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ECHS1 disease in two unrelated families of Samoan descent: Common variant ‐ rare disorder
Author(s) -
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.
Publication year - 2021
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.61936
Subject(s) - medicine , endocrinology , compound heterozygosity , biology , population , mutation , genetics , gene , environmental health
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.