The genetic landscape of autism spectrum disorder in an ancestrally diverse cohort

Ashlesha Gogate; Kiran Kaur; Raida Khalil; Mahmoud Bashtawi; Mary Ann Morris; Kimberly Goodspeed; Patricia Evans; Maria H Chahrour

doi:10.1038/s41525-024-00444-6

The genetic landscape of autism spectrum disorder in an ancestrally diverse cohort

NPJ Genom Med. 2024 Dec 4;9(1):62. doi: 10.1038/s41525-024-00444-6.

Authors

Ashlesha Gogate¹, Kiran Kaur¹, Raida Khalil², Mahmoud Bashtawi³, Mary Ann Morris⁴, Kimberly Goodspeed^{4

5

6

7}, Patricia Evans^{4

5

6

7}, Maria H Chahrour^{8

9

10

11

12}

Affiliations

¹ Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
² Department of Biotechnology and Genetic Engineering, Faculty of Science, University of Philadelphia, Amman, Jordan.
³ Department of Psychiatry, Jordan University of Science and Technology, King Abdullah University Hospital, Ramtha, Jordan.
⁴ UT Southwestern and Children's Health Center for Autism Care, Children's Medical Center Dallas, Dallas, TX, 75247, USA.
⁵ Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
⁶ Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
⁷ Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
⁸ Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA. [email protected].
⁹ Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA. [email protected].
¹⁰ Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA. [email protected].
¹¹ Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA. [email protected].
¹² Peter O'Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA. [email protected].

Abstract

Autism spectrum disorder (ASD) comprises neurodevelopmental disorders with wide variability in genetic causes and phenotypes, making it challenging to pinpoint causal genes. We performed whole exome sequencing on a modest, ancestrally diverse cohort of 195 families, including 754 individuals (222 with ASD), and identified 38,834 novel private variants. In 68 individuals with ASD (~30%), we identified 92 potentially pathogenic variants in 73 known genes, including BCORL1, CDKL5, CHAMP1, KAT6A, MECP2, and SETD1B. Additionally, we identified 158 potentially pathogenic variants in 120 candidate genes, including DLG3, GABRQ, KALRN, KCTD16, and SLC8A3. We also found 34 copy number variants in 31 individuals overlapping known ASD loci. Our work expands the catalog of ASD genetics by identifying hundreds of variants across diverse ancestral backgrounds, highlighting convergence on nervous system development and signal transduction. These findings provide insights into the genetic underpinnings of ASD and inform molecular diagnosis and potential therapeutic targets.