Objective: To screen for interferon regulatory factor 6 (IRF6) pathogenic variants in patients clinically diagnosed with nonsyndromic cleft lip palate (NSCL/P) and establish the proportion of misdiagnosed Van der Woude syndrome (VWS) cases, which could have biased previous NSCL/P case-control association studies.
Design: Retrospective case series.
Setting: Tertiary care children's hospital.
Participants: One hundred seventy-two unrelated Mexican patients with NSCL/P, 128 of whom had previously been included in a NSCL/P case-control association study.
Main outcomes measurements: Sanger sequencing of the 9 IRF6 exons were performed, all variants respect with sequence reference were reported and classified for their pathogenic significance according to the American College of Medical Genetics and Genomics guidelines.
Results: Seven percent of cases were familial. No pathogenic variant was identified in IRF6. We identified 12 previously reported benign variants; their frequencies did not significantly differ from those reported for individuals of Mexican ancestry. Three of them were uncommon intronic variants not reported in ClinVar. The rs2235371 and rs2235375 variants, which were previously analyzed in a NSCL/P case-control association study (containing 132 patients, 128 of whom were analyzed herein) did not show discordant association results comparing to the 370 controls from the previous study.
Conclusions: The misdiagnosis of IRF6-related VWS as NSCL/P appears to be infrequent in our sample, suggesting that mutational screening of IRF6 would have a low diagnostic yield in patients with NSCL/P. The absence of IRF6 pathogenic alleles could be related to the application of an exhaustive clinical evaluation that discarded the syndromic forms and/or the low proportion of familial cases included.
Keywords: etiology; genes; genetics.