A Large Deletion in the <i>NSDHL</i> Gene 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 the <i>NSDHL</i> gene, 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 the <i>NSDHL</i> gene. 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 the <i>NSDHL</i> gene cause CHILD syndrome in humans, and the bare patches (<i>Bpa</i>) and striated (<i>Str</i>) phenotypes in mice. Taken together, our genetic data and the known role of <i>NSDHL</i> in X-linked skin disorders strongly suggest that the identified structural variant in the <i>NSDHL</i> gene is causative for the phenotype in the two affected dogs.