3-Hydroxyacyl-CoA Dehydrogenase Deficiency via the HADH Gene

3-hydroxyacyl-CoA dehydrogenase deficiency is a disorder of mitochondrial fatty acid beta-oxidation characterized by hypoglycemic seizures and hyperinsulinism (HI) within the first 3 years of life (Martins et al. 2011; Clayton et al. 2001). Clinical features include hyperinsulinemic hypoglycemia, poor appetite, vomiting, diarrhea, lethargy, hypotonia, and liver problems. Most cases are responsive to treatment with diazoxide.

Recessive inactivating HADH pathogenic variants cause 3-hydroxyacyl-CoA dehydrogenase deficiency with hyperinsulinemic hypoglycemia (Martins et al. 2011; Clayton et al. 2001). The HADH gene (9 coding exons) encodes 3-hydroxyacyl-CoA dehydrogenase which catalyzes the reversible dehydrogenation of 3-hydroxyacyl-CoAs to their corresponding 3-ketoacyl-CoAs in mitochondrial fatty acid beta-oxidation. Genetic defects of HADH found to date include missense, nonsense, splicing, small indels and one large deletion (Human Gene Mutation Database).

Homozygous HADH pathogenic variants were identified in 11 (10%) of 115 unrelated patients with diazoxide-responsive hyperinsulinemic hypoglycemia who were negative for pathogenic variants in the hyperinsulinemia-associated genes ABCC8, KCNJ11, GCK, and HNF4A (Flanagan et al. 2011).

To date, only one large deletion was found in HADH (Flanagan et al. 2011). Large deletions and duplications are expected to be rare.

This test provides full coverage of all coding exons of the HADH gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.