Genomic architecture of autism spectrum disorder in Qatar: The BARAKA-Qatar Study
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Date
2023-10-07Author
Abdi, MonaAliyev, Elbay
Trost, Brett
Kohailan, Muhammad
Aamer, Waleed
Syed, Najeeb
Shaath, Rulan
Gandhi, Geethanjali Devadoss
Engchuan, Worrawat
Howe, Jennifer
Thiruvahindrapuram, Bhooma
Geng, Melissa
Whitney, Joe
Syed, Amira
Lakshmi, Jyothi
Hussein, Sura
Albashir, Najwa
Hussein, Amal
Poggiolini, Ilaria
Elhag, Saba F.
Palaniswamy, Sasirekha
Kambouris, Marios
de Fatima Janjua, Maria
Tahir, Mohamed O.El
Nazeer, Ahsan
Shahwar, Durre
Azeem, Muhammad Waqar
Mokrab, Younes
Aati, Nazim Abdel
Akil, Ammira
Scherer, Stephen W.
Kamal, Madeeha
Fakhro, Khalid A.
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Background: Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by impaired social and communication skills, restricted interests, and repetitive behaviors. The prevalence of ASD among children in Qatar was recently estimated to be 1.1%, though the genetic architecture underlying ASD both in Qatar and the greater Middle East has been largely unexplored. Here, we describe the first genomic data release from the BARAKA-Qatar Study—a nationwide program building a broadly consented biorepository of individuals with ASD and their families available for sample and data sharing and multi-omics research. Methods: In this first release, we present a comprehensive analysis of whole-genome sequencing (WGS) data of the first 100 families (372 individuals), investigating the genetic architecture, including single-nucleotide variants (SNVs), copy number variants (CNVs), tandem repeat expansions (TREs), as well as mitochondrial DNA variants (mtDNA) segregating with ASD in local families. Results: Overall, we identify potentially pathogenic variants in known genes or regions in 27 out of 100 families (27%), of which 11 variants (40.7%) were classified as pathogenic or likely-pathogenic based on American College of Medical Genetics (ACMG) guidelines. Dominant variants, including de novo and inherited, contributed to 15 (55.6%) of these families, consisting of SNVs/indels (66.7%), CNVs (13.3%), TREs (13.3%), and mtDNA variants (6.7%). Moreover, homozygous variants were found in 7 families (25.9%), with a sixfold increase in homozygous burden in consanguineous versus non-consanguineous families (13.6% and 1.8%, respectively). Furthermore, 28 novel ASD candidate genes were identified in 20 families, 23 of which had recurrent hits in MSSNG and SSC cohorts. Conclusions: This study illustrates the value of ASD studies in under-represented populations and the importance of WGS as a comprehensive tool for establishing a molecular diagnosis for families with ASD. Moreover, it uncovers a significant role for recessive variation in ASD architecture in consanguineous settings and provides a unique resource of Middle Eastern genomes for future research to the global ASD community.
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