title: Exome sequencing identifies a new mutation in SERAC1 in a patient with 3-methylglutaconic aciduria.
abstract: 3-Methylglutaconic aciduria (3-MGA-uria) is a heterogeneous group of syndromes characterized by an increased excretion of 3-methylglutaconic and 3-methylglutaric acids. Five types of 3-MGA-uria (I to V) with different clinical presentations have been described. Causative mutations in TAZ, OPA3, DNAJC19, ATP12, ATP5E, and TMEM70 have been identified. After excluding the known genetic causes of 3-MGA-uria we used exome sequencing to investigate a patient with Leigh syndrome and 3-MGA-uria. We identified a homozygous variant in SERAC1 (c.202C>T; p.Arg68*), that generates a premature stop codon at position 68 of SERAC1 protein. Western blot analysis in patient's fibroblasts showed a complete absence of SERAC1 that was consistent with the prediction of a truncated protein and supports the pathogenic role of the mutation. During the course of this project a parallel study identified mutations in SERAC1 as the genetic cause of the disease in 15 patients with MEGDEL syndrome, which was compatible with the clinical and biochemical phenotypes of the patient described here. In addition, our patient developed microcephaly and optic atrophy, two features not previously reported in MEGDEL syndrome. We highlight the usefulness of exome sequencing to reveal the genetic bases of human rare diseases even if only one affected individual is available.
authors.affiliation: Secció d'Errors Congènits del Metabolisme, Servei de Bioquímica i Genètica Molecular, Hospital Clinic, IDIBAPS, 08028, Barcelona, Spain.
authors.forename: Frederic
authors.initials: F
authors.lastname: Tort
authors.forename: María Teresa
authors.initials: MT
authors.lastname: García-Silva
authors.forename: Xènia
authors.initials: X
authors.lastname: Ferrer-Cortès
authors.forename: Aleix
authors.initials: A
authors.lastname: Navarro-Sastre
authors.forename: Judith
authors.initials: J
authors.lastname: Garcia-Villoria
authors.forename: Maria Josep
authors.initials: MJ
authors.lastname: Coll
authors.forename: Enrique
authors.initials: E
authors.lastname: Vidal
authors.forename: Jorge
authors.initials: J
authors.lastname: Jiménez-Almazán
authors.forename: Joaquín
authors.initials: J
authors.lastname: Dopazo
authors.forename: Paz
authors.initials: P
authors.lastname: Briones
authors.forename: Orly
authors.initials: O
authors.lastname: Elpeleg
authors.forename: Antonia
authors.initials: A
authors.lastname: Ribes
mesh_terms: D000293:Adolescent; D000328:Adult; D002265:Carboxylic Ester Hydrolases / Q000235:genetics*; D002648:Child; D059472:Exome / Q000235:genetics*; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007223:Infant; D008297:Male; D008661:Metabolism, Inborn Errors / Q000235:genetics* / Q000473:pathology; D009154:Mutation
chemical_list: D002265:Carboxylic Ester Hydrolases; C576043:SERAC1 protein, human
keywords: 3-Methylglutaconic; Exome; MEGDEL; SERAC1