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Trio-based exome sequencing reveals a high rate of the de novo variants in intellectual disability

European Journal of Human Genetics (2022)Cite this article

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Abstract

Intellectual disability (ID), a neurodevelopmental disorder affecting 1–3% of the general population, is characterized by limitations in both intellectual function and adaptive skills. The high number of conditions associated with ID underlines its heterogeneous origin and reveals the difficulty of obtaining a rapid and accurate genetic diagnosis. However, the Next Generation Sequencing, and the whole exome sequencing (WES) in particular, has boosted the diagnosis rate associated with ID. In this study, WES performed on 244 trios of patients clinically diagnosed with isolated or syndromic ID and their respective unaffected parents has allowed the identification of the underlying genetic basis of ID in 64 patients, yielding a diagnosis rate of 25.2%. Our results suggest that trio-based WES facilitates ID’s genetic diagnosis, particularly in patients who have been extensively waiting for a definitive molecular diagnosis. Moreover, genotypic information from parents provided by trio-based WES enabled the detection of a high percentage (61.5%) of de novo variants inside our cohort. Establishing a quick genetic diagnosis of ID would allow early intervention and better clinical management, thus improving the quality of life of these patients and their families.

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Data availability

Identified variants have been deposited on the Leiden OpenVariation Database (LOVD, https://www.lovd.nl/). Complementary data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

We are sincerely grateful to patients and their families for participating in this study. This study has been funded by Instituto de Salud Carlos III through the project PI19/00809 (Co-funded by European Regional Development Fund/European Social Fund “A way to make Europe”/“Investing in your future”). We also acknowledge support from Fundación María José Jove.

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Authors and Affiliations

  1. Grupo de Medicina Xenómica, Universidade de Santiago de Compostela, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Santiago de Compostela, Spain

    Alejandro J. Brea-Fernández, Jorge Amigo, Francisco Barros & Ángel Carracedo

  2. Grupo de Medicina Xenómica, Fundación Instituto de Investigación Sanitaria de Santiago de Compostela (FIDIS), Universidade de Santiago de Compostela, Santiago de Compostela, Spain

    Miriam Álvarez-Barona, María Tubío-Fungueiriño, Francisco Barros & Ángel Carracedo

  3. Fundación Pública Galega de Medicina Xenómica (FPGMX), Santiago de Compostela, Spain

    Jorge Amigo, Pilar Caamaño, Francisco Barros & Ángel Carracedo

  4. Genomics and Bioinformatics Group, Center for Research in Molecular Medicine and Chronic Diseases (CiMUS), Universidade de Santiago de Compostela, Santiago de Compostela, Spain

    María Tubío-Fungueiriño & Ángel Carracedo

  5. Genetics Group, GC05, Instituto de Investigación Sanitaria de Santiago (IDIS), Santiago de Compostela, Spain

    Montserrat Fernández-Prieto

  6. Grupo de Medicina Xenómica, Center for Research in Molecular Medicine and Chronic Diseases (CiMUS), Universidade de Santiago de Compostela, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Santiago de Compostela, Spain

    Montserrat Fernández-Prieto

  7. Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Silvia De Rubeis & Joseph Buxbaum

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  1. Alejandro J. Brea-Fernández
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Contributions

AJBF and MAB should be considered joint first author. Study concept and design, AJBF, MAB, JB, AC; writing – original draft preparation, AJBF, MAB; writing – review and editing, JB, AC, AJBF, MAB; clinical diagnosis or clinical data gathering, MTF, MFP, PC; bioinformatic analysis, JA, AJBF, SDR; genetic data acquisition or analysis, AJBF, MAB, FB, SDR. All authors have approved the final version of the manuscript.

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Correspondence to Alejandro J. Brea-Fernández.

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The authors declare no competing interests.

Ethical approval

The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Institutional Review Board of the Research Ethics Committee of Galicia (Comité Ético de Investigación Galicia; the only IEC authorized in this autonomous region); Number: 2015/608; Approval: 18-November-2015; Title: DISECMAS: Bases genéticas de la discapacidad intelectual: aplicación de las nuevas tecnologías de secuenciación masiva al análisis de variantes genéticas. Informed consent was obtained from all participants included in the study.

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Brea-Fernández, A.J., Álvarez-Barona, M., Amigo, J. et al. Trio-based exome sequencing reveals a high rate of the de novo variants in intellectual disability. Eur J Hum Genet (2022). https://doi.org/10.1038/s41431-022-01087-w

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