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

Abstract

<b><i>Introduction:</i></b> 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. <b><i>Methods:</i></b> 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. <b><i>Results:</i></b> 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: <i>TUBA1A</i> (c.787C>G), <i>TMEM63A</i> (c.334-2A>G), <i>YY1AP1</i> (c.2051_2052del), <i>ABCA13</i> (c.12064C>T), <i>ABCA13</i> (c.13187G>A), <i>USP9X</i> (c.1189T>C), <i>ANKRD17</i> (c.328_330dup), and <i>GRIA4</i> (c.17G>A). <b><i>Conclusion:</i></b> 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.

Rare heterozygous genetic variants of NRXN and NLGN gene families involved in synaptic function and their association with neurodevelopmental disorders

“…In this study, the 2p16.3 deletion was detected in two different individuals. To date, mono/biallelic CNVs in NRXN genes have been mainly associated with incomplete penetrance and pleiotropy, DD, and neuropsychiatric disorders such as ASD (Dabell et al, 2013;Gerik-Celebi et al, 2023;Molloy et al, 2023). Homozygous deletion of the 2p16.3 region, including the NRXN1 gene, has been better identified.…”