Identification of a novel homozygous mutation of the BCKDHB gene in an Iranian patient with maple syrup disease using next-generation sequencing

Background: Maple syrup urine disease (MSUD) is an autosomal recessive disorder caused by decreased branchedchain alpha-keto acid dehydrogenase (BCKD) activity in human tissues. The BCKD enzyme is mostly active in the human body in the muscles and the brain; thus, genetic deficiency of the BCKD complex can result in neurological damage in patients. Deleterious mutations in BCKDHB, BCKDHA, DBT, and DLD genes have a significant impact on BCKD activity.Methods: In this study, we described a case of MSUD in a consanguineous Iranian family without a history of metabolic disorders. A 7-year-old boy was diagnosed 21 days after birth with lethargy, feeding problems, and vomiting. Plasma amino acid concentration and level of ammonia were measured. And then, whole-exome sequencing (WES) 100x was used to identify causative mutation along with some bioinformatics analysis.Results: A novel pathogenic homozygous mutation, c.552_553insA; P185Tfs*17, was detected in the BCKDHB gene's exon5. This variant was predicted as a pathogenic mutation using bioinformatics tools including Mutationtaster, Fathmm-mkl, Provean, DEOGEN2, SNPs & GO, PhyloP, and PhastCons. This mutation leads to a truncated protein in which conserved regions are lost. Besides, the variant is completely co-segregated with the disease in this family.Conclusion: A novel pathogenic mutation c.552_553insA in the BCKDHB gene related to MSUD was diagnosed in an Iranian family. This finding from the present study can be efficient in upgrading mutation databases and recognizing MSUD causes.