Monoallelic pathogenic variants in KLHL24 as the cause of epidermolysis bullosa simplex (EBS), generalized, with scarring and hair loss (MIM 617294) were first described in 2016 by two independent groups, and confirmed by subsequent reports. So far all pathogenic variants described in EBS involve the translation initiation codon of KLHL24, resulting in a truncation of the N-terminus and in gain-of-function.
Biallelic KLHL24 loss-of-function pathogenic variants have been reported in individuals with hypertrophic cardiomyopathy.
KLHL24 variants of uncertain significance have been identified in individuals with intellectual disability.
KLHL24, encoding the kelch-like family 24 (KLHL24, also known as DRE1, EBSSH or KRIP6) is a protein of the kelch-like (KLHL) family. KLHL proteins are almost ubiquitously expressed at low levels. They contain a BTB domain which binds to cullin 3, a scaffold protein required for ubiquitination and proteasomal degradation of substrate proteins.
Clinical features
The main clinical features of EBS-KLHL24 include congenital skin defects and generalized skin blistering, skin hypopigmentation, atrophy and scarring, alopecia (hair loss) and nail dystrophy. Dilated cardiomyopathy may occur in young adults leading to premature cardiac death.
Prevalence
Worldwide, about 45 cases have been reported with EBS due to KLHL24 pathogenic variants, but the real number is probably higher. Although epidermolysis bullosa is a well-studied disease, this clinical subtype had remained unrecognized for a long time. The prevalence of EBS-KLHL24 cannot be ascertained with precision yet owing to the limited number of cases identified thus far. More studies are needed to determine an unbiased prevalence of the syndrome. Only two families with autosomal recessive cardiomyopathy with KLHL24 pathogenic variants are reported so far.
Inheritance
KLHL24 pathogenic variants causing EBS are inherited in an autosomal dominant manner. There is a high rate of about of de novo mutations (50% in the reported cases). Biallelic loss-of-function KLHL24 variants have been reported in two families with autosomal recessive hypertrophic cardiomyopathy.