The genetic basis of DOORS syndrome: An exome-sequencing study

Philippe M. Campeau, Dalia Kasperaviciute, James T. Lu, Lindsay C. Burrage, Choel Kim, Mutsuki Hori, Berkley R. Powell, Fiona Stewart, Têmis Maria Félix, Jenneke van den Ende, Marzena Wisniewska, Hülya Kayserili, Patrick Rump, Sheela Nampoothiri, Salim Aftimos, Antje Mey, Lal D.V. Nair, Michael L. Begleiter, Isabelle De Bie, Girish MeenakshiMitzi L. Murray, Gabriela M. Repetto, Mahin Golabi, Edward Blair, Alison Male, Fabienne Giuliano, Ariana Kariminejad, William G. Newman, Sanjeev S. Bhaskar, Jonathan E. Dickerson, Bronwyn Kerr, Siddharth Banka, Jacques C. Giltay, Dagmar Wieczorek, Anna Tostevin, Joanna Wiszniewska, Sau Wai Cheung, Raoul C. Hennekam, Richard A. Gibbs, Brendan H. Lee, Sanjay M. Sisodiya

Research output: Contribution to journalArticle

68 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)44-58
Number of pages15
JournalThe Lancet Neurology
Volume13
Issue number1
DOIs
StatePublished - Jan 1 2014
Externally publishedYes

Fingerprint

Exome
Seizures
Mutation
Deafness
Intellectual Disability
Real-Time Polymerase Chain Reaction
Digitorenocerebral Syndrome
Phenotype
Charities
Infantile Spasms
Health Services Research
RNA Stability
National Institutes of Health (U.S.)
Chondrocytes
Skull
Genes
Canada
Biomedical Research
Exons
Fibroblasts

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Campeau, P. M., Kasperaviciute, D., Lu, J. T., Burrage, L. C., Kim, C., Hori, M., ... Sisodiya, S. M. (2014). The genetic basis of DOORS syndrome: An exome-sequencing study. The Lancet Neurology, 13(1), 44-58. https://doi.org/10.1016/S1474-4422(13)70265-5

The genetic basis of DOORS syndrome : An exome-sequencing study. / Campeau, Philippe M.; Kasperaviciute, Dalia; Lu, James T.; Burrage, Lindsay C.; Kim, Choel; Hori, Mutsuki; Powell, Berkley R.; Stewart, Fiona; Félix, Têmis Maria; van den Ende, Jenneke; Wisniewska, Marzena; Kayserili, Hülya; Rump, Patrick; Nampoothiri, Sheela; Aftimos, Salim; Mey, Antje; Nair, Lal D.V.; Begleiter, Michael L.; De Bie, Isabelle; Meenakshi, Girish; Murray, Mitzi L.; Repetto, Gabriela M.; Golabi, Mahin; Blair, Edward; Male, Alison; Giuliano, Fabienne; Kariminejad, Ariana; Newman, William G.; Bhaskar, Sanjeev S.; Dickerson, Jonathan E.; Kerr, Bronwyn; Banka, Siddharth; Giltay, Jacques C.; Wieczorek, Dagmar; Tostevin, Anna; Wiszniewska, Joanna; Cheung, Sau Wai; Hennekam, Raoul C.; Gibbs, Richard A.; Lee, Brendan H.; Sisodiya, Sanjay M.

In: The Lancet Neurology, Vol. 13, No. 1, 01.01.2014, p. 44-58.

Research output: Contribution to journalArticle

Campeau, PM, Kasperaviciute, D, Lu, JT, Burrage, LC, Kim, C, Hori, M, Powell, BR, Stewart, F, Félix, TM, 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, SW, Hennekam, RC, Gibbs, RA, Lee, BH & Sisodiya, SM 2014, 'The genetic basis of DOORS syndrome: An exome-sequencing study', The Lancet Neurology, vol. 13, no. 1, pp. 44-58. https://doi.org/10.1016/S1474-4422(13)70265-5
Campeau PM, Kasperaviciute D, Lu JT, Burrage LC, Kim C, Hori M et al. The genetic basis of DOORS syndrome: An exome-sequencing study. The Lancet Neurology. 2014 Jan 1;13(1):44-58. https://doi.org/10.1016/S1474-4422(13)70265-5
Campeau, Philippe M. ; Kasperaviciute, Dalia ; Lu, James T. ; Burrage, Lindsay C. ; Kim, Choel ; Hori, Mutsuki ; Powell, Berkley R. ; Stewart, Fiona ; Félix, Têmis Maria ; van den Ende, Jenneke ; Wisniewska, Marzena ; Kayserili, Hülya ; Rump, Patrick ; Nampoothiri, Sheela ; Aftimos, Salim ; Mey, Antje ; Nair, Lal D.V. ; Begleiter, Michael L. ; De Bie, Isabelle ; Meenakshi, Girish ; Murray, Mitzi L. ; Repetto, Gabriela M. ; Golabi, Mahin ; Blair, Edward ; Male, Alison ; Giuliano, Fabienne ; Kariminejad, Ariana ; Newman, William G. ; Bhaskar, Sanjeev S. ; Dickerson, Jonathan E. ; Kerr, Bronwyn ; Banka, Siddharth ; Giltay, Jacques C. ; Wieczorek, Dagmar ; Tostevin, Anna ; Wiszniewska, Joanna ; Cheung, Sau Wai ; Hennekam, Raoul C. ; Gibbs, Richard A. ; Lee, Brendan H. ; Sisodiya, Sanjay M. / The genetic basis of DOORS syndrome : An exome-sequencing study. In: The Lancet Neurology. 2014 ; Vol. 13, No. 1. pp. 44-58.
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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.

PY - 2014/1/1

Y1 - 2014/1/1

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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