Combining chromosomal microarray and clinical exome sequencing for genetic diagnosis of intellectual disability

Abstract

Despite the current widespread use of chromosomal microarray analysis (CMA) and exome/genome sequencing for the genetic diagnosis of unexplained intellectual disability (ID) in children, gaining improved diagnostic yields and defined guidelines remains a significant challenge. This is a cohort study of children with unexplained ID. We analyzed the diagnostic yield and its correlation to clinical phenotypes in children with ID who underwent concurrent CMA and clinical exome sequencing (CES). A total of 154 children were included (110 [71.4%] male; mean [SD] age, 51.9 [23.1] months). The overall diagnosis yield was 26.0–33.8%, with CMA contributing 12.3–14.3% and CES contributing 13.6–19.4%, showing no significant difference. The diagnostic rate was significantly higher when gross motor delay (odds ratio, 6.69; 95% CI, 3.20–14.00; P < 0.001), facial dysmorphism (odds ratio, 9.34; 95% CI 4.29–20.30; P < 0.001), congenital structural anomaly (odds ratio 3.62; 95% CI 1.63–8.04; P = 0.001), and microcephaly or macrocephaly (odds ratio 4.87; 95% CI 2.05–11.60; P < 0.001) were presented. Patients with only ID without any other concomitant phenotype (63/154, 40.9%) exhibited a 6.3–11.1% diagnostic rate.