title: A relatively mild skeletal ciliopathy phenotype consistent with cranioectodermal dysplasia is associated with a homozygous nonsynonymous mutation in WDR35.
abstract: Ciliopathies are a class of clinically and genetically heterogeneous disorders characterized by deficits of the primary cilium, an important organelle for cellular signaling and development. Here we report on a patient from a consanguineous family presenting with renal cysts, short stature, distinctive facial features, missing teeth, brachydactyly, narrow chest, and abnormal ribs. His phenotype resembled a skeletal ciliopathy and the initial clinical differential diagnosis included Jeune thoracic dystrophy and cranioectodermal dysplasia. Due to the presence of parental consanguinity, a homozygous recessive mutation was the suspected cause and homozygosity mapping was used to direct candidate gene sequencing. WDR35, an intraflagellar transport protein previously associated with cranioectodermal dysplasia, the more severe short rib polydactyly syndrome type V and recently Ellis van Creveld syndrome, is present within a region of homozygosity and sequencing of all coding exons identified a novel homozygous nonsynonymous variant, p.Trp1153Cys. This variant affects a highly conserved tryptophan residue, is predicted to be deleterious, and is the most distal mutation yet reported in WDR35. This case expands the spectrum of phenotypes caused by WDR35 mutations, which we review herein.
authors.affiliation: Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Christopher
authors.initials: C
authors.lastname: Smith
authors.affiliation: Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.|Alberta Children's Hospital Research Institute, Calgary, Albeta, Canada.
authors.forename: Ryan E
authors.initials: RE
authors.lastname: Lamont
authors.affiliation: Department of Pediatrics, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Andrew
authors.initials: A
authors.lastname: Wade
authors.affiliation: Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.|Alberta Children's Hospital Research Institute, Calgary, Albeta, Canada.
authors.forename: Francois P
authors.initials: FP
authors.lastname: Bernier
authors.affiliation: Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.|Alberta Children's Hospital Research Institute, Calgary, Albeta, Canada.
authors.forename: Jillian S
authors.initials: JS
authors.lastname: Parboosingh
authors.affiliation: Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.|Alberta Children's Hospital Research Institute, Calgary, Albeta, Canada.
authors.forename: A Micheil
authors.initials: AM
authors.lastname: Innes
mesh_terms: D000293:Adolescent; D001842:Bone and Bones / Q000002:abnormalities*; D003398:Craniosynostoses / Q000175:diagnosis* / Q000235:genetics*; D003598:Cytoskeletal Proteins; D004476:Ectodermal Dysplasia / Q000175:diagnosis* / Q000235:genetics*; D004613:Ellis-Van Creveld Syndrome / Q000175:diagnosis / Q000235:genetics; D053823:Hedgehog Proteins; D006720:Homozygote; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D009154:Mutation; D010641:Phenotype; D011506:Proteins / Q000235:genetics*; D012863:Skeleton / Q000000981:diagnostic imaging / Q000473:pathology
chemical_list: D003598:Cytoskeletal Proteins; D053823:Hedgehog Proteins; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; C558596:WDR35 protein, human
keywords: Sensenbrenner syndrome; asphyxiating thoracic dystrophy; homozygosity mapping; polycystic kidney; short stature