Association of a novel homozygous mutation in the HMGCS2 gene with an HMGCSD in an Iranian patient

BACKGROUND: 3‐Hydroxy‐3‐methylglutaryl‐CoA (HMG‐CoA) synthase 2 gene (HMGCS2) encodes a mitochondrial enzyme catalyzing the first reaction of ketogenesis metabolic pathway which provides lipid‐derived energy for various organs during times of carbohydrate deprivation, such as fasting. Mutations in this gene are responsible for HMG‐CoA synthase deficiency (HMGCSD). The aim of present study was to investigate the association of mutation in the HMGCS2 gene with HMGCSD in a patient with atypical symptoms. METHODS: The clinical and genetic features of an 8‐months‐old girl with HMGCSD were evaluated. Molecular genetic testing was conducted using whole‐exome sequencing (WES) in order to identify potential disease‐causing mutation. The WES finding was confirmed by the polymerase chain reaction (PCR) amplification of the target sequence carried out for the patient and her parents. The PCR products were subjected to direct sequencing using forward and reverse specific primers corresponding to the HMGCS2 gene. RESULTS: A novel homozygous missense mutation (c.266G>A p.Gly89Asp) was detected in the HMGCS2 gene. Sanger sequencing along with co‐segregation analysis of all family members confirmed this novel pathogenic germline mutation. The mutant gene was found to be pathogenic by bioinformatics analysis. CONCLUSION: To our best knowledge, this is the first report of HMGCSD in Iran which would expand our knowledge about the mutational spectrum of the HMGCS2 gene and the phenotype variations of the disease.