Novel mutations found in genes involved in global developmental delay and intellectual disability by whole-exome sequencing, homology modeling, and systems biology.

Background: Genes associated with global developmental delay (GDD) and intellectual disability (ID) are increasingly being identified through next-generation sequencing (NGS) technologies. This study aimed to identify novel mutations in GDD/ID phenotypes through whole-exome sequencing (WES) and additional in silico analyses.

Material and methods: WES was performed on 27 subjects, among whom 18 were screened for potential novel mutations. In silico analyses included protein-protein interactions (PPIs), gene-miRNA interactions (GMIs), and enrichment analyses. The identified novel variants were further modelled using I-Tasser-MTD and SWISS-MODEL, with structural superimposition performed.

Results: Novel mutations were detected in 18 patients, with 10 variants reported for the first time. Among these, three were classified as pathogenic (DNMT1:c.856dup, KCNQ2:c.1635_1636insT, and TMEM94:c.2598_2599insC), and six were likely pathogenic. DNMT1 and MRE11 were highlighted as key players in PPIs and GMIs. GMIs analysis emphasised the roles of hsa-miR-30a-5p and hsa-miR-185-5p. The top-scoring pathways included the neuronal system (R-HSA-112316, p = 7.73E-04) and negative regulation of the smooth muscle cell apoptotic process (p = 3.37E-06). Homology modelling and superimposition revealed a significant functional loss in the mutated DNMT1 enzyme structure.

Conclusion: This study identified 10 novel pathogenic/likely pathogenic variants associated with GDD/ID, supported by clinical findings and in silico analyses focused on DNMT1 mutations.