A Large Deletion in theGene in Labrador Retrievers with a Congenital Cornification Disorder.

Abstract

In heterozygous females affected by an X-linked skin disorder, lesions often appear in a characteristic pattern, the so-called Blaschko's lines. We investigated a female Labrador Retriever and her crossbred daughter, which both showed similar clinical lesions that followed Blaschko's lines. The two male littermates of the affected daughter had died at birth, suggesting a monogenic X-chromosomal semidominant mode of inheritance. Whole genome sequencing of the affected daughter, and subsequent automated variant filtering with respect to 188 nonaffected control dogs of different breeds, revealed 332 hetero-zygous variants on the X-chromosome private to the affected dog. None of these variants was protein-changing. By visual inspection of candidate genes located on the X-chromosome, we identified a large deletion in thegene, encoding NAD(P) dependent steroid dehydrogenase-like, a 3β-hydroxysteroid dehydrogenase involved in cholesterol biosynthesis. The deletion spanned >14 kb, and included the last three exons of thegene. By PCR and fragment length analysis, we confirmed the presence of the variant in both affected dogs, and its absence in 50 control Labrador Retrievers. Variants in thegene cause CHILD syndrome in humans, and the bare patches () and striated () phenotypes in mice. Taken together, our genetic data and the known role ofin X-linked skin disorders strongly suggest that the identified structural variant in thegene is causative for the phenotype in the two affected dogs.