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Burden re-analysis of neurodevelopmental disorder cohorts for prioritization of candidate genes

European Journal of Human Genetics (2024)Cite this article

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Abstract

This study aimed to uncover novel genes associated with neurodevelopmental disorders (NDD) by leveraging recent large-scale de novo burden analysis studies to enhance a virtual gene panel used in a diagnostic setting. We re-analyzed historical trio-exome sequencing data from 745 individuals with NDD according to the most recent diagnostic standards, resulting in a cohort of 567 unsolved individuals. Next, we designed a virtual gene panel containing candidate genes from three large de novo burden analysis studies in NDD and prioritized candidate genes by stringent filtering for ultra-rare de novo variants with high pathogenicity scores. Our analysis revealed an increased burden of de novo variants in our selected candidate genes within the unsolved NDD cohort and identified qualifying de novo variants in seven candidate genes: RIF1, CAMK2D, RAB11FIP4, AGO3, PCBP2, LEO1, and VCP. Clinical data were collected from six new individuals with de novo or inherited LEO1 variants and three new individuals with de novo PCBP2 variants. Our findings add additional evidence for LEO1 as a risk gene for autism and intellectual disability. Furthermore, we prioritize PCBP2 as a candidate gene for NDD associated with motor and language delay. In summary, by leveraging de novo burden analysis studies, employing a stringent variant filtering pipeline, and engaging in targeted patient recruitment, our study contributes to the identification of novel genes implicated in NDDs.

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Fig. 1: Diagnostic process overview and candidate gene assembly.
Fig. 2: LEO1 variants reported in patients with ASD/ID.

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Data availability

The authors declare that the data supporting the findings of this study are available within the article and its��Supplementary Information. Raw sequencing data are available from the corresponding author on reasonable request if in line with the provided consent of the families.

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Funding

NS received funding from UA-Bijzonder Onderzoeksfonds (BOF)-DOCPRO4 (FFB180186). FM received funding from the H2020-Twinning SEED project. SW received funding from Fonds Wetenchappelijk Onderzoek (FWO: 1861419 N, 1861424 N, and G056122N). Research reported in this publication was supported by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health under Award Number U01HG007709. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Author information

Author notes

  1. These authors contributed equally: Noor Smal, Fatma Majdoub.

  2. These authors jointly supervised this work: R. Frank Kooy, Sarah Weckhuysen.

Authors and Affiliations

  1. Applied and Translational Neurogenomics Group, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium

    Noor Smal, Fatma Majdoub & Sarah Weckhuysen

  2. Applied and Translational Neurogenomics Group, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium

    Noor Smal & Fatma Majdoub

  3. Medical Genetics Department, University Hedi Chaker Hospital of Sfax, University of Sfax, Sfax, Tunisia

    Fatma Majdoub

  4. Department of Medical Genetics, University of Antwerp, Antwerp, Belgium

    Katrien Janssens, Edwin Reyniers, Marije E. C. Meuwissen & R. Frank Kooy

  5. Center of Medical Genetics, University Hospital Antwerp, Drie Eikenstraat 655, Edegem, 2650, Belgium

    Katrien Janssens, Edwin Reyniers & Marije E. C. Meuwissen

  6. Translational Neurosciences, Faculty of Medicine and Health Science, University of Antwerp, Antwerp, Belgium

    Berten Ceulemans & Sarah Weckhuysen

  7. Department of Pediatric Neurology, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium

    Berten Ceulemans

  8. Department of Pediatrics, McGovern Medical School at the University of Texas Health Science Center at Houston (UTHealth) and Children’s Memorial Hermann Hospital, Houston, TX, USA

    Hope Northrup, Jeremy B. Hill & Lingying Liu

  9. Department of Molecular Medicine, University of Pavia, Pavia, Italy

    Edoardo Errichiello

  10. Neurogenetics Research Center, IRCCS Mondino Foundation, Pavia, Italy

    Edoardo Errichiello & Simone Gana

  11. Division of Human Genetics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Alanna Strong

  12. Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA

    Alanna Strong

  13. Division of Medical Genetics, Department of Pediatrics, San Antonio Military Medical Center, San Antonio, TX, USA

    Luis Rohena

  14. Department of Pediatrics, Long School of Medicine-UT Health San Antonio, San Antonio, TX, USA

    Luis Rohena

  15. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA

    Rachel Franciskovich, Chaya N. Murali, Jill A. Rosenfeld, Seema R. Lalani & Haley Streff

  16. Texas Children’s Hospital, Houston, TX, USA

    Rachel Franciskovich, Chaya N. Murali, Seema R. Lalani & Haley Streff

  17. Department of Pediatrics, Heilig Hart Ziekenhuis, Lier, Belgium

    An Huybrechs

  18. deCODE genetics/Amgen Inc., Reykjavik, Iceland

    Telma Sulem, Run Fridriksdottir, Patrick Sulem & Kari Stefansson

  19. GeneDx, Gaithersburg, MD, USA

    Yan Bai

  20. Department of Neurology, University Hospital Antwerp, Antwerp, Belgium

    Sarah Weckhuysen

  21. µNEURO Research Centre of Excellence, University of Antwerp, Antwerp, Belgium

    Sarah Weckhuysen

Authors
  1. Noor Smal
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  2. Fatma Majdoub
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  3. Katrien Janssens
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  4. Edwin Reyniers
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Consortia

Undiagnosed Diseases Network

  • Jill A. Rosenfeld
  •  & Seema R. Lalani

Contributions

Conceptualization: NS, FM, RFK, SW; data curation: NS, FM, HN, JBH, LL, EE, SG, AS, LR, RF, CNM, AH, TS, RF, PS, KS, JAR, SRL, HS; formal analysis: NS, FM; supervision: RFK, SW; writing – original draft: NS, FM; writing – review & editing: NS, FM, KJ, ER, MECM, BC, HN, JBH, LL, EE, SG, AS, LR, RF, CNM, AH, TS, RF, PS, KS, YB, JAR, SRL, HS, RFK, SW.

Corresponding author

Correspondence to Sarah Weckhuysen.

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Competing interests

YB is an employee of GeneDx, LLC. The Department of Molecular and Human Genetics at Baylor College of Medicine receives revenue from clinical genetic testing completed at Baylor Genetics Laboratories. All other authors declare no conflict of interest.

Ethics approval and consent to participate

This study was conducted with approval from the Ethical Committee of the University of Antwerp. All institutions involved in human participant research received local IRB approval. All families or legal guardians of recruited participants provided informed consent for this study. Participant data were de-identified.

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Smal, N., Majdoub, F., Janssens, K. et al. Burden re-analysis of neurodevelopmental disorder cohorts for prioritization of candidate genes. Eur J Hum Genet (2024). https://doi.org/10.1038/s41431-024-01661-4

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