rs12139639 (FYB2): Bilateral Cleft Lip Modifier
Key takeaways
- This variant modifies cleft lip type (bilateral vs. unilateral), not whether a cleft lip occurs at all
- The association does not extend to cleft lip and palate cases
- Discovery p-value reached genome-wide significance and independently replicated in a second cohort
- The same locus is linked to normal nasal shape variation in people without clefts
- The bilateral cleft lip group was small (n=44), so effect size estimates should be interpreted with caution
Key takeaways
- This variant acts as a modifier - it influences which type of cleft lip forms (bilateral vs. unilateral), not whether a cleft occurs at all
- The association is specific to cleft lip: no significant effect was detected in cleft lip and palate cases
- The locus sits approximately 300 kb downstream of PAX1 on chromosome 20p11 (FYB2 region)
- Discovery reached genome-wide significance (p = 7.53 × 10^-9) and replicated in an independent cohort (p = 0.0018)
- The same locus is also associated with variation in normal human nasal shape
What the research says A genome-wide scan for genetic modifiers of nonsyndromic orofacial clefts identified a significant locus at chromosome 20p11 (FYB2 region), approximately 300 kb downstream of PAX1, that increased the odds of bilateral cleft lip (BCL) relative to unilateral cleft lip (UCL) at genome-wide significance (p = 7.53 × 10^-9; 44 BCL and 434 UCL individuals with 1,626 controls). The association replicated in an independent cohort (p = 0.0018) and showed no significant effect in bilateral or unilateral cleft lip and palate cases (p > 0.05). The locus was further found to associate with normal variation in human nasal shape in unaffected individuals.
Reported associations
- Bilateral cleft lip vs. unilateral cleft lip: Higher odds of bilateral cleft lip relative to unilateral cleft lip at genome-wide significance (p = 7.53 × 10^-9); discovery cohort included 44 BCL and 434 UCL individuals alongside 1,626 unrelated controls across 18 sites in 13 countries
- Bilateral cleft lip vs. unilateral cleft lip (replication): Association replicated in an independent cohort (p = 0.0018), supporting the discovery finding
- Bilateral cleft lip and palate (null finding): No significant effect detected for bilateral vs. unilateral cleft lip and palate (p > 0.05), suggesting the modifier effect may be specific to the cleft lip subtype
- Normal human nasal shape: The locus was also associated with variation in nasal morphology in individuals without clefts, indicating a potential broader role in midface development
Evidence quality The discovery analysis used a mixed-model approach in a multiethnic cohort spanning 18 sites across 13 countries, with 44 BCL individuals, 434 UCL individuals, 530 bilateral CLP, 1,123 unilateral CLP, and 1,626 unrelated controls. The primary association reached genome-wide significance (p = 7.53 × 10^-9) and independently replicated (p = 0.0018). Importantly, the BCL discovery group is notably small (n = 44), which limits statistical power and raises the possibility of effect-size inflation - a well-known issue in underpowered GWAS subgroup analyses. Odds ratios or beta coefficients were not reported in the available study text. The replication result supports the association but does not fully resolve uncertainty from the small BCL sample. No other novel loci emerged from the broader OFC subtype scan; this modifier locus was the primary finding. Overall, evidence is preliminary given the limited BCL sample size and single published replication.
Lifestyle considerations No lifestyle considerations on file for this variant.
Frequently asked questions
What does rs12139639 do?
rs12139639 is located in the FYB2 region, about 300 kb downstream of PAX1 on chromosome 20p11. Research suggests it acts as a genetic modifier that influences whether a cleft lip develops on one side (unilateral) or both sides (bilateral), rather than determining whether a cleft occurs at all.
Is rs12139639 linked to cleft palate?
No significant association was found between this variant and bilateral versus unilateral cleft lip and palate. The modifier effect appears specific to cleft lip cases.
What is a genetic modifier?
A genetic modifier is a variant that does not directly cause a condition but can alter how that condition presents - for example, changing its severity, which structures are affected, or which side of the body is involved.
What is the FYB2 gene?
The study identifying this association describes the locus as lying approximately 300 kb downstream of PAX1 on chromosome 20p11, in the region containing FYB2. The research focused on the statistical association findings rather than characterizing the functional role of FYB2 itself.
Is rs12139639 associated with nasal shape?
Yes. Beyond its association with cleft lip subtype, the same locus was found to associate with normal variation in human nasal shape in individuals without clefts, suggesting a broader role in midface development.