Abstract
A deficiency of GTP cyclohydrolase, encoded by the GCH1 gene, results in two neurological diseases: hyperphenylalaninaemia type HPABH4B and DOPA-responsive dystonia. Genes involved in neurotransmitter metabolism and motor systems may contribute to palatogenesis. The purpose of the study was to analyse polymorphic variants of the GCH1 gene as risk factors for non-syndromic cleft lip with or without cleft palate (NSCL/P). Genotyping of nine polymorphisms was conducted in a group of 281 NSCL/P patients and 574 controls. The GCH1 variant rs17128077 was associated with a 1.7-fold higher risk for NSCL/P (95 %CI = 1.224-2.325; p = 0.001). We also found a significant correlation between the rs8004018 and rs17128050 variants and an increased risk of oral clefts (p trend = 0.003 and 0.004, respectively). The best evidence of the global haplotype association was observed for rs17128050 and rs8004018 (p corr = 0.0152). This study demonstrates that the risk of NSCL/P is associated with variants of the GCH1 gene related to BH4 metabolism and provides some evidence of the relationships between morphological/functional shifts in the central nervous system and orofacial clefts.