A Novel MID1 Mutation Identified in a Patient With Craniofacial Anomalies and X-Linked Intellectual Disability

Genetic variations in MID1 were initially identified as the cause of X-linked Opitz G/BBB syndrome, which is characterized by hypertelorism, hypospadias, and a high incidence of intellectual disability. However, increasing evidence has shown that MID1 mutations are associated with a broader spectrum of phenotypes, and the genotype-phenotype correlation remains unclear. In this study, the authors report a 4-year-old boy presenting with congenital unilateral nostril hypoplasia, preaxial polydactyly, hemispheric brain asymmetry, and moderate intellectual disability. Whole-exome sequencing identified a novel hemizygous missense variant in MID1 (c.1600G>T; p.Val534Leu), inherited from an unaffected heterozygous mother and also present in the proband's clinically normal sister. Functional analysis suggested that this variant may affect protein-protein interactions and microtubule-associated cellular processes. In addition, expression profiling revealed that MID1 is highly enriched in the central nervous system, supporting its essential role in neurodevelopment. Structural modeling with AlphaFold3 showed preservation of the overall protein fold, whereas DynaMut2 predicted local destabilization and increased hydrophobic packing near the variant site. The variant segregated in the family in an X-linked manner and was classified as possibly damaging by PolyPhen-2. In conclusion, our findings expand the mutational and phenotypic spectrum of MID1-related disorders and suggest a potential pathogenic role of this variant in neurodevelopmental and craniofacial abnormalities.