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Mechanistic insights into 16p13.3 microdeletions encompassing TBC1D24 and ATP6V0C through advanced sequencing approaches

European Journal of Human Genetics volume 33, pages 1136–1143 (2025)Cite this article

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Abstract

Chromosomal microdeletions represent a complex class of genetic disorders. Recently, 16p13.3 microdeletions encompassing TBC1D24 and ATP6V0C have gained prominence as structural variants associated with neurodevelopmental disorders, but their occurrence mechanisms remain unexplored. We used a comprehensive range of sequencing technologies (mate pair genome sequencing, linked-pair genome sequencing, nanopore sequencing, targeted locus amplification (TLA), long range and nested PCR followed by Sanger sequencing), to map the exact 16p13.3 microdeletion breakpoints in eight previously reported individuals. Microdeletion breakpoints were successfully mapped in all patients using TLA, split read analysis, PCR/Sanger sequencing, or nanopore sequencing. Alu sequences and/or non-B DNA motifs were detected in all patients. Mechanistic analysis identified distinct pathways underlying these rearrangements. Noteworthy, two unrelated individuals carried identical microdeletions that might have been mediated by an atypical form of non-allelic homologous recombination, given the presence of a 639 bp sequence with 96.2% homology. Microhomology-mediated end-joining and non-homologous end-joining emerged as other mechanisms driving these 16p13.3 microdeletions, which differs from other studied contiguous gene deletion syndromes. This research contributes to a deeper understanding of microdeletion-associated disorder pathophysiology in medical genetics.

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Fig. 1: Analysis conducted for each patient to delineate the breakpoints of each microdeletion.
Fig. 2: Representation of 16p13.3 microdeletions suggested occurrence mechanisms and corresponding chromatograms when available or relevant.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

We thank the patients and their families for taking part in the study. We also thank the physicians who contributed to our initial microdeletion study.

Funding

This work was supported by Canadian Institutes of Health Research (CIHR) grant 137093.

Author information

Author notes

  1. These authors contributed equally: Benoit Mazel, Emilia Aisha Coleman.

Authors and Affiliations

  1. Centre de Recherche Azrieli du CHU Sainte-Justine, Université de Montréal, Montréal, QC, Canada

    Benoit Mazel, Emilia Aisha Coleman, Justine Rousseau, Norbert Fonya Ajeawung & Philippe M. Campeau

  2. Centre de Référence Anomalies du Développement et Syndromes Malformatifs et Centre de Référence Déficiences Intellectuelles de Causes Rares, FHU TRANSLAD, CHU Dijon Bourgogne, Dijon, France

    Benoit Mazel

  3. Canadian Center for Computational Genomics, Montréal, QC, Canada

    Senthilkumar Kailasam

  4. Department of Human Genetics, McGill University, Montréal, QC, Canada

    Senthilkumar Kailasam & Carl Ernst

  5. Victor Phillip Dahdaleh Institute of Genomic Medicine, McGill University, Montréal, QC, Canada

    Senthilkumar Kailasam

  6. Bioinformatics Platform, Research Institute of the McGill University Health Centre, Montréal, QC, Canada

    Daniel Alexander Jimenez Cruz

  7. Molecular Biology Program, Université de Montréal, Montréal, QC, Canada

    Sophie Ehresmann

  8. Psychiatric Genetics Group, Douglas Hospital Research Institute, McGill University, Montreal, QC, Canada

    Gang Chen & Carl Ernst

  9. Montreal Neurological Institute, McGill University, Montréal, QC, Canada

    Carl Ernst

  10. Department of Pediatrics, Centre Hospitalier Universitaire Sainte-Justine and Université de Montréal, Montreal, QC, Canada

    Philippe M. Campeau

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Contributions

BM and EAC wrote the manuscript and were responsible for data collection and interpretation. EAC, SK, NFA, DAJC, SE, GC and CE contributed to the data collection and data interpretation. BM, PMC and JR contributed to the data collection, data interpretation, writing, review, and editing of the manuscript. All authors reviewed and approved the latest version of the manuscript.

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Correspondence to Philippe M. Campeau.

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This study was approved by an institutional review board and adheres to the tenets of the Declaration of Helsinki. Written informed consent was obtained from all individuals before participation in the study.

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Mazel, B., Coleman, E.A., Rousseau, J. et al. Mechanistic insights into 16p13.3 microdeletions encompassing TBC1D24 and ATP6V0C through advanced sequencing approaches. Eur J Hum Genet 33, 1136–1143 (2025). https://doi.org/10.1038/s41431-025-01912-y

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