Novel HMGCS2 pathogenic variants in a Chinese family with mitochondrial 3‐hydroxy‐3‐methylglutaryl‐CoA synthase deficiency

IMPORTANCE: Mitochondrial 3‐hydroxy‐3‐methylglutaryl‐CoA (HMG‐CoA) synthase deficiency is a rare and underdiagnosed disorder with fewer than 30 patients reported worldwide. The application of whole‐exome sequencing in patients could improve our understanding of this disorder. OBJECTIVE: To identify the genetic causes and evaluate the phenotype of mitochondrial HMG‐CoA synthase deficiency in a pediatric patient with uncommon features that included ketosis and elevated lactate and ammonia. METHODS: The proband was referred to the pediatric intensive care unit of Beijing Children's Hospital and selected for molecular testing with whole‐exome sequencing. Her parents and sibling also underwent sequencing for segregation information. RESULTS: We identified two novel mutations (c.1347_1351delAGCCT/p.Ala450Profs*7 and c.1201G>T/ p.Glu401*) in the HMG‐CoA synthase‐2 gene (HMGCS2, NM_005518.3) in the proband and her brother. Both variants were classified as pathogenic variants according to the American College of Medical Genetics and Genomics/ Association for Molecular Pathology guidelines. Metabolic acidosis in the proband was corrected with continuous renal replacement therapy and she left hospital after 21 days of treatment. INTERPRETATION: Our results extend the genotypic and phenotypic spectrum of HMGCS2 mutation in mitochondrial HMG‐CoA synthase deficiency patients and serve as a reminder for physicians to consider mitochondrial HMG‐CoA synthase deficiency in newborns and children with coma and hypoketotic hypoglycemia after fasting.