Kiener, SarahSarahKienerWiener, Dominique JDominique JWienerHopke, KaitlinKaitlinHopkeDiesel, Alison BAlison BDieselJagannathan, VidyaVidyaJagannathanMauldin, Elizabeth AElizabeth AMauldinCasal, Margret LMargret LCasalLeeb, TossoTossoLeeb0000-0003-0553-48802025-01-082025-01-082022-02-04https://boris-portal.unibe.ch/handle/20.500.12422/201937Ichthyoses are hereditary skin disorders characterized by the formation of scales and defects in the outermost layer of the epidermis. In dogs, at least six different breed-specific ichthyoses including a relatively common PNPLA1-related autosomal recessive ichthyosis in Golden Retrievers are known. In this study, we investigated 14 Golden Retrievers with scales that were not homozygous for the mutant PNPLA1 allele suggesting a genetically distinct new form of ichthyosis. Histopathological examinations showed lamellar, orthokeratotic hyperkeratosis, and mildly hyperplastic epidermis that led to the diagnosis of a nonepidermolytic ichthyosis. Combined linkage and homozygosity mapping in 14 cases and 30 nonaffected family members delimited a critical interval of ∼12.7 Mb on chromosome 23. Whole-genome sequencing of an affected dog revealed a single protein-changing variant within this region that was not present in 795 control genomes. The identified variant is a 14 bp deletion in the ABHD5 gene (c.1006_1019del), leading to a frameshift and altering the last 14 codons p.(Asp336Serfs*6). The genotypes at this variant showed perfect cosegregation with the ichthyosis phenotype in a large family comprising 14 cases and 72 controls. ABHD5 encodes an acyltransferase required for lipid metabolism. In humans, variants in ABHD5 cause Chanarin-Dorfman syndrome, a neutral lipid storage disease with ichthyosis. Our data in dogs together with the knowledge on the effects of ABHD5 variants in humans strongly suggest ABHD5:c.1006_1019del as candidate causative genetic variant for a new canine form of ichthyosis, which we propose to designate as Golden Retriever ichthyosis type 2 (ICH2).enCanis lupus familiaris animal model dermatology dog genodermatosis lipid storage disorder metabolism precision medicine veterinary medicine500 - Science::590 - Animals (Zoology)600 - Technology::630 - Agriculture500 - Science::570 - Life sciences; biology600 - Technology::610 - Medicine & healtharticle10.48350/1684353479122510.1093/g3journal/jkab397