The exploration of genetic aetiology and diagnostic strategy for 321 Chinese individuals with intellectual disability

Intellectual disability is a heterogeneous neurodevelopmental disorder with complex genetic architectures. Different sequential methodologies are usually applied to identify the genetic aetiologies of ID patients.We collected 321 consecutive ID patients. All patients underwent karyotyping, while 293 and 164 cases further received copy number variation sequencing (CNV-seq) and whole-exome sequencing (WES). The updated WES technology can detect CNVs simultaneously. The diagnostic data from 137 patients who received WES and CNV-seq were used to define the approach that could be recommended as the first-tier test.WES obtains the highest diagnostic yield of 50% (82/164), compared with karyotyping (7.79%, 25/321) and CNV-seq (19.80%, 58/293). Among the variants detected by WES, 66.67% (44/66) de novo and 57.58% (38/66) novel pathogenic/likely pathogenic (P/LP) variants were identified in patients with ID. Besides, 24 out of 25P/LP CNVs discovered by CNV-seq can also be accurately identified using WES in 137 patients who received WES and CNV-seq. Thus, genetic abnormalities found through karyotyping, CNV-seq, and WES can be completely detected by combined karyotyping and WES.This study illustrates the genetic aberrations of a Chinese ID cohort and expands the mutation spectrum of ID-related genes. Compared with the conventional diagnostic strategy, a combination of karyotype analysis and WES could be recommended as the first-tier diagnostic strategy for ID patients.