OBSERVATION A Novel OPA3 Mutation Revealed by Exome Sequencing An Example of Reverse Phenotyping Beenish Arif, MPhil; Kishore R. Kumar, MBBS, FRACP; Philip Seibler, PhD; Franca Vulinovic, MS; Amara Fatima, MS; Susen Winkler, BS; Gudrun Nu ¨ rnberg, MSc; Holger Thiele, PhD; Peter Nu ¨ rnberg, PhD; Ahmad Zeeshan Jamil, MBBS, MCPS, FCPS, FRCS; Anne Bru ¨ ggemann, MD; Ghazanfar Abbas, MBBS; Christine Klein, MD; Sadaf Naz, PhD; Katja Lohmann, PhD Importance: We sought to unravel the genetic cause in a consanguineous Pakistani family with a complex neu- rological phenotype. Observations: Neurological and ophthalmological ex- amination, including videotaping and fundoscopy, and genetic investigations, including homozygosity map- ping and exome sequencing, were performed at the Uni- versity of the Punjab and the University of Lu ¨ beck. Par- ticipants included 2 severely affected cousins from consanguineous parents, 10 of their reportedly unaf- fected relatives, and 342 Pakistani controls. Motor symp- toms in the 2 patients started at the age of 3 to 4 years and included chorea, cerebellar ataxia, dystonia, and py- ramidal tract signs. Genome-wide genotyping delin- eated 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 assess- ment revealed bilateral optic atrophy in both patients. Conclusions and Relevance: 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 atro- phy was initiated only after genetic analysis, a phenom- enon referred to as reverse phenotyping. JAMA Neurol. 2013;70(6):783-787. Published online April 29, 2013. doi:10.1001/jamaneurol.2013.1174 C OSTEFF OPTIC ATROPHY syndrome (or optic atro- phy plus syndrome; MIM 258501) is a rare autoso- mal recessive disorder originally described in the Iraqi-Jewish community in Israel. 1 Patients typically de- velop optic atrophy and/or a choreoath- etoid movement disorder within the first decade of life. Subsequent developments include spastic paraparesis, ataxia, and oc- casionally a mild cognitive deficit in the second decade of life. 1,2 Costeff optic atrophy syndrome is caused by mutations in the optic atrophy 3(OPA3) gene. 3 This gene has 3 exons and is expressed in 2 transcripts, OPA3A (RefSeq NM_025136) and OPA3B (RefSeq NM_001017989). A homozygous splice site mutation (IVS1-1GC) has been iden- tified in OPA3 in all cases of Costeff optic atrophy syndrome in the Iraqi-Jewish population. 3 Two additional homozy- gous mutations were found in a Turkish- Kurdish patient (c.320_337del [p.Q108_E113del]) 4 and an Indian pa- tient (c.415CT [p.Q139X]). 5 In addi- tion, 2 heterozygous missense muta- tions, c.277GA (p.G93S) and c.313CG (p.Q105E), have been detected in pa- tients with autosomal dominant optic at- rophy and cataract (ADOAC [MIM 165300]). 6 We performed homozygosity map- ping and exome sequencing in a consan- guineous Pakistani family affected by a complex neurological disorder. A novel OPA3 mutation was identified, prompt- ing reevaluation of the clinical pheno- type and the diagnosis of an optic atro- phy plus syndrome. METHODS The study was approved by the institutional re- view board at the University of the Punjab, and all participants gave written informed con- sent. Neurological examination was per- Author Aff Neurogene Vulinovic, a Kumar, Seib Lohmann), Ophthalmo Bru ¨ ggeman Lu ¨ beck, Lu ¨ School of B University Arif and Fa Departmen Layton Reh Trust (Dr Ja Hospital (D Pakistan; D Neurogene of Medical North Shor University Australia (D Center for M Cologne (M Thiele and Cologne Ce (Ms Nu ¨ rnb Nu ¨ rnberg), Cologne, C Author Affiliations: Institute of Neurogenetics (Mss Arif, Vulinovic, and Winkler and Drs Kumar, Seibler, Klein, and Lohmann), and Department of Ophthalmology (Dr Bru ¨ ggemann), University of Lu ¨ beck, Lu ¨ beck, Germany; School of Biological Sciences, University of the Punjab (Mss Arif and Fatima and Dr Naz), Department of Ophthalmology, Layton Rehmatullah Benevolent Trust (Dr Jamil), and Services Hospital (Dr Abbas), Lahore, Pakistan; Department of Neurogenetics, Kolling Institute of Medical Research, Royal North Shore Hospital and University of Sydney, Sydney, Australia (Dr Kumar); and Center for Molecular Medicine Cologne (Ms Nu ¨ rnberg and Drs Thiele and Nu ¨ rnberg) and Cologne Center for Genomics (Ms Nu ¨ rnberg and Dr Nu ¨ rnberg), University of Cologne, Cologne, Germany. JAMA NEUROL/ VOL 70 (NO. 6), JUNE 2013 WWW.JAMANEURO.COM 783 ©2013 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 06/20/2020