Competing Interest: None.
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†
Article first published online: 7 DEC 2010
Copyright © 2010 Wiley-Liss, Inc.
Birth Defects Research Part A: Clinical and Molecular Teratology
Volume 91, Issue 2, pages 85–92, February 2011
How to Cite
Jugessur, A., Shi, M., Gjessing, H. K., Lie, R. T., Wilcox, A. J., Weinberg, C. R., Christensen, K., Boyles, A. L., Daack-Hirsch, S., Nguyen, T. T., Christiansen, L., Lidral, A. C. and Murray, J. C. (2011), 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. Birth Defects Research Part A: Clinical and Molecular Teratology, 91: 85–92. doi: 10.1002/bdra.20747
- Issue published online: 11 FEB 2011
- Article first published online: 7 DEC 2010
- Manuscript Accepted: 7 SEP 2010
- Manuscript Revised: 5 SEP 2010
- Manuscript Received: 7 JUL 2010
- Supported by a grant from: This research was supported in part by the Intramural Research Program of the U.S. National Institute of Environmental Health Sciences (NIEHS); by U.S. National Institutes of Health (NIH) grants DE08559, P60 DE13076, DE08559, DE11948, P30 ES05605, and RO1 DE-11948-04; and by the Norwegian Research Council (NFR 177522)
- birth defects;
- orofacial cleft;
- cleft lip;
- cleft palate;
- genetic epidemiology
BACKGROUND: Cleft lip only (CLO) and cleft lip and palate (CLP) are commonly regarded as variants of the same defect and are 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 subphenotype analysis using two population-based studies of clefts in Scandinavia. One hundred 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, Triad Multi-Marker (TRIMM; Shi et al., 2007)) and HAPLIN (Gjessing and Lie, 2006), 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. Birth Defects Research (Part A), 2010. © 2010 Wiley-Liss, Inc.