THE DIAGNOSTIC YIELD AND GENETIC CONTRIBUTION OF AUTISM SPECTRUM DISORDER CASES IN QATAR POPULATION

Abstract

Autism spectrum disorder (ASD) is a group of clinically and genetically diverse neurodevelopmental conditions. The genetics of ASD has been extensively studied, but the literature on ASD in Qatar is limited. Our study aims to gain new insight into the genetic basis of ASD in Qatar and the diagnostic yield of different genetic tests to improve local and international testing guidelines for ASD. We conducted a retrospective chart review of 301 pediatric cases of clinically confirmed ASD referred to the Medical Genetics department at Hamad Medical Corporation in Qatar between January 2017 and December 2019. This study revealed a male to female ratio of 3.6:1. The clinical presentations of individuals with ASD were classified into five groups: high-functioning ASD, non-verbal ASD, ASD with attention deficit hyperactivity disorder (ADHD), complex ASD, and ASD with developmental delay/intellectual disability (DD/ID). A total of 289 (96%) cases underwent chromosomal microarray analysis (CMA) and 276 (91.7%) cases had Fragile X syndrome (FXS) testing, both as first-tier tests, while only 137 (45.5%) cases had whole exome sequencing (WES) as a second-tier test. Overall, a genetic diagnosis was established in 16 (5.3%) patients with ASD: nine were diagnosed by WES (9/137; diagnostic yield = 6.6%), seven by CMA (7/289; diagnostic yield = 2.4%), and none by FXS testing (0/276; diagnostic yield = 0%). Considering nationality, Qatari patients more commonly underwent WES (p=<0.001), while non-Qatari patients more frequently had CMA (p=0.001), which is primarily explained by the inability of non-Qataris to afford WES. The ASD with DD/ID group had more positive results (p=0.003) by WES, and a higher overall diagnostic yield (p=0.0001) iv compared to other ASD groups. Our data provides evidence of a higher diagnostic yield for WES overall and specifically in cases of ASD with DD/ID compared to CMA, which supports the implementation of WES as a first-tier genetic test in such cases. Our data supports a modest role for CMA in the genetic diagnosis of ASD, thus it could still be offered, especially if WES is negative or not accessible to patients. Our data reveals no clinical utility for FXS testing in the absence of a specific clinical suspicion or family history of FXS. Finally, our findings highlight the diversity of the genetic architecture of ASD even in a highly consanguineous population.