Neuronal ceroid lipofuscinosis (NCL) represents a heterogenous group of lysosomal storage diseases resulting in progressive neurodegeneration. We investigated two Small Swiss Hound littermates that showed progressive ataxia and loss of cognitive functions and vision starting around the age of 12 months. Both dogs had to be euthanized a few months after the onset of disease owing to the severity of their clinical signs. Pathological investigation of one affected dog revealed cerebral and cerebellar atrophy with cytoplasmic accumulation of autofluorescent material in degenerating neurons. The clinical signs in combination with the characteristic histopathology led to a tentative diagnosis of NCL. In the subsequent genetic investigation, the genome of one affected dog was sequenced. This revealed a duplication of 18 819 bp within the MFSD8 gene. The duplication breakpoints were located in intron 3 and exon 12 of the gene and were predicted to disrupt the reading frame. Both affected dogs carried the duplication in a homozygous state and there was perfect cosegregation of the genotypes with the phenotype in a large pedigree, consistent with autosomal recessive inheritance. MFSD8 loss‐of‐function variants are a known cause of NCL7 in human patients, dogs and other mammalian species. The existing knowledge on MFSD8 together with the experimental data strongly suggests that the identified intragenic MFSD8 duplication caused the disease in the Small Swiss Hounds. These results allow their diagnosis to be refined to NCL7 and enable genetic testing in the breed to avoid further unintentional carrier × carrier matings.

Background: Ichthyoses represent a heterogeneous group of cornification disorders characterised by epidermal scaling.Objectives: To describe the clinical, histopathological and genetic analysis of a Labrador retriever with nonepidermolytic ichthyosis, and the results of a population screening for a newly detected PNPLA1 genomic duplication.Animals: Two 7‐year‐old male littermates, 531 population samples.Materials and Methods: Clinical and histopathological analysis, whole genome sequencing and digital PCR‐based genotyping were performed.Results: Generalised scaling and histological laminar orthokeratotic hyperkeratosis confirmed the ichthyosis diagnosis on Dog 1. Dog 2 showed mild clinical signs possibly associated with allergies and not ichthyosis. The genome of Dog 1 was sequenced and compared to 1469 genetically diverse control genomes. The analysis identified a 6099‐bp duplication spanning three internal exons of the PNPLA1 gene, which is predicted to result in an altered C‐terminal tail of the protein, NP_001277038.2:p.(E558Lfs*17). Dog 2 had a heterozygous genotype and carried one copy of the duplicated PNPLA1 allele. Of the screened 531 additional Labrador retrievers, 491 were homozygous wild‐type, 36 were heterozygous carriers and four carried the duplication in a homozygous state.Conclusions and Clinical Relevance: Previously identified PNPLA1 variants cause autosomal recessive ichthyosis in golden retrievers and humans. Given the well‐established function of PNPLA1, the identified genomic duplication represents a likely candidate causal variant for the observed ichthyosis in the examined Labrador retriever. This is the first report of a new form of autosomal recessive ichthyosis in Labrador retrievers, which provides the basis for genetic testing.

Ichthyoses are a heterogenous group of inherited disorders that are characterized by excessive scale formation on the skin. We investigated a Chihuahua with severe scaling since age 12 weeks. The scaling was generalized and involved the entire body and legs. The paw pads were mildly hyperkeratotic. The clinical features together with histopathological findings in skin biopsies were compatible with non‐epidermolytic ichthyosis. To identify a potential genetic cause of the ichthyosis, we sequenced the genome of the affected dog and compared the data to 1567 control genomes. Filtering for private variants identified a homozygous missense variant in ALOXE3 , XP_038392720.1:p.(Gly460Asp). ALOXE3 is a known candidate gene for ichthyosis in humans and encodes arachidonate epidermal lipoxygenase 3. The enzyme is involved in the production of a functional corneocyte lipid envelope, an essential component of the epidermal barrier. Pathogenic variants in ALOXE3 have been described in human patients with autosomal recessive congenital ichthyosis. We assume that the identified missense variant in the affected Chihuahua of this study impairs the normal function of the ALOXE3 protein and the formation of a functioning corneocyte lipid envelope, which ultimately leads to a disorder of cornification that manifests as ichthyosis. To the best of our knowledge, this is the first report of a spontaneous ALOXE3 variant in domestic animals.

Split paw pad disease is a scarcely defined phenotype characterized by skin lesions on the paw pads of dogs. We studied a family of German Shepherd dogs, in which four dogs developed intermittent paw pad lesions and lameness. The paw pads of two of the affected dogs were biopsied and demonstrated cleft formation in the stratum spinosum and stratum corneum, the outermost layers of the epidermis. Whole genome sequencing data from an affected dog revealed a private heterozygous 18 bp in frame deletion in the KRT5 gene. The deletion NM_001346035.1:c.988_1005del or NP_001332964.1:p.(Asn330_Asp335del) is predicted to lead to a loss of six amino acids in the L12 linker domain of the encoded keratin 5. KRT5 variants in human patients lead to various subtypes of epidermolysis bullosa simplex (EBS). Localized EBS is the mildest of the KRT5‐related human diseases and may be caused by variants affecting the L12 linker domain of keratin 5. We therefore think that the detected KRT5 deletion in dogs represents a candidate causal variant for the observed skin lesions in dogs. However, while the clinical phenotype of KRT5‐mutant dogs of this study closely resembles human patients with localized EBS, there are differences in the histopathology. EBS is defined by cleft formation within the basal layer of the epidermis while the cleft formation in the dogs described herein occurred in the outermost layers, a hallmark of split paw pad disease. Our study provides a basis for further studies into the exact relation of split paw pad disease and EBS.

Hypohidrotic ectodermal dysplasia is a developmental defect characterized by sparse or absent hair, missing or malformed teeth and defects in eccrine glands. Loss-of-function variants in the X-chromosomal EDA gene have been reported to cause hypohidrotic ectodermal dysplasia in humans, mice, dogs and cattle. We investigated a male cat exhibiting diffuse truncal alopecia with a completely absent undercoat. The cat lacked several teeth, and the remaining teeth had an abnormal conical shape. Whole-genome sequencing revealed a hemizygous missense variant in the EDA gene, XM_011291781.3:c.1042G>A or XP_011290083.1:p.(Ala348Thr). The predicted amino acid exchange is located in the C-terminal TNF signaling domain of the encoded ectodysplasin. The corresponding missense variant in the human EDA gene, p.Ala349Thr, has been reported as a recurring pathogenic variant in several human patients with X-linked hypohidrotic ectodermal dysplasia. The identified feline variant therefore represents the likely cause of the hypohidrotic ectodermal dysplasia in the investigated cat, and the genetic investigation confirmed the suspected clinical diagnosis. This is the first report of an EDA-related hypohidrotic ectodermal dysplasia in cats.