Exome sequencing reveals mutation in GJA1 as a cause of keratoderma-hypotrichosis-leukonychia totalis syndrome

Keratoderma-hypotrichosis-leukonychia totalis syndrome (KHLS) is an extremely rare, autosomal-dominantdisordercharacterizedbysevereskinhyperkeratosis,congenitalalopeciaandleukonychiatotalis.Thegeneticdefect underlying KHLS remained undetermined. By performing whole-exome sequencing in a family withKHLS, we identified a heterozygous mutation (c.23G>T [p.Gly8Val]) inGJA1, which cosegregated with thephenotype in the family. In an additional affected individual, we also found the identicalde novomutationwhich was absent in his unaffected family members. GJA1 encodes a gap junction protein connexin 43 (Cx43)which is ubiquitously expressed in various organs, including the epidermis and hair follicles. In vitro studieson HEK293 cells expressing Cx43