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<p>We aimed to study the diagnostic yield and clinical impact of trio exome sequencing (tES) in children with autism spectrum disorder (ASD). Participants (<i>n</i> = 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&#xa0;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%, <i>p</i> = 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.</p>

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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

  • 期刊论文

  • 发表日期：

    2025年8月21日

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  • Shruti Bajaj,
  • Shreya Gandhi,
  • Thenral S. Geetha,
  • Malini Venkata,
  • Anita Chitre,
  • Nazema Sagi,
  • Nisha Agrawal,
  • Suhani Shah,
  • Ruta Deo,
  • Sudharshana Pai,
  • Kripa Saira Jacob,
  • Sakthivel Murugan,
  • Ramesh Menon,
  • Ravi Gupta,
  • Jeevana Praharsha Athota,
  • Vishakha Mali,
  • Nagaraja M. Phani,
  • Koyeli Sengupta,
  • Puja Mehta,
  • Vrajesh Udani,
  • Akshi Bassi,
  • Sandeep Charugulla,
  • Pradnya Gadgil,
  • Ramprasad Vedam,
  • Anaita Udwadia Hegde

摘要

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.