ROR2 gene is associated with risk of non-syndromic cleft palate in an Asian population.

Non-syndromic orofacial clefts are among the most common structural human birth defects and can have lifelong adverse influence on patients, families and society. In etiologic studies, orofacial clefts are often classified as cleft lip with or without cleft palate (CL/P) and cleft palate (CP) alone due to their distinct developmental origins, epidemiological characteristics, as well as the evidence that they do not typically segregate in the same family.1 Many genes are involved in altering susceptible risk to CL/P and CP.2,3 However, the complex and heterogeneous etiology remains largely undefined. A multifactorial threshold model of inheritance with multiple, distinct causal genes is often assumed for CL/P,4 and there is no single gene model to explain the strong familial aggregation of CP. The receptor tyrosine kinase-like orphan receptor 2 (ROR2) gene on chromosome 9q22 is a promising candidate for both CL/P and CP. It plays a crucial role in palatal development through mediating Wnt5a signaling in the regulation of directional cell migration and proliferation.5 Defects in this gene can cause the autosomal recessive Robinow syndrome (MIM: 268310), a disorder characterized by skeletal dysplasia with generalized limb bone shortening, segmental defects of the spine, brachydactyly and a dysmorphic facial appearance including cleft lip and palate.6,7 ROR2 mutant mice showed complete cleft palate phenotype.5 In humans, genome-wide linkage scans linked the relevant chromosomal region around 9q22 to CL/P in various populations, although no evidence at genome-wide significant level was shown for markers in the ROR2 gene in subsequent association studies.8-10 To further study its risk for orofacial clefts, here we tested genetic association of the ROR2 gene to both CL/P and CP using 297 CL/P case parent trios from four populations and 82 CP trios from three populations.