Genetic Variants of the MTMR 9 Gene Are Associated with Nonspecific Intellectual Disability: A Family-Based Association Study.

Background: Mutations within the myotubularin-related protein 9 gene ( MTMR 9) have been identified in several families with nonsyndromic intellectual disability (NSID), a generalized neurodevelopmental disorder; however, the relationship between MTMR 9 and NSID needs to be verified using a larger sample size. Aim: To explore whether genetic variants in the MTMR 9 gene are linked to susceptibility of NSID among the Chinese population. Materials and Methods: Seven single nucleotide polymorphisms (SNPs) of the MTMR 9 gene (rs4559208, rs3824211, rs2164272, rs2164273, rs1897951, rs6991606, and rs7815802) were analyzed using family-based association testing among 258 Han Chinese NSID families. Results: Three SNPs of MTMR 9 were significantly associated with NSID ( z  = 2.152, p  = 0.031 for rs4559208; z  = 2.403, p  = 0.016 for rs2164273; and z  = 2.758, p  = 0.006 for rs7815802). Three alleles of these SNPs were more likely to be transferred from the carrier parents to the affected offspring. Haplotypes constructed using these SNPs also showed a similar transmitting trend ( z  = 2.505, p  = 0.012, χ ² ₍₃₎  = 8.835, and global p  = 0.032). Carriers with the G-G-C haplotype showed a higher risk of NSID (odds ratio = 1.46, 95% confidence interval [1.01-2.09], p  = 0.04) than others. In silico functional predictions supported an etiological role for these three SNPs in NSID biology. Conclusions: This study provides additional insights into the association of NSID with specific alleles, and haplotypes within the MTMR 9 gene. Genotypic analyses of the MTMR 9 gene should be considered for patients presenting with NSID of unknown etiology.