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

Researchers studied genetic testing in 137 Indian children with autism using advanced DNA analysis. They found genetic causes in 16% of children, with higher rates in children who had autism plus other medical features (35%) versus autism alone (8%). Most genetic changes were new (not inherited from parents). Having a genetic diagnosis helped families with family planning, monitoring health issues, and sometimes treatment options.

This prospective study evaluated trio exome sequencing (tES) in 137 Indian children with autism spectrum disorder, excluding those with known cytogenetic abnormalities or fragile X syndrome. The diagnostic yield for pathogenic/likely pathogenic variants was 16.1% (22/137 participants), with significantly higher rates in syndromic ASD (35%) compared to non-syndromic ASD (8.2%). Most variants (91.3%) were de novo mutations, and 52.2% were novel. Including variants of uncertain significance and autism candidate genes increased the yield to 37.9%.

Clinical benefits for those with definitive genetic diagnoses included improved prognostication (100%), reproductive counselling (100%), disease-specific surveillance (86.4%), and therapeutic implications (27.3%).

Trio exome sequencing shows clinical utility in ASD diagnosis, particularly for syndromic cases. Results support genetic testing protocols and highlight the importance of genetic counselling. Findings suggest genetic testing should be prioritized for children with syndromic features and can inform family planning and medical management decisions.

Single-centre study from India may limit generalizability to other populations. Study excluded children with known cytogenetic abnormalities and fragile X syndrome. Clinical impact assessment appears descriptive rather than systematically measured with validated tools.

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.