Bettina E Mucha1, Siddharth Banka2, Norbert Fonya Ajeawung3, Sirinart Molidperee3, Gary G Chen4, Mary Kay Koenig5, Rhamat B Adejumo5, Marianne Till6, Michael Harbord7, Renee Perrier8, Emmanuelle Lemyre9, Renee-Myriam Boucher10, Brian G Skotko11, Jessica L Waxler11, Mary Ann Thomas8, Jennelle C Hodge12, Jozef Gecz13, Jillian Nicholl14, Lesley McGregor14, Tobias Linden15, Sanjay M Sisodiya16,17, Damien Sanlaville6, Sau W Cheung18, Carl Ernst4, Philippe M Campeau19. 1. Division of Medical Genetics, Department of Specialized Medicine, McGill University Health Centre, Montreal, QC, Canada. 2. Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, M13 9PL, Manchester, UK. 3. Centre de Recherche du CHU Sainte-Justine, Montreal, QC, Canada. 4. Department of Psychiatry, McGill University, Montreal, QC, Canada. 5. Department of Pediatrics, Division of Child & Adolescent Neurology, The University of Texas McGovern Medical School, Houston, TX, USA. 6. Service de Génétique CHU de Lyon-GH Est, Lyon, France. 7. Department of Pediatrics, Flinders Medical Centre, Bedford Park, SA, Australia. 8. Department of Medical Genetics, University of Calgary, Calgary, AB, Canada. 9. Department of Pediatrics, Université de Montréal, Montreal, QC, Canada. 10. Department of Pediatrics, CHU Laval, Quebec City, QC, Canada. 11. Division of Medical Genetics, Department of Pediatrics, Massachusetts General Hospital, Boston, MA, USA. 12. Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA. 13. Adelaide Medical School and Robinson Research Institute, The University of Adelaide, Adelaide, Australia. 14. South Australian Clinical Genetics Service, SA Pathology, Women's and Children's Hospital, Adelaide, Australia. 15. Klinik für Neuropädiatrie und Stoffwechselerkrankungen, Zentrum für Kinder- und Jugendmedizin, Oldenburg, Germany. 16. Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, London, United Kingdom. 17. Chalfont Centre for Epilepsy, Bucks, United Kingdom. 18. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. 19. Department of Pediatrics, Université de Montréal, Montreal, QC, Canada. p.campeau@umontreal.ca.
Abstract
PURPOSE: Contiguous gene deletions are known to cause several neurodevelopmental syndromes, many of which are caused by recurrent events on chromosome 16. However, chromosomal microarray studies (CMA) still yield copy-number variants (CNVs) of unknown clinical significance. We sought to characterize eight individuals with overlapping 205-kb to 504-kb 16p13.3 microdeletions that are distinct from previously published deletion syndromes. METHODS: Clinical information on the patients and bioinformatic scores for the deleted genes were analyzed. RESULTS: All individuals in our cohort displayed developmental delay, intellectual disability, and various forms of seizures. Six individuals were microcephalic and two had strabismus. The deletion was absent in all 13 parents who were available for testing. The area of overlap encompasses seven genes including TBC1D24, ATP6V0C, and PDPK1 (also known as PDK1). Bi-allelic TBC1D24 pathogenic variants are known to cause nonsyndromic deafness, epileptic disorders, or DOORS syndrome (deafness, onychodystrophy, osteodystrophy, mental retardation, seizures). Sanger sequencing of the nondeleted TBC1D24 allele did not yield any additional pathogenic variants. CONCLUSIONS: We propose that 16p13.3 microdeletions resulting in simultaneous haploinsufficiencies of TBC1D24, ATP6V0C, and PDPK1 cause a novel rare contiguous gene deletion syndrome of microcephaly, developmental delay, intellectual disability, and epilepsy.
PURPOSE: Contiguous gene deletions are known to cause several neurodevelopmental syndromes, many of which are caused by recurrent events on chromosome 16. However, chromosomal microarray studies (CMA) still yield copy-number variants (CNVs) of unknown clinical significance. We sought to characterize eight individuals with overlapping 205-kb to 504-kb 16p13.3 microdeletions that are distinct from previously published deletion syndromes. METHODS: Clinical information on the patients and bioinformatic scores for the deleted genes were analyzed. RESULTS: All individuals in our cohort displayed developmental delay, intellectual disability, and various forms of seizures. Six individuals were microcephalic and two had strabismus. The deletion was absent in all 13 parents who were available for testing. The area of overlap encompasses seven genes including TBC1D24, ATP6V0C, and PDPK1 (also known as PDK1). Bi-allelic TBC1D24 pathogenic variants are known to cause nonsyndromic deafness, epileptic disorders, or DOORS syndrome (deafness, onychodystrophy, osteodystrophy, mental retardation, seizures). Sanger sequencing of the nondeleted TBC1D24 allele did not yield any additional pathogenic variants. CONCLUSIONS: We propose that 16p13.3 microdeletions resulting in simultaneous haploinsufficiencies of TBC1D24, ATP6V0C, and PDPK1 cause a novel rare contiguous gene deletion syndrome of microcephaly, developmental delay, intellectual disability, and epilepsy.
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Authors: Mattéa J Finelli; Davide Aprile; Enrico Castroflorio; Alexander Jeans; Matteo Moschetta; Lauren Chessum; Matteo T Degiacomi; Julia Grasegger; Alexis Lupien-Meilleur; Andrew Bassett; Elsa Rossignol; Philippe M Campeau; Michael R Bowl; Fabio Benfenati; Anna Fassio; Peter L Oliver Journal: Hum Mol Genet Date: 2019-02-15 Impact factor: 6.150