title: A novel OPA3 mutation revealed by exome sequencing: an example of reverse phenotyping.
abstract: OBJECTIVE
  We sought to unravel the genetic cause in a consanguineous Pakistani family with a complex neurological phenotype.
  
  
  METHODS
  Neurological and ophthalmological examination, including videotaping and fundoscopy, and genetic investigations, including homozygosity mapping and exome sequencing, were performed at the University of the Punjab and the University of Lübeck. Participants included 2 severely affected cousins from consanguineous parents, 10 of their reportedly unaffected relatives, and 342 Pakistani controls. Motor symptoms in the 2 patients started at the age of 3 to 4 years and included chorea, cerebellar ataxia, dystonia, and pyramidal tract signs. Genome-wide genotyping delineated 2 regions of homozygosity on chromosomes 13q12.11 to 13q12.13 and 19q12 to 19q13.41. Exome sequencing revealed 2 rare, homozygous variants (c.32 T>A [p.L11Q] in OPA3 and c.941 C>G [p.A314G] in TSHZ3) that segregated with the disease. Only the OPA3 variant was absent in the control subjects and predicted to be damaging. Subsequent ophthalmological assessment revealed bilateral optic atrophy in both patients.
  
  
  CONCLUSIONS
  Mutations in OPA3 have been reported in Costeff optic atrophy syndrome. We identify a novel missense mutation in OPA3 as the cause of a complex neurological disorder, expanding the OPA3 -linked phenotype by early-onset pyramidal tract signs and marked lower limb dystonia. Investigation of optic atrophy was initiated only after genetic analysis, a phenomenon referred to as reverse phenotyping.
authors.affiliation: Institute of Neurogenetics, University of Lübeck, Lübeck, Germany.
authors.forename: Beenish
authors.initials: B
authors.lastname: Arif
authors.forename: Kishore R
authors.initials: KR
authors.lastname: Kumar
authors.forename: Philip
authors.initials: P
authors.lastname: Seibler
authors.forename: Franca
authors.initials: F
authors.lastname: Vulinovic
authors.forename: Amara
authors.initials: A
authors.lastname: Fatima
authors.forename: Susen
authors.initials: S
authors.lastname: Winkler
authors.forename: Gudrun
authors.initials: G
authors.lastname: Nürnberg
authors.forename: Holger
authors.initials: H
authors.lastname: Thiele
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.forename: Ahmad Zeeshan
authors.initials: AZ
authors.lastname: Jamil
authors.forename: Anne
authors.initials: A
authors.lastname: Brüggemann
authors.forename: Ghazanfar
authors.initials: G
authors.lastname: Abbas
authors.forename: Christine
authors.initials: C
authors.lastname: Klein
authors.forename: Sadaf
authors.initials: S
authors.lastname: Naz
authors.forename: Katja
authors.initials: K
authors.lastname: Lohmann
mesh_terms: D000293:Adolescent; D002648:Child; D002819:Chorea / Q000175:diagnosis* / Q000235:genetics*; D004421:Dystonia / Q000175:diagnosis / Q000235:genetics; D059472:Exome / Q000235:genetics*; D005260:Female; D055106:Genome-Wide Association Study / Q000379:methods; D006801:Humans; D008297:Male; D008661:Metabolism, Inborn Errors / Q000175:diagnosis* / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics*; D009422:Nervous System Diseases / Q000175:diagnosis / Q000235:genetics; D009896:Optic Atrophy / Q000175:diagnosis* / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D011506:Proteins / Q000235:genetics*; D017422:Sequence Analysis, DNA / Q000379:methods*; D015419:Spastic Paraplegia, Hereditary / Q000175:diagnosis* / Q000235:genetics*
chemical_list: C443108:OPA3 protein, human; D011506:Proteins