Clinical and Genetic Characteristics of Patients with Unexplained Intellectual Disability/Developmental Delay without Epilepsy.

INTRODUCTION: Global developmental delay (DD), intellectual disability (ID), and autism spectrum disorder (ASD) are mainly evaluated under the neurodevelopmental disorder framework. In this study, we aimed to determine the genetic diagnosis yield using step-by-step genetic analysis in 38 patients with unexplained ID/DD and/or ASD.

METHODS: In 38 cases (27 male, 11 female) with unexplained ID/DD and/or ASD, chromosomal microarray (CMA) analysis, clinical exome sequencing (CES), and whole-exome sequencing (WES) analysis were applied, respectively.

RESULTS: We found a diagnostic rate of only CMA analysis as 21% (8/38) presenting 8 pathogenic and likely pathogenic CNVs. The rate of patients diagnosed with CES/WES methods was 32.2% (10/31). When all pathogenic and likely pathogenic variants were evaluated, the diagnosis rate was 44.7% (17/38). A dual diagnosis was obtained in a case with 16p11.2 microduplication and de novo SNV. We identified eight novel variants: TUBA1A (c.787C>G), TMEM63A (c.334-2A>G), YY1AP1 (c.2051_2052del), ABCA13 (c.12064C>T), ABCA13 (c.13187G>A), USP9X (c.1189T>C), ANKRD17 (c.328_330dup), and GRIA4 (c.17G>A).

CONCLUSION: We present diagnostic rates of a complementary approach to genetic analysis (CMA, CES, and WES). The combined use of genetic analysis methods in unexplained ID/DD and/or ASD cases has contributed significantly to diagnosis rates. Also, we present detailed clinical characteristics to improve genotype-phenotype correlation in the literature for rare and novel variants.