| Abstract |
Methylmalonic aciduria is caused by mutations affecting the mitochondrial
enzyme methylmalonyl-CoA mutase, the synthesis of its cofactor,
adenosylcobalamin, and certain other steps in propionyl-CoA metabolism.
Biallelic mutations in the MUT gene, which encodes methylmalonyl-CoA
mutase, are responsible for the mut form of methylmalonic aciduria.
Patients with this disorder present symptoms of metabolic acidosis,
failure to thrive, recurrent vomiting, hypotonia, lethargy, and
dehydration in the newborn period. Nearly 330 MUT gene mutations are known
to cause mut methylmalonic aciduria. In this study, a next generation
sequencing based gene panel recently developed at Baylor Miraca Genetics
Laboratories was used to analyze 53 patients that had been diagnosed with
mut methylmalonic aciduria by somatic cell complementation analysis. A
total of 54 different mutations in MUT were identified in 48 of 53 (91%)
patients. Of these, 16 mutations were novel, including the largest
insertion mutation in the MUT gene to date. Phenotypic rescue studies and
analysis of cDNA were used to confirm that the large insertion was
responsible for the MCM deficiency observed in the patient's fibroblasts.
No MUT gene mutations were detected in 5 of 53 (9%) patients. Review of
the cellular complementation data used to initially diagnosis these
patients showed the results to be equivocal, putting the initial mut
diagnosis into question. One patient was found to carry two novel
mutations in the SUCLG1 gene which are likely responsible for the
patient's phenotype. Another patient was found to carry a novel
heterozygous variant in SUCLG2. Deficiency of SUCLG2 was investigated in
cells from this patient as a novel cause of human disease. In conclusion,
combination of gene panel analysis and somatic cell studies provided
optimal diagnoses for this cohort of patients.
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