Canine Disorder Mirrors Human Disease: Exonic Deletion in HES7 Causes Autosomal Recessive Spondylocostal Dysostosis in Miniature Schnauzer Dogs

Spondylocostal dysostosis is a congenital disorder of the axial skeleton documented in human families from diverse racial backgrounds. The condition is characterised by truncal shortening, extensive hemivertebrae and rib anomalies including malalignment, fusion and reduction in number. Mutations in the Notch signalling pathway genes DLL3, MESP2, LFNG, HES7 and TBX6 have been associated with this defect. In this study, spondylocostal dysostosis in an outbred family of miniature schnauzer dogs is described. Computed tomography demonstrated that the condition mirrors the skeletal defects observed in human cases, but unlike most human cases, the affected dogs were stillborn or died shortly after birth. Through gene mapping and whole genome sequencing, we identified a single-base deletion in the coding region of HES7. The frameshift mutation causes loss of functional domains essential for the oscillatory transcriptional autorepression of HES7 during somitogenesis. A restriction fragment length polymorphism test was applied within the immediate family and supported a highly penetrant autosomal recessive mode of inheritance. The mutation was not observed in wider testing of 117 randomly sampled adult miniature schnauzer and six adult standard schnauzer dogs; providing a significance of association of Praw = 4.759e-36 (genome-wide significant). Despite this apparently low frequency in the Australian population, the allele may be globally distributed based on its presence in two unrelated sires from geographically distant locations. While isolated hemivertebrae have been observed in a small number of other dog breeds, this is the first clinical and genetic diagnosis of spontaneously occurring spondylocostal dysostosis in a non-human mammal and offers an excellent model in which to study this devastating human disorder. The genetic test can be utilized by dog breeders to select away from the disease and avoid unnecessary neonatal losses.脊柱肋骨发育不良（Spondylocostal dysostosis）是一种累及中轴骨骼的先天性疾病，已在不同种族背景的人类家庭中被报道。该疾病以躯干缩短、广泛半椎体及肋骨异常（包括排列异常、融合与数目减少）为典型特征。Notch信号通路（Notch signalling pathway）相关基因DLL3、MESP2、LFNG、HES7及TBX6的突变，已被证实与该疾病的发生相关。本研究报道了一例发生于远交繁殖迷你雪纳瑞犬家系中的脊柱肋骨发育不良病例。计算机断层扫描（Computed tomography）结果显示，该病例的骨骼缺陷表型与人类患者高度相似，但与多数人类病例不同的是，患病幼犬均为死产或出生后不久即死亡。通过基因定位与全基因组测序（whole genome sequencing），我们在HES7基因的编码区发现一处单碱基缺失。该移码突变导致体节发生（somitogenesis）过程中，HES7发挥周期性转录自我调控功能所必需的结构域发生丢失。我们针对该核心家系成员开展了限制性片段长度多态性（restriction fragment length polymorphism）检测，结果支持该疾病以外显率极高的常染色体隐性遗传模式传递。在对117份随机采样的成年迷你雪纳瑞犬及6份成年标准雪纳瑞犬的扩大筛查中，未检测到该突变，其关联显著性达Praw=4.759×10⁻³⁶（达到全基因组显著性水平）。尽管该突变在澳大利亚犬种群中频率较低，但鉴于其在两匹来自地理距离遥远地区的无关种公犬中均存在，提示该等位基因可能在全球范围内广泛分布。尽管少数其他犬品种中曾报道过孤立性半椎体病例，但本研究是首次在非人类哺乳动物中确诊自发性脊柱肋骨发育不良，可为研究这一严重人类疾病提供优质的动物模型。该基因检测方法可被犬繁育者用于规避该疾病的传播，减少不必要的新生幼犬死亡。