Intragenic PNPLA1 duplication in Labrador retrievers with nonepidermolytic ichthyosis

BackgroundIchthyoses represent a heterogeneous group of cornification disorders characterised by epidermal scaling.ObjectivesTo 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.AnimalsTwo 7-year-old male littermates, 531 population samples.Materials and MethodsClinical and histopathological analysis, whole genome sequencing and digital PCR-based genotyping were performed.ResultsGeneralised 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 RelevancePreviously 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. Xxxxxxxx. Xxxxxxxx. Xxxxxxxx.