TY - JOUR
T1 - The genetic basis of DOORS syndrome
T2 - An exome-sequencing study
AU - Campeau, Philippe M.
AU - Kasperaviciute, Dalia
AU - Lu, James T.
AU - Burrage, Lindsay C.
AU - Kim, Choel
AU - Hori, Mutsuki
AU - Powell, Berkley R.
AU - Stewart, Fiona
AU - Félix, Têmis Maria
AU - van den Ende, Jenneke
AU - Wisniewska, Marzena
AU - Kayserili, Hülya
AU - Rump, Patrick
AU - Nampoothiri, Sheela
AU - Aftimos, Salim
AU - Mey, Antje
AU - Nair, Lal D.V.
AU - Begleiter, Michael L.
AU - De Bie, Isabelle
AU - Meenakshi, Girish
AU - Murray, Mitzi L.
AU - Repetto, Gabriela M.
AU - Golabi, Mahin
AU - Blair, Edward
AU - Male, Alison
AU - Giuliano, Fabienne
AU - Kariminejad, Ariana
AU - Newman, William G.
AU - Bhaskar, Sanjeev S.
AU - Dickerson, Jonathan E.
AU - Kerr, Bronwyn
AU - Banka, Siddharth
AU - Giltay, Jacques C.
AU - Wieczorek, Dagmar
AU - Tostevin, Anna
AU - Wiszniewska, Joanna
AU - Cheung, Sau Wai
AU - Hennekam, Raoul C.
AU - Gibbs, Richard A.
AU - Lee, Brendan H.
AU - Sisodiya, Sanjay M.
N1 - Funding Information:
We thank David Liu for technical assistance, Alyssa Tran and Dale Kerr for clinical research support, Shalini N Jhangiani for exome sequencing coordination, Sabrina Hong for the representation of the structural model of TBC1D24, and Costin Leu for assistance with exome sequencing statistics. Funding was provided by NIH grants PO1 HD22657 (BHL), U54 HG006542 (RAG), and U54 HG003273-09 (RAG); by The Rolanette and Berdon Lawrence Bone Disease Program of Texas (BHL), by the Wellcome Trust (SMS), the Henry Smith Charity (SMS), and Action Medical Research (SMS). This work was supported by the BCM Intellectual and Developmental Disabilities Research Center (HD024064) from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. This work was partly undertaken at UCLH/UCL, which received a proportion of funding from the Department of Health's NIHR Biomedical Research Centres funding scheme. PMC is supported by a CIHR clinician-scientist training award and the O'Malley Foundation. JTL is supported by Ruth L Kirschstein National Research Service Award F30 MH098571-01 . LCB was supported by the Medical Genetics Research Fellowship Program NIH/NIGMS NIH T32 GM07526 .
PY - 2014/1
Y1 - 2014/1
N2 - Background: Deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures (DOORS) syndrome is a rare autosomal recessive disorder of unknown cause. We aimed to identify the genetic basis of this syndrome by sequencing most coding exons in affected individuals. Methods: Through a search of available case studies and communication with collaborators, we identified families that included at least one individual with at least three of the five main features of the DOORS syndrome: deafness, onychodystrophy, osteodystrophy, intellectual disability, and seizures. Participants were recruited from 26 centres in 17 countries. Families described in this study were enrolled between Dec 1, 2010, and March 1, 2013. Collaborating physicians enrolling participants obtained clinical information and DNA samples from the affected child and both parents if possible. We did whole-exome sequencing in affected individuals as they were enrolled, until we identified a candidate gene, and Sanger sequencing to confirm mutations. We did expression studies in human fibroblasts from one individual by real-time PCR and western blot analysis, and in mouse tissues by immunohistochemistry and real-time PCR. Findings: 26 families were included in the study. We did exome sequencing in the first 17 enrolled families; we screened for TBC1D24 by Sanger sequencing in subsequent families. We identified TBC1D24 mutations in 11 individuals from nine families (by exome sequencing in seven families, and Sanger sequencing in two families). 18 families had individuals with all five main features of DOORS syndrome, and TBC1D24 mutations were identified in half of these families. The seizure types in individuals with TBC1D24 mutations included generalised tonic-clonic, complex partial, focal clonic, and infantile spasms. Of the 18 individuals with DOORS syndrome from 17 families without TBC1D24 mutations, eight did not have seizures and three did not have deafness. In expression studies, some mutations abrogated TBC1D24 mRNA stability. We also detected Tbc1d24 expression in mouse phalangeal chondrocytes and calvaria, which suggests a role of TBC1D24 in skeletogenesis. Interpretation: Our findings suggest that mutations in TBC1D24 seem to be an important cause of DOORS syndrome and can cause diverse phenotypes. Thus, individuals with DOORS syndrome without deafness and seizures but with the other features should still be screened for TBC1D24 mutations. More information is needed to understand the cellular roles of TBC1D24 and identify the genes responsible for DOORS phenotypes in individuals who do not have a mutation in TBC1D24. Funding: US National Institutes of Health, the CIHR (Canada), the NIHR (UK), the Wellcome Trust, the Henry Smith Charity, and Action Medical Research.
AB - Background: Deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures (DOORS) syndrome is a rare autosomal recessive disorder of unknown cause. We aimed to identify the genetic basis of this syndrome by sequencing most coding exons in affected individuals. Methods: Through a search of available case studies and communication with collaborators, we identified families that included at least one individual with at least three of the five main features of the DOORS syndrome: deafness, onychodystrophy, osteodystrophy, intellectual disability, and seizures. Participants were recruited from 26 centres in 17 countries. Families described in this study were enrolled between Dec 1, 2010, and March 1, 2013. Collaborating physicians enrolling participants obtained clinical information and DNA samples from the affected child and both parents if possible. We did whole-exome sequencing in affected individuals as they were enrolled, until we identified a candidate gene, and Sanger sequencing to confirm mutations. We did expression studies in human fibroblasts from one individual by real-time PCR and western blot analysis, and in mouse tissues by immunohistochemistry and real-time PCR. Findings: 26 families were included in the study. We did exome sequencing in the first 17 enrolled families; we screened for TBC1D24 by Sanger sequencing in subsequent families. We identified TBC1D24 mutations in 11 individuals from nine families (by exome sequencing in seven families, and Sanger sequencing in two families). 18 families had individuals with all five main features of DOORS syndrome, and TBC1D24 mutations were identified in half of these families. The seizure types in individuals with TBC1D24 mutations included generalised tonic-clonic, complex partial, focal clonic, and infantile spasms. Of the 18 individuals with DOORS syndrome from 17 families without TBC1D24 mutations, eight did not have seizures and three did not have deafness. In expression studies, some mutations abrogated TBC1D24 mRNA stability. We also detected Tbc1d24 expression in mouse phalangeal chondrocytes and calvaria, which suggests a role of TBC1D24 in skeletogenesis. Interpretation: Our findings suggest that mutations in TBC1D24 seem to be an important cause of DOORS syndrome and can cause diverse phenotypes. Thus, individuals with DOORS syndrome without deafness and seizures but with the other features should still be screened for TBC1D24 mutations. More information is needed to understand the cellular roles of TBC1D24 and identify the genes responsible for DOORS phenotypes in individuals who do not have a mutation in TBC1D24. Funding: US National Institutes of Health, the CIHR (Canada), the NIHR (UK), the Wellcome Trust, the Henry Smith Charity, and Action Medical Research.
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U2 - 10.1016/S1474-4422(13)70265-5
DO - 10.1016/S1474-4422(13)70265-5
M3 - Article
C2 - 24291220
AN - SCOPUS:84892372632
SN - 1474-4422
VL - 13
SP - 44
EP - 58
JO - The Lancet Neurology
JF - The Lancet Neurology
IS - 1
ER -