Independent COL5A1 Variants in Cats with Ehlers-Danlos Syndrome

Kiener, Sarah; Apostolopoulos, Neoklis; Schissler, Jennifer R.; Hass, Pascal-Kolja; Leuthard, Fabienne; Jagannathan, Vidhya; Schuppisser, Carole; Soto, Sara; Welle, Monika Maria; Mayer, U.; Leeb, Tosso; Fischer, Nina; Kaessmeyer, Sabine

doi:10.3390/genes13050797

Cited by 6 publications

(15 citation statements)

References 35 publications

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“…Reported SEIs ranged from 19% to 27%. 15,16 Both perineal and diaphragmatic hernias have been described in EDS cats. 13 Wound healing in EDS animals is reportedly normal, and these animals may safely undergo procedures such as onychectomy, routine castration and ovariohysterectomy if perioperative precautions are taken.…”

Section: Discussionmentioning

confidence: 99%

“…Neurological signs associated with EDS are poorly described in animals, but seizures and flattened cerebral gyri were noted in a previous report and hyperesthesia and mild lower motor neuron paraparesis were noted in our case. 15,16 Cardiovascular signs are also poorly described in cats. Although mild SAM was observed in our case, we also have observed sudden death, presumably secondary to aneurysm or other vascular events, in cats with EDS.…”

Section: Discussionmentioning

confidence: 99%

“…The 99 Lives dataset had 2 289 566 variants, the unique variants for the case cat are presented (Supplementary Table S1a). Considering dominant inheritance (ie, heterozygous for the case) and unique variants with a passing VQSRTranche score 23 16 The variant for the presented case is above the image, the c.501-2A>C variant at the end of exon 4, which could lead to exon skipping or a frameshift in the cat.…”

Section: Geneticsmentioning

confidence: 99%

“…All variants detected in 99 Lives Cat Genome Sequencing Consortium dataset for COL5A1 are presented in (Supplementary Table S1c) including 2 previously published variants as those EDS cats in the 99 Lives dataset. 16 This nucleotide position for the splice-acceptor variant is highly conserved in mammalian species and the protein homology is high for exon 4 in mammals, including 98% homology between humans and cats (Supplementary Figures S1 and S2). Using 2 different splice site prediction tools, this alteration is predicted by the Berkeley Drosophila Genome Project 29 and ESEfinde to abolish the native splice acceptor site.…”

Section: Geneticsmentioning

confidence: 99%

“…15 After the initial discovery, 3 new COL5A1 mutations were reported in cats. 16 The mutations are a c.112_118+15del a 22-base pair (bp) deletion removing the boundary between exon 1 and intron 1, a c.3514A>T nonsense variant predicted to truncate 36% of the coding sequence, and a 1 bp deletion at c.3066del leading to a frameshift mutation predicted to truncate 44% of the open reading frame. 16 Herein the clinical, histopathological, ultrastructural, and genetic findings of a 4-year-old male castrated domestic medium hair cat presented with clinical signs consistent with cEDS are reported.…”

Section: Introductionmentioning

confidence: 99%

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Precision medicine using whole genome sequencing in a cat identifies a novel COL5A1 variant for classical Ehlers‐Danlos syndrome

McElroy,

Gray‐Edwards,

Coghill

et al. 2023

Veterinary Internal Medicne

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BackgroundEhlers‐Danlos syndromes (EDS) are a heterogeneous group of heritable connective tissue disorders occurring in both human and veterinary patients. The genetics of these disorders are poorly described in small animal patients.Hypothesis/ObjectivesDefine the clinical manifestations and genetic cause of a suspected form of EDS in a cat.AnimalsA 14‐week‐old male domestic medium hair cat was presented with skin hyperextensibility and fragility. The classic tragic facial expression was observed as well as chronic pruritus and mild hyperesthesia.MethodsBlood samples and a skin biopsy sample were collected from the affected cat. Clinical examinations, histology, electron microscopy and whole genome sequencing were conducted to characterize the clinical presentation and identify possible pathogenic DNA variants to support a diagnosis. Criteria defining variant pathogenicity were examined including human disease variant databases.ResultsHistology showed sparse, disorganized collagen and an increase in cutaneous mast cells. Electron microscopy identified ultrastructural defects commonly seen in collagen type V alpha 1 chain (COL5A1) variants including flower‐like collagen fibrils in cross‐section. Whole genome sequencing and comparison with 413 cats in the 99 Lives Cat Genome Sequencing Consortium database identified a novel splice acceptor site variant at exon 4 in COL5A1 (c.501‐2A>C).Conclusions and Clinical ImportanceOur report broadens the current understanding of EDS in veterinary patients and supports the use of precision medicine techniques in clinical veterinary practice. The classification of variants for pathogenicity should be considered in companion animals.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Geneticsmentioning

confidence: 99%

Section: Geneticsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Precision medicine using whole genome sequencing in a cat identifies a novel COL5A1 variant for classical Ehlers‐Danlos syndrome

McElroy,

Gray‐Edwards,

Coghill

et al. 2023

Veterinary Internal Medicne

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Beta-mannosidosis in a domestic cat associated with a missense variant in MANBA

Katz,

Cook,

Vite

et al. 2024

Gene

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Identification of an ADAMTS2 frameshift variant in a cat family with Ehlers–Danlos syndrome

Simon

Kiener

Thom

et al. 2023

G3: Genes, Genomes, Genetics

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We investigated four European domestic shorthair kittens with skin lesions consistent with the dermatosparaxis type of the Ehlers-Danlos syndrome (EDS), a connective tissue disorder. The kittens were sired by the same tomcat, but were born by three different mothers. The kittens had easily torn skin resulting in non-healing skin wounds. Both clinically and histologically, the skin showed thin epidermis in addition to inflammatory changes. Changes in collagen fibers were visible in electron micrographs. The complete genome of an affected kitten was sequenced. A one base pair duplication leading to a frameshift in the candidate gene ADAMTS2 was identified, p.(Ser235fs*3). All four affected cats carried the frameshift duplication in a homozygous state. Genotypes at this variant showed perfect co-segregation with the autosomal recessive EDS phenotype in the available family. The mutant allele did not occur in 48 unrelated control cats. ADAMTS2 loss-of-function variants cause autosomal recessive forms of EDS in humans, mice, dogs, cattle and sheep. The available evidence from our investigation together with the functional knowledge on ADAMTS2 in other species allow to classify the identified ADAMTS2 variant as pathogenic and most likely causative variant for the observed EDS.

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Independent COL5A1 Variants in Cats with Ehlers-Danlos Syndrome

Cited by 6 publications

References 35 publications

Precision medicine using whole genome sequencing in a cat identifies a novel COL5A1 variant for classical Ehlers‐Danlos syndrome

Precision medicine using whole genome sequencing in a cat identifies a novel COL5A1 variant for classical Ehlers‐Danlos syndrome

Beta-mannosidosis in a domestic cat associated with a missense variant in MANBA

Identification of an ADAMTS2 frameshift variant in a cat family with Ehlers–Danlos syndrome

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