Autism spectrum disorder (ASD) is caused by combined genetic and environmental factors. Genetic heritability in ASD is estimated as 60–90%, and genetic investigations have revealed many monogenic factors. We analyzed 405 patients with ASD using family-based exome sequencing to detect disease-causing single-nucleotide variants (SNVs), small insertions and deletions (indels), and copy number variations (CNVs) for molecular diagnoses. All candidate variants were validated by Sanger sequencing or quantitative polymerase chain reaction and were evaluated using the American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines for molecular diagnosis. We identified 55 disease-causing SNVs/indels in 53 affected individuals and 13 disease-causing CNVs in 13 affected individuals, achieving a molecular diagnosis in 66 of 405 affected individuals (16.3%). Among the 55 disease-causing SNVs/indels, 51 occurred de novo, 2 were compound heterozygous (in one patient), and 2 were X-linked hemizygous variants inherited from unaffected mothers. The molecular diagnosis rate in females was significantly higher than that in males. We analyzed affected sibling cases of 24 quads and 2 quintets, but only one pair of siblings shared an identical pathogenic variant. Notably, there was a higher molecular diagnostic rate in simplex cases than in multiplex families. Our simulation indicated that the diagnostic yield is increasing by 0.63% (range 0–2.5%) per year. Based on our simple simulation, diagnostic yield is improving over time. Thus, periodical reevaluation of ES data should be strongly encouraged in undiagnosed ASD patients.
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The datasets generated and/or analyzed during the current study are not publicly available due to privacy or ethical restrictions but are available from the corresponding author on reasonable request.
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We thank the affected individuals and their families for participating in this study. We also thank Ms. Sayaka Sugimoto and Ms. Kaori Takabe from Yokohama City University Graduate School of Medicine for their technical assistance. This study makes use of data generated by the DECIPHER community. A full list of centers that contributed to the generation of the data is available from https://deciphergenomics.org/about/stats and via e-mail from firstname.lastname@example.org. Funding for the DECIPHER project was provided by Wellcome. Finally, we thank Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.
This work was supported by AMED under grant numbers JP22ek0109486, JP22ek0109549, JP22ek0109493 (NMa), JP21wm0425007, and JP21dk0307103 (NO); JSPS KAKENHI under grant numbers JP19H03621 and 22H03047 (NMi), the Takeda Science Foundation (TM and NMa), and the NCGM Intramural Research Fund under grant number 21A1011 (NMi).
The authors declare no competing interests.
This study was approved by the Institutional Review Board of Yokohama City University Faculty of Medicine. After obtaining written informed consent, peripheral blood leukocytes were collected from the patients and their parents.
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Miyake, N., Tsurusaki, Y., Fukai, R. et al. Molecular diagnosis of 405 individuals with autism spectrum disorder. Eur J Hum Genet (2023). https://doi.org/10.1038/s41431-023-01335-7