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Large-scale sequencing efforts have captured a rapidly growing catalogue of genetic variations. However, the accurate establishment of gene variant pathogenicity remains a central challenge in translating personal genomics information to clinical decisions. Interferon Regulatory Factor 6 ( IRF6 ) gene variants are significant genetic contributors to orofacial clefts. Although approximately three hundred  IRF6  gene variants have been documented, their effects on protein functions remain difficult to interpret. Here, we demonstrate the protein functions of human  IRF6  missense gene variants could be rapidly assessed in detail by their abilities to rescue the  irf6    -/-   phenotype in zebrafish through variant mRNA microinjections at the one-cell stage. The results revealed many missense variants previously predicted by traditional statistical and computational tools to be loss-of-function and pathogenic retained partial or full protein function and rescued the zebrafish  irf6    -/-   periderm rupture phenotype. Through mRNA dosage titration and analysis of the Exome Aggregation Consortium (ExAC) database,  IRF6  missense variants were grouped by their abilities to rescue at various dosages into three functional categories: wild type function, reduced function, and complete loss-of-function. This sensitive and specific biological assay was able to address the nuanced functional significances of  IRF6  missense gene variants and overcome many limitations faced by current statistical and computational tools in assigning variant protein function and pathogenicity. Furthermore, it unlocked the possibility for characterizing yet undiscovered human  IRF6  missense gene variants from orofacial cleft patients, and illustrated a generalizable functional genomics paradigm in personalized medicine.

Rapid functional analysis of computationally complex rare human IRF6 gene variants using a novel zebrafish model