Background: Mutations within the myotubularin-related protein 9 gene (MTMR9) have been identified in several families with nonsyndromic intellectual disability (NSID), a generalized neurodevelopmental disorder; however, the relationship between MTMR9 and NSID needs to be verified using a larger sample size. Aim: To explore whether genetic variants in the MTMR9 gene are linked to susceptibility of NSID among the Chinese population. Materials and Methods: Seven single nucleotide polymorphisms (SNPs) of the MTMR9 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 MTMR9 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, χ2(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 MTMR9 gene. Genotypic analyses of the MTMR9 gene should be considered for patients presenting with NSID of unknown etiology.
Keywords: family-based association testing; myotubularin-related protein 9 gene; nonsyndromic intellectual disability; transmission disequilibrium.