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

• Published in: The world journal of biological psychiatry Vol. 26; no. 3; p. 130
• Main Authors: Moeinifar, Nafiseh, Hojati, Zohreh
• Format: Journal Article
• Language: English
• Published: England 03.04.2025
• Subjects: Adolescent; Child; Child, Preschool; Developmental Disabilities - genetics; DNA (Cytosine-5-)-Methyltransferase 1 - genetics; Exome Sequencing; Female; Humans; Intellectual Disability - genetics; Male; MicroRNAs - genetics; Mutation; Systems Biology; in silico analysis; Intellectual disability; global developmental delay; whole-exome sequencing; novel mutations
• ISSN: 1814-1412
• DOI: 10.1080/15622975.2025.2453198

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 analyses. WES was performed on 27 subjects, among whom 18 were screened for potential novel mutations. 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. Novel mutations were detected in 18 patients, with 10 variants reported for the first time. Among these, three were classified as pathogenic ( :c.856dup, :c.1635_1636insT, and :c.2598_2599insC), and six were likely pathogenic. and 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,  = 7.73E-04) and negative regulation of the smooth muscle cell apoptotic process (  = 3.37E-06). Homology modelling and superimposition revealed a significant functional loss in the mutated DNMT1 enzyme structure. This study identified 10 novel pathogenic/likely pathogenic variants associated with GDD/ID, supported by clinical findings and analyses focused on mutations.