title: DOCK6 mutations are responsible for a distinct autosomal-recessive variant of Adams-Oliver syndrome associated with brain and eye anomalies.
abstract: Adams-Oliver syndrome (AOS) is characterized by the association of aplasia cutis congenita with terminal transverse limb defects, often accompanied by additional cardiovascular or neurological features. Both autosomal-dominant and autosomal-recessive disease transmission have been observed, with recent gene discoveries indicating extensive genetic heterogeneity. Mutations of the DOCK6 gene were first described in autosomal-recessive cases of AOS and only five DOCK6-related families have been reported to date. Recently, a second type of autosomal-recessive AOS has been attributed to EOGT mutations in three consanguineous families. Here, we describe the identification of 13 DOCK6 mutations, the majority of which are novel, across 10 unrelated individuals from a large cohort comprising 47 sporadic cases and 31 AOS pedigrees suggestive of autosomal-recessive inheritance. DOCK6 mutations were strongly associated with structural brain abnormalities, ocular anomalies, and intellectual disability, thus suggesting that DOCK6-linked disease represents a variant of AOS with a particularly poor prognosis.
authors.affiliation: Institute of Human Genetics, University Hospital Magdeburg, Magdeburg, Germany.
authors.forename: Maja
authors.initials: M
authors.lastname: Sukalo
authors.affiliation: Institute of Human Genetics, University Hospital Magdeburg, Magdeburg, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Tilsen
authors.affiliation: Medical Genetics Department, Istanbul Medical Faculty, Istanbul, Turkey.|Medical Genetics Department, School of Medicine, Koc University, Istanbul, Turkey.
authors.forename: Hülya
authors.initials: H
authors.lastname: Kayserili
authors.affiliation: Institut für Medizinische Genetik, Klinikum Chemnitz, Chemnitz, Germany.
authors.forename: Dietmar
authors.initials: D
authors.lastname: Müller
authors.affiliation: Department of Pediatric Genetics, Istanbul University, Istanbul, Turkey.
authors.forename: Beyhan
authors.initials: B
authors.lastname: Tüysüz
authors.affiliation: Department of Clinical Genetics, Guy's Hospital, London, UK.
authors.forename: Deborah M
authors.initials: DM
authors.lastname: Ruddy
authors.affiliation: North West Thames Regional Genetics Service, North West London Hospitals NHS Trust, Harrow, UK.
authors.forename: Emma
authors.initials: E
authors.lastname: Wakeling
authors.affiliation: Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
authors.forename: Karen Helene
authors.initials: KH
authors.lastname: Ørstavik
authors.affiliation: Department of Clinical Genetics, St. George's Healthcare NHS Trust, London, UK.
authors.forename: Katie M
authors.initials: KM
authors.lastname: Snape
authors.affiliation: Department of Clinical Genetics, Guy's Hospital, London, UK.|Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Trembath
authors.affiliation: Department of Medical Genetics, Leuven University Hospital, Leuven, Belgium.
authors.forename: Maryse
authors.initials: M
authors.lastname: De Smedt
authors.affiliation: Department of Medical Genetics, Antwerp University Hospital, Antwerp, Belgium.
authors.forename: Nathalie
authors.initials: N
authors.lastname: van der Aa
authors.affiliation: Institute of Neuroradiology, University Hospital Magdeburg, Magdeburg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Skalej
authors.affiliation: Institute for Medical and Human Genetics Charité, Universitätsmedizin Berlin and Max Planck Institute for Molecular Genetics Berlin, Berlin, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Mundlos
authors.affiliation: Department of Medical Genetics, Antwerp University Hospital, Antwerp, Belgium.|Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
authors.forename: Wim
authors.initials: W
authors.lastname: Wuyts
authors.affiliation: Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.|Division of Genetics and Molecular Medicine, King's College London, London, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: Southgate
authors.affiliation: Institute of Human Genetics, University Hospital Magdeburg, Magdeburg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Zenker
mesh_terms: D000293:Adolescent; D001921:Brain / Q000002:abnormalities* / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D004476:Ectodermal Dysplasia / Q000175:diagnosis* / Q000235:genetics*; D005124:Eye Abnormalities / Q000235:genetics*; D005260:Female; D005808:Genes, Recessive; D056726:Genetic Association Studies; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D017880:Limb Deformities, Congenital / Q000175:diagnosis* / Q000235:genetics*; D008279:Magnetic Resonance Imaging; D008297:Male; D009154:Mutation; D012536:Scalp Dermatoses / Q000151:congenital* / Q000175:diagnosis / Q000235:genetics; D014057:Tomography, X-Ray Computed; D055815:Young Adult
chemical_list: D020662:Guanine Nucleotide Exchange Factors
keywords: AOS; Adams-Oliver syndrome; DOCK6; brain anomalies; eye anomalies