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

Division of Epidemiology, Norwegian Institute of Public Health, Nydalen, Oslo, Norway.
Birth Defects Research Part A Clinical and Molecular Teratology (Impact Factor: 2.09). 02/2011; 91(2):85-92. DOI: 10.1002/bdra.20747
Source: PubMed


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.

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    • "* Risk haplotypes of FGF12 , VCL and CX43 were based on Jugessur et al . ( 2011 )"
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    ABSTRACT: Background Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is the most common orofacial birth defect with a wide range prevalence among different populations. Previous association studies with populations from Europe and Asia have identified putative susceptibility markers for NSCL/P in fibroblast growth factor 12 (FGF12), vinculin (VCL), connexin 43 (CX43) and in a region close to the ventral anterior homeobox 1 (VAX1) gene. However, there have thus far been no studies of these markers in NSCL/P Brazilian patients, and as the genetic ancestry of the Brazilian population is highly varied, the predisposition to those disease markers can be different. Methods Herein we conducted a structured association study conditioned on the individual ancestry proportions to determine the role of 16 polymorphic markers within those genes in 300 patients with NSCL/P and 385 unaffected controls. Results None of the alleles and genotypes showed association with NSCL/P, though there was a significant association of the haplotype formed by VAX1 rs10787760, rs6585429 and rs1871345 polymorphisms with NSCL/P that did not persist Bonferroni correction for multiple tests. Conclusions Our results are consistent with a lack of involvement of FGF12, VCL and CX43 variants with NSCL/P pathogenesis in Brazilian patients. Furthermore, the higher frequency of a haplotype of VAX1 with NSCL/P patients suggests a low penetrant gene for oral cleft, and warrants further studies.
    Full-text · Article · May 2013 · BMC Medical Genetics
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    • "The phenotypic variants of cleft lip (CLO and CL1P) are usually considered to be the same defect and are thought to differ etiologically from CPO. However, there is also some evidence that CLO and CL1P may be etiologically distinct (Harville et al., 2005; Genisca et al., 2009; Jugessur et al., 2011). "
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    ABSTRACT: Background: The reported birth prevalence of orofacial clefts (OFCs) varies considerably. This study describes the epidemiology of OFCs in an Australian population. Methods: We studied infants diagnosed with cleft lip, with or without cleft palate (CL±P), and cleft palate only (CPO) since 1980 and reported to the population based Western Australian Register of Developmental Anomalies. We calculated prevalence rates by sex, Aboriginal status, geographic location, and socio-economic status. Associations between clefts and folate availability, pregnancy characteristics, pregnancy outcomes, other congenital anomalies, and age at diagnosis were also investigated. Results: From 1980 to 2009, 917 infants with CL±P (12.05 per 10,000) and from 1980 to 2004, 621 infants with CPO (10.12 per 10,000) were registered. Prevalence rates for CL±P and CPO were 1.9 and 1.3 times higher, respectively, for Aboriginal Australians. Additional anomalies were reported for 31% of infants with CL±P and for 61% with CPO; chromosomal anomalies and other specific diagnoses accounted for 46% and 66%, respectively, of those with CL±P and CPO with additional anomalies. Almost all (99.7%) children with CL±P were diagnosed before 1 year of age, but 12% of CPO diagnoses were made after 1 year of age; 94% of these diagnoses were of submucous clefts and bifid uvula. Conclusions: These data provide a picture of the prevalence of OFCs in WA since 1980, and provide a useful reference for OFC data in Australia and internationally. The quality and completeness of the WARDA data are high, reflected in high prevalence rates, and proportions of clefts occurring with other anomalies.
    Full-text · Article · Feb 2013 · Birth Defects Research Part A Clinical and Molecular Teratology
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    • "For example, in the discovery of the causative gene for Kabuki syndrome, reassessment of the images and clinical description was crucial when the first attempt of exome sequencing was unsuccessful [Ng et al., 2010]. Likewise, subphenotype analysis indicates that at least a subgroup of isolated cleft lip may be etiologically distinct from isolated cleft lip and palate [Jugessur et al., 2011]. Detailed description of external ear malformations would enable future reassessment of this information and reclassification if necessary to aggregate cases in multiple ways. "
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    ABSTRACT: Microtia is a congenital anomaly of the ear that ranges in severity from mild structural abnormalities to complete absence of the ear, and can occur as an isolated birth defect or as part of a spectrum of anomalies or a syndrome. Microtia is often associated with hearing loss and patients typically require treatment for hearing impairment and surgical ear reconstruction. The reported prevalence varies among regions, from 0.83 to 17.4 per 10,000 births, and the prevalence is considered to be higher in Hispanics, Asians, Native Americans, and Andeans. The etiology of microtia and the cause of this wide variability in prevalence are poorly understood. Strong evidence supports the role of environmental and genetic causes for microtia. Although some studies have identified candidate genetic variants for microtia, no causal genetic mutation has been confirmed. The application of novel strategies in developmental biology and genetics has facilitated elucidation of mechanisms controlling craniofacial development. In this paper we review current knowledge of the epidemiology and genetics of microtia, including potential candidate genes supported by evidence from human syndromes and animal models. We also discuss the possible etiopathogenesis in light of the hypotheses formulated to date: Neural crest cells disturbance, vascular disruption, and altitude. © 2011 Wiley Periodicals, Inc.
    Full-text · Article · Jan 2012 · American Journal of Medical Genetics Part A
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