X-chromosomal genetic variants and haplotype analysis in male cerebral palsy patients: insights into genetic susceptibility and sex-specific risk.

BACKGROUND

Cerebral palsy (CP) is a neurodevelopmental disorder with a significant male predisposition, yet the underlying genetic mechanisms driving this sex-specific risk remain poorly understood. Given the hemizygous state of X-linked variants in males, we hypothesized that X-chromosomal genetic variations may contribute to CP susceptibility in male patients.

METHODS

We performed an X-chromosome-wide association study (XWAS) using whole-exome sequencing (WES) data from 1,076 male CP patients and 1,057 healthy male controls of Chinese ancestry. Quality control, principal component analysis (PCA), and logistic regression were applied to identify risk loci for CP. Six candidate single nucleotide variants (SNVs) in UTP14A were genotyped via MassARRAY, and haplotype analysis was conducted using SHEsis.

RESULT: We identified a significant association between the intronic variant rs2281277 in UTP14A and CP (P = 1.38E-05, FDR q-value = 0.0465, OR = 0.644). In addition to the lead SNV rs2281277, five other SNVs in UTP14A also showed a suggestive association with CP, including rs141750783, rs61318448, rs2273021, rs2281278, and rs111975985. Haplotype analysis further revealed a risk haplotype (CGTATC) defined by these six SNVs, which was associated with a 53.1% increased susceptibility to CP (P = 9.40E-8, OR = 1.531).

CONCLUSION

This study nominates X-linked UTP14A as a candidate susceptibility locus for CP in male Chinese, which warrants replication based on large, independent cohorts and functional validation.