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Three generation families: Analysis of de novo variants in autism

European Journal of Human Genetics volume 31, pages 1017–1022 (2023)Cite this article

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Abstract

De novo variants (DNVs) analysis has proven to be a powerful approach to gene discovery in Autism Spectrum Disorder (ASD), which has not yet been shown in a Brazilian ASD cohort. The relevance of inherited rare variants has also been suggested, particularly in oligogenic models. We hypothesized that three-generation analyses of DNVs could provide new insights into the relevance of de novo and inherited variants across generations. To accomplish this goal, we performed whole-exome sequencing of 33 septet families composed of probands, parents, and grandparents (n = 231 individuals) and compared DNV rates (DNVr) between generations and those from two control cohorts. The DNVr in the probands (DNVr = 1.16) was marginally higher than in parents (DNVr = 0.60; p = 0.054), and in controls (DNVr = 0.68; p = 0.035, congenital heart disorder and DNVr = 0.70; p = 0.047, unaffected ASD siblings from Simons Simplex Collection). Moreover, most of the DNVs were found to have paternal origin in both generations (84.6%). Finally, we observed that 40% (6/15) of the DNVs in parents transmitted for probands are in ASD or ASD candidate genes, representing recently emerged risk variants to ASD in their families and suggest ZNF536, MSL2 and HDAC9 as ASD candidate genes. We did not observe an enrichment of risk variants nor sex bias of transmitted variants in the three generations, that can be due to sample size. These results further reinforce the relevance of de novo variants in ASD.

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Fig. 1: Poisson regression analysis.

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Data availability

Data generated as part of this study are available from the corresponding author on reasonable request. All de novo variants described in this work were submitted to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/), accession numbers SCV003914734 - SCV003914804.

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Acknowledgements

The authors thank the ASD families that participated and the researchers that contributed indirectly to this study: Ana Cristina de Sanctis Girardi, Susan Walker and Giovanna Pellachia. We also thank Dr. André Fujita for support in statistical analysis. We wish to acknowledge support and resources of MSSNG (https://research.mss.ng), Autism Speaks, and The Centre for Applied Genomics, at The Hospital for Sick Children, Toronto, Canada. We also appreciate the contributions of Wilson WL Sung and Darwin D’Souza.

Funding

This work was supported by grants from the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP, CEGH-CEL/CEPID process 2013/08028-1, Ph.D. scholarship process 2017/05824-2 and 2018/13743-5), and by the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, process 466651/2014-7).

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Author notes

  1. These authors contributed equally: Claudia I. Samogy Costa, Gabriele da Silva Campos, Eduarda Morgana da Silva Montenegro.

Authors and Affiliations

  1. Departamento de Genética e Biologia Evolutiva, Centro de Estudos do Genoma Humano e Células-tronco, Instituto de Biociências, Universidade de São Paulo, São Paulo, SP, Brasil

    Claudia I. Samogy Costa, Gabriele da Silva Campos, Eduarda Morgana da Silva Montenegro, Jaqueline Yu Ting Wang, Marília Scliar, Frederico Monfardini, Elaine Cristina Zachi, Naila C. V. Lourenço & Maria Rita Passos-Bueno

  2. The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada

    Ada J. S. Chan, Sergio L. Pereira, Worrawat Engchuan, Bhooma Thiruvahindrapuram, Mehdi Zarrei & Stephen W. Scherer

  3. Department of Molecular Genetics and McLaughlin Centre, University of Toronto, Toronto, ON, Canada

    Stephen W. Scherer

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  1. Claudia I. Samogy Costa
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Contributions

EMSM and MRPB designed the study. EMSM, GSC, and CISC performed data collection, analysis and helped write the manuscript. SWS conceived and designed MSSNG project and revised the manuscript. FM performed statistical analysis. MS helped with DeNovoGear pipeline and analysis for de novo variants identification. JYTW helped with data annotation and inherited risk variants analysis. AJSC, SLP, WE, BT, and MZ helped perform different components of analysis and data interpretations. MZ revised the manuscript. ECZ contributed to clinical evaluation. NCVL helped with data collection and additional genetic tests of the probands. All authors contributed to data discussion and interpretation of the results.

Corresponding author

Correspondence to Maria Rita Passos-Bueno.

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Competing interests

SWS is on the Scientific Advisory Committee of Population Bio, and serves as a Highly Cited Academic Advisor for the King Abdulaziz University. The remaining authors declare no conflicts of interest.

Ethics approval and consent to participate

The ethics committee of the Instituto de Biociências at Universidade de São Paulo approved the project (accession number 1.133.486), and all the research participants signed a consent term, with written informed consent for publication of individual details obtained.

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Costa, C.I.S., da Silva Campos, G., da Silva Montenegro, E.M. et al. Three generation families: Analysis of de novo variants in autism. Eur J Hum Genet 31, 1017–1022 (2023). https://doi.org/10.1038/s41431-023-01398-6

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