Genomic architecture of autism spectrum disorder in Qatar: The BARAKA-Qatar Study

Abstract

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.

Reanalysis of Trio Whole-Genome Sequencing Data Doubles the Yield in Autism Spectrum Disorder: De Novo Variants Present in Half

“…While that requirement could and often was met by sporadic disease in the proband for cases with recessive disease, disease manifestation in a relative(s) was required for dominant and maternal inheritance patterns. Overall, our finding that 20% of ASD cases can be assigned to a known inherited condition is in line with previous reports in ASD [27,[29][30][31][32]. In particular, the three WGS studies [30][31][32] assigned causality to inherited variants in 32%, 27%, and 31% of their subjects, combining the data that is 21% (50/233 subjects), a figure virtually identical to our data.…”

“…Overall, our finding that 20% of ASD cases can be assigned to a known inherited condition is in line with previous reports in ASD [27,[29][30][31][32]. In particular, the three WGS studies [30][31][32] assigned causality to inherited variants in 32%, 27%, and 31% of their subjects, combining the data that is 21% (50/233 subjects), a figure virtually identical to our data.…”

“…Our finding of a de novo PDV variant in 25 subjects, fully in 50% of our cases, is substantially higher than that previously reported in studies on ASD (Table 4, combining the prior three WGS reports [30][31][32], p < 0.0001 compared to our data). 1 De novo yield indicates the percentage of subjects with at least one de novo variant thought by the authors to be likely to be disease related.…”

“…WGS holds the potential to extend rare-variant discovery to the ~99% of the genome that is noncoding, leading to the potential use of genetics in personalized diagnostics and treatment. Three WGS studies in ASD had yields between 33 and 50% [30][31][32].…”

The genetic landscape of autism spectrum disorder in the Middle Eastern population

“…Furthermore, we crossed our findings with the most recent study from the region that shared a similar scope to our project ( Abdi et al, 2023 ). Regarding the patient background, our cohort had a broader representation of the Middle East and North Africa, with ∼89% versus approximately 50% of Arab in Abdi et al study.…”