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Prospective study to analyze the yield and clinical impact of trio exome sequencing in 137 Indian children with autism spectrum disorder

Journal of Human Genetics volume 70, pages 611–624 (2025)Cite this article

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Abstract

We aimed to study the diagnostic yield and clinical impact of trio exome sequencing (tES) in children with autism spectrum disorder (ASD). Participants (n = 137) between 2 and 18 years with syndromic and non-syndromic ASD underwent tES, after excluding karyotype-detectable cytogenetic abnormalities and fragile X syndrome. The diagnostic yield was 22/137 (16.1%) when considering only pathogenic (P) and likely-pathogenic (LP) variants in known disease-causing genes. We reported 23 significant (P, LP) variants in 22 individuals, with one participant (AGS041) harbouring a dual genetic diagnosis. Nearly half of these (12/23, 52.2%) were novel, while 21/23 (91.3%) occurred de novo. 20/23 (86.9%) of the variants were single nucleotide variants, while 3/23 (13.1%) were copy number variants. The diagnostic yield in syndromic ASD (14/40, 35%) was significantly higher than the non-syndromic group (8/97, 8.2%, p = 0.000258). Variants of uncertain significance in two participants were considered to be likely causative for the phenotype, given the strong clinical correlation (likely-causative variant of uncertain significance, LcVUS). On considering these two participants and an additional 28 participants with significant variants in autism candidate genes (vACG), the net diagnostic yield increased to 37.9%. The clinical benefits among those receiving a definite genetic diagnosis (P/LP variants only) included better prognostication (100%), availing reproductive counselling (100%), disease-specific surveillance (86.4%), and therapeutic implications (27.3%). Thus, in conclusion, in our cohort of 137 children with ASD, tES provided a definite genetic diagnosis in 16.1% of the participants, the yield being higher in syndromic ASD. A confirmed genetic diagnosis aided in holistic clinical care, extending beyond reproductive counselling.

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Data availability

The data that support the findings of this study is available on request from the corresponding author. The data is not publicly available due to privacy or ethical restrictions.

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Acknowledgements

We would like to thank Ms. Niharika Jadeja and Ms. Tasneem Shaikh for their technical support in drafting the manuscript. The study was supported by an academic grant from MedGenome Labs, Bangalore.

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Authors and Affiliations

  1. NH SRCC Children’s Hospital, Mumbai, India

    Shruti Bajaj, Shreya Gandhi, Anita Chitre, Nazema Sagi, Nisha Agrawal, Suhani Shah, Ruta Deo, Koyeli Sengupta, Puja Mehta, Vrajesh Udani, Pradnya Gadgil & Anaita Udwadia Hegde

  2. The Purple Gene Clinic, Mumbai, India

    Shruti Bajaj, Vishakha Mali & Ramprasad Vedam

  3. MedGenome Labs Limited, Bengaluru, India

    Thenral S. Geetha, Malini Venkata, Sudharshana Pai, Kripa Saira Jacob, Sakthivel Murugan, Ramesh Menon, Ravi Gupta, Jeevana Praharsha Athota, Vishakha Mali, Akshi Bassi & Sandeep Charugulla

  4. LifeCell International Pvt Limited, Chennai, India

    Nagaraja M. Phani

  5. PD Hinduja National Hospital and Medical Research Centre, Mumbai, India

    Vrajesh Udani

  6. Jaslok Hospital and Research Centre, Mumbai, India

    Anaita Udwadia Hegde

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  1. Shruti Bajaj
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Contributions

Shruti Bajaj: conceptualization, methodology, data analysis, data curation, clinical collaborator, drafting and critical review of the manuscript; Shreya Gandhi: data collection and analysis, drafting the manuscript; Thenral S. Geetha and Malini Venkata: conceptualization, methodology, data analysis, data curation, drafting and critical review of the manuscript; Anita Chitre: conceptualization, data curation, neuropsychological analysis of the participants, critical review of the manuscript; Nazema Sagi: project conceptualization, data curation, neuropsychological analysis of the participants, critical review of the manuscript; Nisha Agrawal: project conceptualization, data curation, neuropsychological analysis of the participants, critical review of the manuscript; Suhani Shah: data collection and analysis, drafting the manuscript; Ruta Deo: data collection and analysis, critical review of the manuscript; Sudharshana Pai, Kripa Saira Jacob, Sakthivel Murugan, Ramesh Menon, Ravi Gupta, Jeevana Praharsha Athota, Nagaraja M. Phani, Akshi Bassi, Sandeep Charugulla: data analysis, data curation, critical review of the manuscript; Vishakha Mali: data analysis, data curation, drafting the manuscript; Koyeli Sengupta, Puja Mehta, Vrajesh Udani, Pradnya Gadgil: clinical collaborator, data curation, critical review of the manuscript; Ramprasad Vedam: conceptualization, methodology, data analysis and curation, critical review of the manuscript; Anaita Udwadia Hegde: conceptualization, methodology, clinical collaborator, data analysis, drafting and critical review of the manuscript. All authors have contributed significantly to the preparation of this manuscript, have reviewed its contents, and have approved the final version for submission.

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Correspondence to Shruti Bajaj or Anaita Udwadia Hegde.

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The authors confirm that the ethical policies of the journal, as noted on the journal’s author guidelines page, have been adhered to. The study was approved by an ethics committee, study number: R-202112.

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Bajaj, S., Gandhi, S., Geetha, T.S. et al. Prospective study to analyze the yield and clinical impact of trio exome sequencing in 137 Indian children with autism spectrum disorder. J Hum Genet 70, 611–624 (2025). https://doi.org/10.1038/s10038-025-01368-4

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