Extrapolation of Variant Phase in Mitochondrial Short-Chain Enoyl-CoA Hydratase (ECHS1) Deficiency
Loss-of-function and hypomorphic ECHS1 variants are associated with mitochondrial short-chain enoyl-CoA hydratase deficiency, an inborn error of valine metabolism. We report an 8-year-old boy with developmental delay, ataxia, hemiplegia, and hearing loss with abnormalities in the basal ganglia. Biochemical studies were essentially normal except for a persistent mildly elevated CSF alanine. This patient demonstrates an intermediate phenotype between a Leigh-like, early-onset presentation and paroxysmal exercise-induced dyskinesia. Two novel ECHS1 variants (c.79T>G; p.Phe27Val and c.789_790del; p.Phe263fs) were identified via exome sequencing in the proband, and pathogenicity was confirmed by enzyme assay performed on patient fibroblasts. Neither of the ECHS1 variants detected in the child were present in the mother. However, due to nearby polymorphisms, it was possible to determine that p.Phe263fs occurred de novo on the maternal chromosome and that p.Phe27Val likely derived from the paternal chromosome. Nearby polymorphisms can help set phase of variants when only a single parent is available for testing or when an identified variant occurs de novo.
KeywordsECHS1 Exome interpretation Mitochondrial short-chain enoyl-CoA hydratase deficiency Phase determination
We are grateful to the family for their willingness to share this case with the medical community. We also would like to thank the members of Genomics Lab and Genetic Sequencing Lab at ARUP laboratories for performing testing on the individuals included in this study.
- Bedoyan JK, Yang SP, Ferdinandusse S et al (2017) Lethal neonatal case and review of primary short-chain enoyl-CoA hydratase (SCEH) deficiency associated with secondary lymphocyte pyruvate dehydrogenase complex (PDC) deficiency. Mol Genet Metab 120:342–349. https://doi.org/10.1016/j.ymgme.2017.02.002 CrossRefPubMedPubMedCentralGoogle Scholar
- Yamada K, Aiba K, Kitaura Y et al (2015) Clinical, biochemical and metabolic characterisation of a mild form of human short-chain enoyl-CoA hydratase deficiency: significance of increased N-acetyl-S-(2-carboxypropyl)cysteine excretion. J Med Genet 52:691–698. https://doi.org/10.1136/jmedgenet-2015-103231 CrossRefPubMedGoogle Scholar