Response to Drs. Herring and Grundmann

To the Editor:

We thank you for the opportunity to respond to the important points raised by Drs. Herring and Grundmann in their comment, “The IRF6 p.274V polymorphism is not a risk factor for isolated cleft lip.” These authors raise a critical point regarding population-based risk factors versus those relevant to individual cases. As they correctly point out, isolated forms of cleft lip and palate have a complex etiology with multiple genetic and environmental factors contributing to causal mechanisms. Thus, it is unlikely that any single genetic factor can explain a large portion of that clefting risk. The findings reported in Zucchero et al.¹ identified the common “V” variant as a risk factor that was highest in Asian or South American populations and far less so in European populations. However, our article discussed not only the V274I variant but also the more general genetic background in which it resided, including an extensive haplotype analysis of an additional 35 SNPs surrounding the IRF6 gene. In the aggregate, haplotypes that include p.274V variant did generate both the overall population-specific association quoted in the article as well as a 3-fold increased risk for clefting recurrence in families when compared to population-based data on recurrence risk in a Filipino population.² It was unclear to us why Drs. Herring and Grundmann did not incorporate into their analysis the additional SNP variants we reported given that the haplotype analysis provides the most accurate risk estimates, particularly in European populations. In addition, as we acknowledged within the article, we do not believe that the V274I variant itself is likely etiologic but rather that it resides on a haplotype on which another mutation, yet to be identified, is the specific risk factor. Most importantly, this haplotype-based analysis has recently been confirmed in a Southern European population by Scapoli et al.³

We agree with the comments of Drs. Herring and Grundmann that the V274I variant itself is not yet useful for genetic counseling in individual families. This will await more specific identification of the risk allele within those haplotypes conferring greatest risk, which may be different in groups of different ancestral origins. Nonetheless, as they acknowledge, we have already made substantial strides in identifying risk factors for isolated forms of clefting through the identification of phenocopies of some recognized genes such as MSX1,^4,5 IRF6,^1,3 TBX22,⁶ and FGFR1.⁷ Although it may not yet be time to apply risk analysis to individual families until further information is available for IRF6, we nonetheless disagree with the title of the comment in that we believe that both the work of Zucchero et al.,¹ and the confirmation data of Scapoli et al.,³ clearly identify this polymorphism as a risk factor for clefting across a range of different populations.