Gene function & annotation

Report of a bovine form of Ehlers-Danlos Syndrome in Holstein cattle due to a de novo COL5A1 nonsense variant

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Abstract

As in humans, numerous skin abnormalities have been described in animals, including Ehlers-Danlos syndrome (EDS). This complex condition primarily affects the skin, but depending on the subtype and the genes involved, it can also affect other connective tissues, leading to varying degrees of severity. Beyond the welfare implications, repetitive skin damage compromises its protective function. In livestock such defects often lead to increase juvenile mortality due to infection or euthanasia, making the identification and management of these conditions a critical issue for breeding companies.Since 2021, sixteen descendants of the same Holstein bull have been reported to the National Observatory for Bovine Abnormalities for exhibiting skin fragility and hyperextensibility reminiscent of EDS. The aim of this study was to characterise the EDS-like phenotype and identify its genetic basis.Clinical investigations, including necropsies and histological analyses, revealed hyperextensible and fragile skin with healed scars and abnormally thin areas, as well as an altered collagen architecture, with irregular, intensely eosinophilic fibres arranged in a comma-shaped pattern and separated by spaces. These findings were consistent with Ehlers-Danlos syndrome, despite the absence of joint hypermobility. Based on the pedigree structure, a dominant mode of inheritance with potential mosaicism in the sire was hypothesized. Transmission disequilibrium test (TDT) mapping was performed considering 16 affected animals and 113 control half-sibs genotyped with the Illumina EuroGMD SNP array, revealing a 13.7 Mb region at the end of chromosome 11 between positions 92.2 and 105.9 Mb. This region contained a strong candidate gene, COL5A1, that is known to cause the classical form of EDS in humans.The whole genome of an affected animal was sequenced and compared with 1,869 control genomes. After applying stringent filtering criteria, ten private heterozygous variants located within the mapping interval were identified. Of these, one was predicted to have a protein-changing effect, a nonsense variant in the candidate gene. Subsequent genotyping by PCR and Sanger sequencing within the affected pedigree confirmed the de novo origin and likely causality of the COL5A1 variant.Finally, analysis of transmission distortion within the control group allowed us to estimate the level of mosaicism for this variant in the sire at 24%. In conclusion, we report the first identification of a COL5A1 variant associated with Ehlers-Danlos syndrome in cattle, displaying clinical features closely resembling those previously described in humans. Genetic counselling and expert recommendations were provided, which in this case led to the removal of the bull from the breeding catalogue.

Keywords: 2026

How to Cite:

Grohs, C., Ravary-Plumioën, B., Besnard, F., Eon, C., Marie, N., Hudrisier, M., Clément, A., Foucras, G., Eche, C., Leclerc, H., Danchin-Burge, C., Boussaha, M., Millemann, Y. & Capitan, A., (2026) “Report of a bovine form of Ehlers-Danlos Syndrome in Holstein cattle due to a de novo COL5A1 nonsense variant”, World Congress on Genetics Applied to Livestock Production Digital Archive 2026(1): 2285547. doi: https://doi.org/10.31274/wcgalp.23738

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