背景:温血脆性Foal综合征1型(WFFS)是一种常染色体隐性遗传疾病,以前仅在温血中报道,被认为是由前胶原赖氨酸基因的变异引起的,2-酮戊二酸5-双加氧酶1(PLOD1,c.2032G>A,p.Gly678Arg)。鉴于这个纯种病例的介绍,我们假设类似的遗传机制导致了这种表型。
目的:描述在英国兽医实践中出现的与其他Ehlers-Danlos综合征相似的皮肤病变的小马驹的病理和遗传发现,包括那些用WFFS记录的温暖血液。
方法:描述遗传调查的单个病例报告。
方法:对表现为难产的纯种小马驹实施安乐死,以治疗多种皮肤损伤和发育异常。从小马驹中提取的DNA进行了PLOD1变体测试(c.2032G>A,p.Gly678Arg)使用可商购的测定法。为了确认因果关系并进一步询问Ehlers-Danlos综合征的潜在新原因,1799个功能候选基因,包括PLOD1,使用从马驹肌肉中提取的DNA产生的全基因组测序数据进行分析。将这些数据与来自至少11个其他品种的34个对照样品进行比较。基于对蛋白质功能的预测影响,将变体优先用于进一步评估。
结果:验尸评估得出结论,这只小马驹患有胶原蛋白发育不良。小马驹对于c.2032G>APLOD1变体是纯合的。从全基因组测序数据中鉴定出的另外两个错义变体也被计算预测为对蛋白质功能有害。(NPHP3c.1253T>C,p.Leu418Pro,EPDR1c.154G>C,p.Glu52Gln)。这些基因都没有与相似的表型相关,或人类或其他物种的Ehlers-Danlos综合征,因此不需要进一步研究这些变异作为EDS的原因。
结论:本研究是纯种中的单例报告,没有来自该品种的其他病例可以复制这一发现。
结论:鉴于临床表现与WFFS相似,PLOD1变体的纯合性,WGS实验中没有另一个更合理的因果变异,我们得出的结论是,PLOD1c.2032G>A是导致这种小马驹状况的可能原因。这是在血液以外的品种中由PLOD1变体引起的脆弱的小马驹综合症的第一个记录证据,纯种。因此,我们建议将这种疾病的名称更改为1型脆弱的小马驹综合征(FFS),并在纯种犬中使用基因检测,以避免产生受影响的小马驹。
BACKGROUND: Warmblood Fragile Foal Syndrome Type 1 (WFFS) is an autosomal recessive disorder reported previously only in warmbloods and thought to be caused by a variant in the gene procollagen-lysine,2-oxoglutarate 5-dioxygenase 1 (PLOD1, c.2032G>A, p.Gly678Arg). Given the presentation of this Thoroughbred
case, we hypothesised that a similar genetic mechanism caused this phenotype.
OBJECTIVE: To describe the pathological and genetic findings on a foal presenting to a veterinary practice in the UK with skin lesions similar to other Ehlers-Danlos Syndromes, including those documented for warmbloods with WFFS.
METHODS: A single
case report describing a genetic investigation.
METHODS: A Thoroughbred foal presenting as dystocia was euthanised for multiple skin lesions and developmental abnormalities. DNA extracted from the foal was tested for the PLOD1 variant (c.2032G>A, p.Gly678Arg) using the commercially available assay. To confirm causality and further interrogate potential novel causes of Ehlers-Danlos Syndrome, 1799 functional candidate genes, including PLOD1, were analysed using whole genome sequencing data generated from DNA extracted from the foal\'s muscle. These data were compared to 34 control samples from at least 11 other breeds. Variants were prioritised for further evaluation based on predicted impact on protein function.
RESULTS: Post-mortem evaluation concluded that this foal suffered from a condition of collagen dysplasia. The foal was homozygous for the c.2032G>A PLOD1 variant. Only two other missense variants identified from whole genome sequencing data were also computationally predicted to be deleterious to protein function, (NPHP3 c.1253T>C, p.Leu418Pro, EPDR1 c.154G>C, p.Glu52Gln). Neither of these genes have been linked to similar phenotypes, or Ehlers-Danlos Syndrome in humans or other species and thus further investigation of these variants as the cause of EDS was not warranted.
CONCLUSIONS: This study is a single
case report in the Thoroughbred with no additional cases from this breed yet identified to replicate this finding.
CONCLUSIONS: Given the clinical presentation similar to WFFS, homozygosity for the PLOD1 variant, and absence of another more plausible causal variant from the WGS experiment, we conclude that PLOD1 c.2032G>A is the likely cause of this foal\'s condition. This is the first documented evidence of fragile foal syndrome caused by the PLOD1 variant in a breed outside of warmbloods, the Thoroughbred. We therefore recommend a change in the name of this disorder to fragile foal syndrome type 1 (FFS) and utilisation of genetic testing in Thoroughbreds to avoid producing affected foals.