title: TMEM231 Gene Conversion Associated with Joubert and Meckel-Gruber Syndromes in the Same Family.
abstract: Joubert and Meckel-Gruber syndromes (JS and MGS) are ciliopathies with overlapping features. JS patients manifest the "molar tooth sign" on brain imaging and variable eye, kidney, and liver disease. MGS presents with polycystic kidneys, occipital encephalocele, and polydactyly; it is typically perinatally fatal. Both syndromes are genetically heterogeneous; some genes cause either syndrome. Here, we report two brothers married to unrelated women. The first brother had three daughters with JS and a son with polycystic kidneys who died at birth. The second brother's wife had a fetal demise due to MGS. Whole exome sequencing identified TMEM231 NM_001077416.2: c.784G>A; p.(Asp262Asn) in all children and the wife of the first brother; the second brother's wife had a c.406T>G;p.(Trp136Gly) change. In-depth analysis uncovered a rare gene conversion event in TMEM231, leading to loss of exon 4, in all the affected children of first brother. We believe that the combination of this gene conversion with different missense mutations led to a spectrum of phenotypes that span JS and MGS.
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.|NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, Maryland.
authors.forename: Dino
authors.initials: D
authors.lastname: Maglic
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Joshi
authors.initials: J
authors.lastname: Stephen
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.|NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, Maryland.
authors.forename: May Christine V
authors.initials: MC
authors.lastname: Malicdan
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Guo
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Roxanne
authors.initials: R
authors.lastname: Fischer
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Konzman
authors.affiliation: NIH Intramural Sequencing Center and Comparative Genomics Unit, Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.
authors.affiliation: NIH Intramural Sequencing Center and Comparative Genomics Unit, Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: James C
authors.initials: JC
authors.lastname: Mullikin
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.|NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, Maryland.|Office of the Clinical Director, NHGRI, National Institutes of Health, Bethesda, Maryland.
authors.forename: William A
authors.initials: WA
authors.lastname: Gahl
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.|Inova Translational Medicine Institute, Falls Church, Virginia.
authors.forename: Thierry
authors.initials: T
authors.lastname: Vilboux
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland. mgaygun@mail.nih.gov.
authors.forename: Meral
authors.initials: M
authors.lastname: Gunay-Aygun
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D002531:Cerebellum / Q000002:abnormalities*; D002925:Ciliary Motility Disorders / Q000235:genetics*; D004677:Encephalocele / Q000235:genetics*; D059472:Exome; D005124:Eye Abnormalities / Q000235:genetics*; D005260:Female; D005785:Gene Conversion; D006801:Humans; D052177:Kidney Diseases, Cystic / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D020125:Mutation, Missense; D010375:Pedigree; D007690:Polycystic Kidney Diseases / Q000235:genetics*; D012160:Retina / Q000002:abnormalities*; D012174:Retinitis Pigmentosa; D017422:Sequence Analysis, DNA / Q000379:methods
chemical_list: D008565:Membrane Proteins; C578841:TMEM231 protein, human
keywords: TMEM231; cilia; gene conversion; translocation; whole exome sequencing