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.