A Heterozygous Missense Variant in the COL5A2 in Holstein Cattle Resembling the Classical Ehlers\u2013Danlos Syndrome

ClassicalEhlers-Danlossyndrome(cEDS)isaheritableconnectivetissuedisordercharacterizedbyvariabledegreesofskinhyperextensibilityandfragility,atrophicscarring,andgeneralizedjointhypermobility.ThepurposeofthisstudywastocharacterizetheclinicopathologicalphenotypeofacEDS\u2010affectedHolsteincalfandtoidentifythecausativegeneticvariantassociatedwiththedisorderbywhole\u2010genomesequencing(WGS).A3\u2010day\u2010oldfemaleHolsteincalfwasreferredbecauseofeasilyinducedskindetachmentandhyperextensibilityintheneck.Acompleteclinicalinvestigationwasperformedinthecalf,dam,andmaternal\u2010grandmother.Thecalfanddamshowedhyperextensibilityoftheneckskinandatrophicscarring;additionally,thecalfpresentedskinfragility.Moreover,thehistopathologyofbiopsiesfromthecalfanditsdamshowedthatthecollagenbundlesinaffectedskinareaswerewavy,short,thin,andsurroundedbyedemaandmoderatetosevereacutehemorrhages.GeneticanalysisrevealedaprivateheterozygousmissensevariantinCOL5A2(c.2366G>T;p.Gly789Val)thatwaspresentonlyinthecalfanddam.ThisconfirmedthediagnosisofcEDSandrepresentsthefirstreportofacausalvariantforcEDSincattleandthefirstCOL5A2\u2010relatedlargeanimalmodel