Iranian Journal of Medical Sciences
Iranian Journal of Medical Sciences

Impacts of New Mutations involved in Metabolic processes Leading to Intellectual Disabilities Found by Whole-Exome Sequencing and In Silico Investigations

Articles InPress

Document Type : Original Article(s)

Authors

Vahid Omarmeli 1
lham Siasi 2
Maryam Peyvandi 3
Sahar Mansoubi 4
Mohaddeseh Mohsenpour 2

1 Department of Genetics, NT.C., Islamic Azad University, Tehran, Iran

2 Department of Microbiology, NT.C., Islamic Azad University, Tehran, Iran

3 Department of Biology, NT.C., Islamic Azad University, Tehran, Iran

4 Cellular and Molecular Bioloy, NT.C., Islamic Azad University, Tehran, Iran

10.30476/ijms.2026.109733.4509
Abstract
Background: Inborn errors of metabolism (IEM), a notable subset of intellectual disabilities (IDs), may increase the likelihood of new mutation hotspots. Thus, this study aimed to investigate whole-exome sequencing (WES) reports of complicated cases.
Methods: The ATP7B mutation (Gly205Glu) was selected for homology modeling with MODELLER, then superimposed with Matchmaker. Moreover, an in silico strategy was designed to identify new molecular relationships among the novel mutations using STRING-MODEL, NetworkAnalyst, Enrichr, and Metascape.
Results: A total of 114 cases that underwent WES testing were included (2023-2025, Kermanshah, Iran). Results showed 73 novel mutations (out of 139) in 56 cases, of which 31 cases had consanguineous backgrounds. All novel mutations were associated with 69 genes, and a candidate group of 19 genes was selected for further analyses. Gene-miRNA interactions predicted hsa-miR-615-3p as the top miRNA. Enrichment Analysis indicated potential processes, including Alanine, aspartate, and glutamate metabolism (P=5.6E-4); Mitochondrial Matrix (P=3.06E-4); Mental Retardation (P=3.11E-10); and ID (P=2.34E-08). Notably, the Alpha-amino acid metabolic process was the best-scored process by Clustering Enrichment Analysis.
Conclusion: Altogether, this study reported novel mutations, identified a candidate gene list, and suggested that metabolic processes may play pivotal roles in disease causation through new mutations leading to ID manifestations.

Highlights

Vahid Omarmeli (Google Scholar)
Elham Siasi (Google Scholar) 

Keywords

Intellectual disability
Metabolic disorders
Exome sequencing
Novel mutation
Systems biology
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Iranian Journal of Medical Sciences

Articles InPress, Corrected Proof
Available Online from 21 October 2026


  • Received 19 November 2025
  • Revised 28 May 2026
  • Accepted 24 June 2026

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