Fetal genetic risk of isolated cleft lip only versus isolated cleft lip and palate: a subphenotype analysis using two population-based studies of orofacial clefts in Scandinavia.

BACKGROUND

Cleft lip only (CLO) and cleft lip and palate (CLP) are commonly regarded as variants of the same defect and traditionally combined to form the single group of cleft lip with or without cleft palate (CL/P) prior to analysis. However, recent data have suggested that at least a subgroup of isolated CLO may be etiologically distinct from isolated CLP.

METHODS

To explore fetal genetic risk of isolated CLO separately from isolated CLP, we performed a sub-phenotype analysis using two population-based studies of clefts in Scandinavia. One hundred and twenty-one isolated CLO, 190 isolated CLP, and 592 control triads were available from Norway(1996–2001), and a further 76 isolated CLO and 107 isolated CLP triads were available from Denmark (1991–2001). Genotypes for 1315 SNPs in 334 autosomal cleft candidate genes were analyzed using two complementary statistical methods, TRIMM and HAPLIN, to look for genetic associations across the two national samples.

RESULTS

Both TRIMM and HAPLIN identified strong associations between FGF12 and isolated CLO in both populations. In addition, only TRIMM identified associations with IRF6 and VCL, and only HAPLIN found an association with CX43. When analyses were repeated on the larger sample of isolated CLP, no significant associations were found with FGF12, IRF6, VCL or CX43.

CONCLUSIONS

Despite some inconsistency in the pattern of associations across the two populations, the associations themselves were phenotype-specific. While both IRF6 and FGF12 have previously shown strong associations with isolated CL/P, the associations with VCL and CX43 are novel and warrant further investigation in other isolated CLO samples.