Pathogenic variants in ITGB4 cause various forms of autosomal recessive epidermolysis bullosa (EB). ITGB4 encodes integrin-β4, which plays a critical role in the maintenance of the skin basement membrane integrity. Here, we aimed to delineate the genetic basis of dominant isolated nail dystrophy in 2 families. We studied a total of five affected individuals with nail dystrophy and no other cutaneous or extra-cutaneous findings. Whole exome sequencing revealed a different heterozygous missense variant in ITGB4 gene in each of the 2 families. Both mutations co-segregated with the disease phenotype in the families, were classified as pathogenic by various prediction tools and are ultra-rare. Of interest, protein modeling revealed that the two ITGB4 variants as well as a previously identified nail dystrophy-causing ITGB4 mutation, are clustered within the highly conserved VWFA domain of integrin-β4 and are predicted to cause structural changes or protein mis-folding. In conclusion, dominant mutations in ITGB4 affecting the VWFA domain of integrin-β4 cause isolated nail dystrophy.

ESDR292 - Heterozygous pathogenic variants affecting the the highly conserved VWFA domain of integrin-β4 cause isolated nail dystrophy

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