DOORS syndrome and a recurrent truncating ATP6V1B2 variant.

Pernille Mathiesen Tørring, Philippe M Campeau, Raoul C M Hennekam, Sanjay M Sisodiya, Alexandre Dionne-Laporte, Juliet Taylor, Sirinart Molidperee, Yolande van Bever, Maria Vittoria Camurri, Marzena Wisniewska, Ed Blair, Eliane Beauregard-Lacroix, Lisbeth Tranebjærg, Claudia Castiglioni, Denes Zadori, Susan M White, Dina Vind-Kezunovic, Tabib Dabir, Klaus Dieterich, Jessica Tardif, Norbert F Ajeawung, Guillermo Pacheco-Cuellar

Journal: Genetics in medicine : official journal of the American College of Medical Genetics 2021;23(1):149-154

PMID: 32873933

Free Full Text on Elsevier Science View on PubMed

Abstract

PURPOSE

Biallelic variants in TBC1D24, which encodes a protein that regulates vesicular transport, are frequently identified in patients with DOORS (deafness, onychodystrophy, osteodystrophy, intellectual disability [previously referred to as mental retardation], and seizures) syndrome. The aim of the study was to identify a genetic cause in families with DOORS syndrome and without a TBC1D24 variant.

METHODS

Exome or Sanger sequencing was performed in individuals with a clinical diagnosis of DOORS syndrome without TBC1D24 variants.

RESULTS

We identified the same truncating variant in ATP6V1B2 (NM_001693.4:c.1516C>T; p.Arg506*) in nine individuals from eight unrelated families with DOORS syndrome. This variant was already reported in individuals with dominant deafness onychodystrophy (DDOD) syndrome. Deafness was present in all individuals, along with onychodystrophy and abnormal fingers and/or toes. All families but one had developmental delay or intellectual disability and five individuals had epilepsy. We also describe two additional families with DDOD syndrome in whom the same variant was found.

CONCLUSION

We expand the phenotype associated with ATP6V1B2 and propose another causal gene for DOORS syndrome. This finding suggests that DDOD and DOORS syndromes might lie on a spectrum of clinically and molecularly related conditions.

Address: Medical Genetics Division, Department of Pediatrics, Sainte-Justine University Hospital Center, Montreal, QC, Canada.; CHU Sainte Justine Research Center, Université de Montréal, Montreal, QC, Canada.; Univ. Grenoble Alpes, Inserm, U1216, CHU Grenoble Alpes, Grenoble Institut Neurosciences (GIN), Grenoble, France.; Department of Genetic Medicine, Belfast City Hospital, Belfast, Northern Ireland, UK.; Department of Dermatology, Copenhagen University Hospital Bispebjerg, Copenhagen, NV, Denmark.; Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, Australia.; Department of Neurology, Interdisciplinary Excellence Center, Faculty of Medicine, Albert Szent-Györgyi Clinical Center, University of Szeged, Szeged, Hungary.; Department of Pediatric Neurology, Clínica Las Condes, Santiago, Chile.; The Kennedy Center, Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.; Institute of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.; Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.; Oxford Regional Genetics Service, Oxford University Hospitals, Oxford, UK.; Department of Medical Genetics, Poznañ University of Medical Sciences, Poznañ, Poland.; Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.; Genetic Health Service New Zealand-Northern Hub, Auckland, New Zealand.; Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, Canada.; Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, UK.; Chalfont Centre for Epilepsy, Bucks, UK.; Department of Pediatrics, Amsterdam University Medical Center, Amsterdam, Netherlands.; Medical Genetics Division, Department of Pediatrics, Sainte-Justine University Hospital Center, Montreal, QC, Canada. [email protected].

DOI: 10.1038/s41436-020-00950-9

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MeSH Terms: Epilepsy, Exome, GTPase-Activating Proteins, Humans, Intellectual Disability, Nails, Malformed, Phenotype, Vacuolar Proton-Translocating ATPases