title: DMRTA2 (DMRT5) is mutated in a novel cortical brain malformation.
abstract: Lissencephaly is a phenotypically and genetically heterogeneous group of cortical brain malformations due to abnormal neuronal migration. The identification of many causative genes has increased the understanding of normal brain development. A consanguineous family was ascertained with three siblings affected by a severe prenatal neurodevelopmental disorder characterised by fronto-parietal pachygyria, agenesis of the corpus callosum and progressive severe microcephaly. Autozygosity mapping and exome sequencing identified a homozygous novel single base pair deletion, c.1197delT in DMRTA2, predicted to result in a frameshift variant p.(Pro400Leufs*33). DMRTA2 encodes doublesex and mab-3-related transcription factor a2, a transcription factor key to the development of the dorsal telencephalon. Data from murine and zebrafish knockout models are consistent with the variant of DMTRA2 (DMRT5) as responsible for the cortical brain phenotype. Our study suggests that loss of function of DMRTA2 leads to a novel disorder of cortical development.
authors.affiliation: Manchester Centre for Genomic Medicine, St. Mary's Hospital, Manchester Academic Health Sciences Centre (MAHSC), Manchester, UK.|Manchester Centre for Genomic Medicine, Institute of Human Development, Manchester, UK.
authors.forename: J E
authors.identifier: 0000-0002-5788-5511
authors.initials: JE
authors.lastname: Urquhart
authors.affiliation: Manchester Centre for Genomic Medicine, St. Mary's Hospital, Manchester Academic Health Sciences Centre (MAHSC), Manchester, UK.|Manchester Centre for Genomic Medicine, Institute of Human Development, Manchester, UK.
authors.forename: G
authors.initials: G
authors.lastname: Beaman
authors.affiliation: Manchester Centre for Genomic Medicine, St. Mary's Hospital, Manchester Academic Health Sciences Centre (MAHSC), Manchester, UK.|Manchester Centre for Genomic Medicine, Institute of Human Development, Manchester, UK.
authors.forename: H
authors.initials: H
authors.lastname: Byers
authors.affiliation: Centre for Paediatrics and Child Health, Institute of Human Development, University of Manchester, Manchester, UK.
authors.forename: N A
authors.initials: NA
authors.lastname: Roberts
authors.affiliation: The Genetic Institute, Emek Medical Center, Afula, Israel.
authors.forename: E
authors.initials: E
authors.lastname: Chervinsky
authors.affiliation: Manchester Centre for Genomic Medicine, St. Mary's Hospital, Manchester Academic Health Sciences Centre (MAHSC), Manchester, UK.|Manchester Centre for Genomic Medicine, Institute of Human Development, Manchester, UK.
authors.forename: J
authors.initials: J
authors.lastname: O'Sullivan
authors.affiliation: Institute of Medical Genetics, University Hospital of Wales, Cardiff, UK.
authors.forename: D
authors.initials: D
authors.lastname: Pilz
authors.affiliation: Institute of Medical Genetics, University Hospital of Wales, Cardiff, UK.
authors.forename: A
authors.initials: A
authors.lastname: Fry
authors.affiliation: Manchester Centre for Genomic Medicine, St. Mary's Hospital, Manchester Academic Health Sciences Centre (MAHSC), Manchester, UK.|Manchester Centre for Genomic Medicine, Institute of Human Development, Manchester, UK.
authors.forename: S G
authors.initials: SG
authors.lastname: Williams
authors.affiliation: Manchester Centre for Genomic Medicine, St. Mary's Hospital, Manchester Academic Health Sciences Centre (MAHSC), Manchester, UK.|Manchester Centre for Genomic Medicine, Institute of Human Development, Manchester, UK.
authors.forename: S S
authors.initials: SS
authors.lastname: Bhaskar
authors.affiliation: The Genetic Institute, Emek Medical Center, Afula, Israel.
authors.forename: M
authors.initials: M
authors.lastname: Khayat
authors.affiliation: Departments of Medical Imaging, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: N
authors.initials: N
authors.lastname: Simanovsky
authors.affiliation: Faculty of Medicine, Ziv Hospital, Zefat, Israel.
authors.forename: I B
authors.initials: IB
authors.lastname: Shachar
authors.affiliation: The Genetic Institute, Emek Medical Center, Afula, Israel.|Rapapport Faculty of Medicine, Haifa, Israel.
authors.forename: S A
authors.initials: SA
authors.lastname: Shalev
authors.affiliation: Manchester Centre for Genomic Medicine, St. Mary's Hospital, Manchester Academic Health Sciences Centre (MAHSC), Manchester, UK.|Manchester Centre for Genomic Medicine, Institute of Human Development, Manchester, UK.
authors.forename: W G
authors.initials: WG
authors.lastname: Newman
mesh_terms: D000818:Animals; D001483:Base Sequence; D002540:Cerebral Cortex / Q000002:abnormalities*; D003241:Consanguinity; D004195:Disease Models, Animal; D059472:Exome / Q000235:genetics; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D054082:Lissencephaly / Q000235:genetics*; D008297:Male; D051379:Mice; D009154:Mutation; D010375:Pedigree; D017422:Sequence Analysis, DNA / Q000379:methods; D035781:Siblings; D014157:Transcription Factors; D014981:Xenopus / Q000235:genetics; D015027:Zebrafish / Q000235:genetics
chemical_list: C000598461:DMRTA2 protein, human; D014157:Transcription Factors
keywords: DMRT5; DMRTA2; agenesis corpus callosum; lissencephaly; microcephaly; pachygyria