Novel COL5A1 variants and associated disease phenotypes in dogs with classical Ehlers‐Danlos syndrome

Abstract

Abstract Background Human patients with Ehlers‐Danlos syndrome (EDS) are categorized into subtypes based on causative genetic variants and phenotypes. The classical form of EDS, primarily caused by variants in COL5A1 or COL5A2, is a very common subtype in people but is poorly characterized in dogs. Objective Describe likely causal COL5A1 variants in dogs with classical EDS, summarize clinical histories, discuss potential disease mechanisms, and draw conclusions about disease prognosis. Animals Seven client‐owned dogs that exhibited clinical signs of classical EDS. Methods Clinical information was recorded from medical records and communication with attending veterinarians and dog owners. To identify potential causal gene sequence variants whole‐genome sequence analyses (n = 6) or Sanger sequencing (n = 1) were performed on DNA isolated from the probands. Pathological abnormalities in skin biopsy samples were assessed using histology and electron microscopy in 3 dogs. Results Six distinct heterozygous COL5A1 sequence variants were identified. The most common clinical signs included fragile skin (n = 7), hyperextensible skin (n = 7), joint hypermobility (n = 6), and atrophic scars (n = 5). The median age at last follow‐up or death was 12 years (range, 6.5‐14 years). Ultrastructural abnormalities in dermal collagen differed among dogs with different COL5A1 variants. Conclusion and Clinical Importance We describe the genotypic and phenotypic spectrum of the classical subtype of EDS by identifying 6 novel COL5A1 variants in conjunction with detailed clinical histories that included long‐term follow‐up information in 7 dogs.

Keywords

• cutaneous asthenia
• genotype‐phenotype
• precision medicine
• transmission electron microscopy
• whole‐genome sequencing