Unravelling the role of Neurotrimin (NTM), a member of the IgLON family, in mild intellectual disability and anxiety-like behaviors

Neurotrimin (NTM) (OMIM #607938), a member of the IgLON family, collaborates with other neural cell adhesion proteins to regulate neurite outgrowth, axonal fasciculation, and synapse formation. Disruption of NTM function in animal models has been associated with deficits in emotional learning and increased anxiety-like behaviours. In this study, we examined an individual presenting with mild intellectual disability, anxiety-like behaviours, and low frustration tolerance, along with generalised hypotonia. Trio-based whole exome sequencing (WES) identified a de novo nucleotides insertion, c.788_791dup, in the NTM (NM_001144058) gene. NTM currently lacks a MIM phenotype entry linking it to a specific disorder, and has been predicted to follow both autosomal dominant and recessive inheritance patterns. The variant was classified as pathogenic according to ACMG guidelines and displays a very low frequency in the gnomAD population (0.000006829). It is located at a highly conserved site (PhyloP: 7.674). In-silico analysis predicted that the variant induces nonsense-mediated decay (NMD) of the transcript, resulting in loss of NTM protein production. However, if the transcript escapes NMD, the insertion is expected to cause a frameshift, altering codons beyond amino acid 262, resulting in Ile263, a novel Asp264, and a premature stop codon (TGA) in position 265. This mutation is predicted to disrupt NTM homodimerization and heterodimerization with other IgLON family proteins (OPCML, LSAMP, NEGR1, and IgLON5), regardless of whether degradation of the transcript occurs or a truncated protein is produced. These findings suggest a potential link between NTM dysfunction and neurodevelopmental phenotypes and highlight its possible role as a candidate gene for mild cognitive and behavioural disorders.