Exome sequencing identifies a TCF 4 mutation in a Chinese pedigree with symmetrical acral keratoderma

Background Symmetrical acral keratoderma ( SAK ) is a rare skin disorder and its pathogenesis and inheritability are unknown. Objectives To investigate the inheritance and pathogenesis of SAK . Methods Four SAK cases occurred in a four‐generation Chinese family. Exome sequencing identified SNP s with potential SAK ‐related mutations, and a potentially responsible gene transcription factor 4 ( TCF 4) was identified. TCF 4 was then sequenced in all 11 family members, and pedigree analysis was performed. Histopathology and immunohistochemistry evaluated TCF 4 expression in skin lesions. The gene mutation was investigated in human keratinocytes for keratin‐related protein expression. Results A novel heterozygous missense mutation, c.85C>A (p.Pro29Thr) was found in TCF 4. The mutation showed autosomal dominant inheritance and perfectly cosegregated with the SAK phenotype in all family members. In skin lesions, TCF 4 was present in the cytoplasm and membranes of the basal layer, the stratum spinosum and the stratum granulosum of the epidermis. The mutant TCF 4 induced overexpression of differentiation markers including KRT 1, KRT 14, loricrin and involucrin. Conclusions A SAK ‐related gene mutation in TCF 4 may function through transcriptional regulation of keratin.