title: A lethal neonatal phenotype of mitochondrial short-chain enoyl-CoA hydratase-1 deficiency.
abstract: Short-chain enoyl-CoA hydratase (SCEH) is a mitochondrial enzyme involved in the oxidation of fatty acids and the catabolic pathway of valine and, to a lesser extent, isoleucine. Deficiency of this enzyme was recently shown to cause an early childhood Leigh syndrome phenotype. The few reported patients were compound heterozygotes for two missense or missense with truncating variants in ECHS1 that encodes SCEH. We describe two siblings with severe refractory lactic acidosis and death within the first 2 days of life. Following negative clinical whole-exome and whole-genome sequencing, we resorted to autozygome/exome analysis on research basis and identified a homozygous splice site mutation (c.88+5G>A) in the two cases. Analysis of cDNA confirmed complete replacement of the normal transcript with an aberrant transcript (r.88_89ins 88+1_88+11) predicting premature truncation of the protein [p.(Ala31Glufs*23)]. Furthermore, quantitative reverse transcriptase polymerase chain reaction (RTPCR) showed marked reduction in ECHS1, most likely nonsense-mediated decay (NMD)-mediated. This is the first report of homozygosity for a truncating mutation in ECHS1, which may explain the severe phenotype. Our report highlights the need to consider SCEH deficiency in patients with lethal neonatal lactic acidosis, and the potentially limited sensitivity of untargeted genomic sequencing towards non-canonical splicing mutations, which may explain at least some of the 'negative' cases on clinical exome/genome sequencing.
authors.affiliation: King Abdullah International Medical Research Centre, King Saud bin Abdulaziz University for Health Sciences, Genetic Division, Department of Pediatrics, King Abdulaziz Medical City, Ministry of National Guard-Health Affairs (NGHA), Riyadh, Saudi Arabia.
authors.forename: F
authors.initials: F
authors.lastname: Al Mutairi
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: H E
authors.initials: HE
authors.lastname: Shamseldin
authors.affiliation: King Abdullah International Medical Research Centre, King Saud bin Abdulaziz University for Health Sciences, Genetic Division, Department of Pediatrics, King Abdulaziz Medical City, Ministry of National Guard-Health Affairs (NGHA), Riyadh, Saudi Arabia.
authors.forename: M
authors.initials: M
authors.lastname: Alfadhel
authors.affiliation: Radboud Center for Mitochondrial Medicine Translational Metabolic Laboratory, Department of Pediatrics, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: R J
authors.initials: RJ
authors.lastname: Rodenburg
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.|Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
authors.forename: F S
authors.initials: FS
authors.lastname: Alkuraya
mesh_terms: D000140:Acidosis, Lactic / Q000235:genetics* / Q000401:mortality / Q000503:physiopathology; D004746:Enoyl-CoA Hydratase / Q000172:deficiency / Q000235:genetics*; D059472:Exome / Q000235:genetics; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006720:Homozygote; D006801:Humans; D007231:Infant, Newborn; D007888:Leigh Disease / Q000235:genetics / Q000503:physiopathology; D008297:Male; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D022821:RNA Splice Sites / Q000235:genetics; D035781:Siblings
chemical_list: D022821:RNA Splice Sites; C000600529:ECHS1 protein, human; D004746:Enoyl-CoA Hydratase
keywords: Leigh syndrome; autozygome; basal ganglia; exome sequencing; lipoic acid