Targeted exome sequencing for the identification of complementation groups in methylmalonic aciduria: A south Indian experience.

OBJECTIVES: In view of high incidence of methylmalonic aciduria (MMA) among South Indians, we have performed clinical, biochemical and molecular genetic evaluation of fifteen patients.

DESIGN AND METHODS: Targeted exome sequencing was performed for a panel of MMA causing genes i.e. MUT, ABCD4, ACSF3, CD320, LMBRD1, MCEE, MMAA, MMAB, MMACHC, MMADHC.

RESULTS: Methylmalonyl-CoA mutase (MUT), MMAB and MMAA genetic variants were found to contribute towards 40%, 33.3% and 6.6% etiology, respectively. Early onset of the disease (during the neonatal period) and presence of MUT and MMAB genetic variants was shown to be associated with higher mortality. The patients with MMAA variants had a milder disease. Among the identified mutations, 66% were already known. Three novel mutations, i.e.MUTp.Ala376Serfs, MMAB p.Glu112* and MMAA p.Tyr24* were identified. We also report three novel variants with predicted pathogenicity, MMAA intron 3 c.562+1_562+2insT, p.Ala668Pro in exon 12 of one of the alleles of the MUT gene and c.519+1G>A in intron 6 of one of the alleles in MMAB gene. We performed prenatal diagnosis in five of these families.

CONCLUSIONS: MMA among South Indian patients is genetically heterogeneous, caused by different complementation groups. Both B12-responsive and non-responsive patients were diagnosed. In biochemically diagnosed patients, targeted exome sequencing is cost effective to identify different MMA causing mutations and facilitate genetic counseling.