disease (MSUD) is an autosomal recessive inherited metabolic disorder caused by mutations in the BCKDHA, BCKDHB, DBT, and DLD genes. Among the wide range of disease-causing mutations in BCKDHB, only one large deletion has been associated with MSUD. Compound heterozygous mutations in BCKDHB were identified in a Chinese patient with typical MSUD using next-generation sequencing, quantitative PCR, and array comparative genomic hybridization. One allele presented a missense mutation (c.391G > A), while the other allele had a large deletion; both were inherited from the patient’s unaffected parents. The deletion breakpoints were characterized using long-range PCR and sequencing. A novel 383,556 bp deletion (chr6: g.80811266_81194921del) was determined, which encompassed the entire BCKDHB gene. The junction site of the deletion was localized within a homologous sequence in two AluYa5 elements. Hence, Alu-mediated non-allelic homologous recombination is speculated as the mutational event underlying the large deletion. In summary, this study reports a recombination mechanism in the BCKDHB gene causing a whole gene deletion in a newborn with MSUD.
Highlights
Maple syrup urine disease (MSUD, OMIM #248600) is an autosomal recessive inherited metabolic disorder, caused by a defective activity of the branched-chain α-keto acid dehydrogenase complex (BCKAD) complex in the mitochondria (Chuang et al, 2004)
To detect the BCKDHB gene deletion/duplication, we developed a gene dosage assay based on real-time quantitative PCR
The patient was diagnosed with MSUD, and he deceased at the age of 20 days
Summary
Maple syrup urine disease (MSUD, OMIM #248600) is an autosomal recessive inherited metabolic disorder, caused by a defective activity of the branched-chain α-keto acid dehydrogenase complex (BCKAD) complex in the mitochondria (Chuang et al, 2004). The deficient activity of BCKAD leads to the accumulation of leucine, isoleucine, valine and their respective metabolites causing systemic toxicity, but especially in the central nervous system (Yudkoff et al, 2005; Lang et al, 2010). Based on the age of onset, clinical manifestation, and BCKAD residual activity, MSUD is divided into five types: classic, intermediate, intermittent, thiamine-responsive, and E3-deficient (Blackburn et al, 2017). We described a Chinese patient with the severe classic form of MSUD caused by a missense mutation and a novel large deletion mutation in the BCKDHB gene
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