Whole exome sequencing coupled with in silico functional analysis identified NID1 as a novel candidate gene causing neuro-psychiatric disorder in a Pakistani family

Abstract

Intellectual disability (ID) is a neuro-developmental condition that affects a person’s cognitive ability and results in a learning defect. It affects 1–3% of the general population; however, the ratio may be expected to be more in a consanguineous population. Herein in the present study, we identified a nuclear family from Dera Ismail Khan City in Pakistan. Whole exome sequencing was performed to map the pathogenic variant. Protein structural modeling and interaction studies were carried out to validate the variant with disease association. Molecular modeling of normal and mutated proteins was performed through I-TASSER and Chimera tools, while docking and interaction analysis was carried out using Cluspro. Clinical analysis of the patient determined mild intellectual disability and gait problem. Candidate gene analysis in this family found a homozygous missense mutation NM_002508:c.C2512T (p.Arg838Cys) in the 12th exon of NID1 gene. Molecular modeling of wild-type and mutant NID1 proteins determined a significant effect on the protein’s secondary and tertiary structure. Hence, based on the exome sequence analysis, NID1 is proposed to be a strong novel candidate ID gene in this family. The genetic mapping of the present family led us to determine a novel candidate gene to be associated with intellectual disability. Linkage of additional ID families with genes would confirm its validity and strengthen our notion. Furthermore, expression studies and pathway analysis will help in exploring the biological mechanism of learning and memory.