ECHS1 disease in two unrelated families of Samoan descent: Common variant ‐ rare disorder. Issue 1 (28th October 2020)

• Record Type: Journal Article
• Authors: Simon, Mariella T.; Eftekharian, Shaya S.; Ferdinandusse, Sacha; Tang, Sha; Naseri, Take; Reupena, Muagututi'a Sefuiva; McGarvey, Stephen T.; Minster, Ryan L.; Weeks, Daniel E.; Nguyen, Daniel D.; Lee, Sansan; Ellsworth, Katarzyna A.; Vaz, Frédéric M.; Dimmock, David; Pitt, James; Abdenur, Jose E.
• Is Part Of: American journal of medical genetics. Volume 185:Issue 1(2021)
• Page Start: 157
• Page End: 167
• Publication Date: 2020-10-28
• Subjects: ECHS1 -- Leigh syndrome -- mitochondrial disease -- Samoan population -- silent variant; Medical genetics -- Periodicals; 616.14205
• DOI: 10.1002/ajmg.a.61936
• Languages: English
• ISSNs: 1552-4825

Abstract

Abstract: Mutations in the short‐chain enoyl‐CoA hydratase (SCEH) gene, ECHS1, cause a rare autosomal recessive disorder of valine catabolism. Patients usually present with developmental delay, regression, dystonia, feeding difficulties, and abnormal MRI with bilateral basal ganglia involvement. We present clinical, biochemical, molecular, and functional data for four affected patients from two unrelated families of Samoan descent with identical novel compound heterozygous mutations. Family 1 has three affected boys while Family 2 has an affected daughter, all with clinical and MRI findings of Leigh syndrome and intermittent episodes of acidosis and ketosis. WES identified a single heterozygous variant in ECHS1 at position c.832G > A (p.Ala278Thr). However, western blot revealed significantly reduced ECHS1 protein for all affected family members. Decreased SCEH activity in fibroblasts and a mild increase in marker metabolites in urine further supported ECHS1 as the underlying gene defect. Additional investigations at the DNA (aCGH, WGS) and RNA (qPCR, RT‐PCR, RNA‐Seq, RNA‐Array) level identified a silent, common variant at position c.489G > A (p.Pro163=) as the second mutation. This substitution, present at high frequency in the Samoan population, is associated with decreased levels of normally spliced mRNA. To our understanding, this is the first report of a novel, hypomorphic allele c.489G > A (p.Pro163=), associated with SCEH deficiency.