Subjects

  • A Correction to this article was published on 14 January 2019

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.

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Change history

  • 14 January 2019

    The original version of this Article contained an error in the spelling of the author Siddharth Banka, which was incorrectly given as Siddhart Banka. This has now been corrected in both the PDF and HTML versions of the Article.

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Author information

Affiliations

  1. Division of Medical Genetics, Department of Specialized Medicine, McGill University Health Centre, Montreal, QC, Canada

    • Bettina E. Mucha MD
  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

    • Siddharth Banka MD
  3. Centre de Recherche du CHU Sainte-Justine, Montreal, QC, Canada

    • Norbert Fonya Ajeawung PhD
    •  & Sirinart Molidperee BA
  4. Department of Psychiatry, McGill University, Montreal, QC, Canada

    • Gary G. Chen PhD
    •  & Carl Ernst PhD
  5. Department of Pediatrics, Division of Child & Adolescent Neurology, The University of Texas McGovern Medical School, Houston, TX, USA

    • Mary Kay Koenig MD
    •  & Rhamat B. Adejumo MD
  6. Service de Génétique CHU de Lyon-GH Est, Lyon, France

    • Marianne Till MD
    •  & Damien Sanlaville MD
  7. Department of Pediatrics, Flinders Medical Centre, Bedford Park, SA, Australia

    • Michael Harbord MD
  8. Department of Medical Genetics, University of Calgary, Calgary, AB, Canada

    • Renee Perrier MD
    •  & Mary Ann Thomas MD
  9. Department of Pediatrics, Université de Montréal, Montreal, QC, Canada

    • Emmanuelle Lemyre MD
    •  & Philippe M. Campeau MD
  10. Department of Pediatrics, CHU Laval, Quebec City, QC, Canada

    • Renee-Myriam Boucher MD
  11. Division of Medical Genetics, Department of Pediatrics, Massachusetts General Hospital, Boston, MA, USA

    • Brian G. Skotko MD
    •  & Jessica L. Waxler MSc, CGC
  12. Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA

    • Jennelle C. Hodge PhD
  13. Adelaide Medical School and Robinson Research Institute, The University of Adelaide, Adelaide, Australia

    • Jozef Gecz MD
  14. South Australian Clinical Genetics Service, SA Pathology, Women’s and Children’s Hospital, Adelaide, Australia

    • Jillian Nicholl MD
    •  & Lesley McGregor MD
  15. Klinik für Neuropädiatrie und Stoffwechselerkrankungen, Zentrum für Kinder- und Jugendmedizin, Oldenburg, Germany

    • Tobias Linden MD
  16. Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, London, United Kingdom

    • Sanjay M. Sisodiya MD
  17. Chalfont Centre for Epilepsy, Bucks, United Kingdom

    • Sanjay M. Sisodiya MD
  18. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA

    • Sau W. Cheung PhD

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Disclosure

The authors declare no conflicts of interest.

Corresponding author

Correspondence to Philippe M. Campeau MD.

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DOI

https://doi.org/10.1038/s41436-018-0290-3