The genetic basis of DOORS syndrome: an exome-sequencing study.

TitleThe genetic basis of DOORS syndrome: an exome-sequencing study.
Publication TypeJournal Article
Year of Publication2014
AuthorsCampeau, PM, Kasperaviciute, D, Lu, JT, Burrage, LC, Kim, C, Hori, M, Powell, BR, Stewart, F, Félix, TMaria, van den Ende, J, Wisniewska, M, Kayserili, H, Rump, P, Nampoothiri, S, Aftimos, S, Mey, A, Nair, LDV, Begleiter, ML, De Bie, I, Meenakshi, G, Murray, ML, Repetto, GM, Golabi, M, Blair, E, Male, A, Giuliano, F, Kariminejad, A, Newman, WG, Bhaskar, SS, Dickerson, JE, Kerr, B, Banka, S, Giltay, JC, Wieczorek, D, Tostevin, A, Wiszniewska, J, Cheung, SWai, Hennekam, RC, Gibbs, RA, Lee, BH, Sisodiya, SM
JournalLancet Neurol
Date Published2014 Jan
KeywordsAdolescent, Carrier Proteins, Child, Child, Preschool, Craniofacial Abnormalities, Exome, Female, Hand Deformities, Congenital, Hearing Loss, Sensorineural, Humans, Infant, Intellectual Disability, Internationality, Male, Nails, Malformed, Phenotype, Sequence Analysis, DNA, Young Adult

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.

Alternate JournalLancet Neurol
PubMed ID24291220
PubMed Central IDPMC3895324
Grant ListU54 HG003273-09 / HG / NHGRI NIH HHS / United States
P01 HD22657 / HD / NICHD NIH HHS / United States
U54 HG006542 / HG / NHGRI NIH HHS / United States
T32 GM007526 / GM / NIGMS NIH HHS / United States
P01 HD022657 / HD / NICHD NIH HHS / United States
HD024064 / HD / NICHD NIH HHS / United States
U54 HG003273 / HG / NHGRI NIH HHS / United States
P30 HD024064 / HD / NICHD NIH HHS / United States
F30 MH098571-01 / MH / NIMH NIH HHS / United States
/ / Canadian Institutes of Health Research / Canada
T32 GM07526 / GM / NIGMS NIH HHS / United States
F30 MH098571 / MH / NIMH NIH HHS / United States
/ / Wellcome Trust / United Kingdom