颅骨关节骨病(CMO)和颅骨增生综合征(CHS)是增生性的,影响幼犬颅骨的非肿瘤性疾病。在许多犬种中已经描述了这些增生性疾病的不同形式。然而,到目前为止,仅在三个Terrier品种中报道了影响SLC37A2剪接的CMO的不完全显性致病变体。这项研究的目的是进一步确定与美国斯塔福德郡梗中CHS相关的可能的致病遗传变异,以及七个不同品种的受影响狗的CMO。我们调查了他们的全基因组序列(WGS),并使用584个不相关的基因组过滤变异,这表明所有受影响的狗都没有变异。然而,在8例病例中的3例中,分别对每个病例的私有变异进行筛选,得出了似乎合理的显性遗传候选变异。在澳大利亚梗中,在COL1A1基因中发现了杂合错义变体(c.1786G>A;p.(Val596Ile))。先前在患有婴儿皮质肥大症的人类中报道了COL1A1中的致病性错义变异,或者卡菲病,类似于犬CMO。此外,在一只巴塞特猎犬里,在SLC37A2(c.1446+1G>A)中发现了一个最可能致病的杂合剪接位点变异体,如之前在SLC37A2相关的猎犬CMO中所示,预测会导致外显子跳跃。最后,在威玛兰中,由于SLC35D1在软骨形成和骨骼发育中的关键作用,SLC35D1中的杂合移码变体(c.1021_1024delTCAG;p。(Ser341ArgfsTer22))可能会导致CMO。我们的研究表明犬CMO的等位基因和基因座异质性,并说明了基于WGS的精准医学在狗中的当前可能性和局限性。
Craniomandibular osteopathy (CMO) and calvarial hyperostotic syndrome (CHS) are proliferative, non-neoplastic disorders affecting the skull bones in young dogs. Different forms of these hyperostotic disorders have been described in many dog breeds. However, an incompletely dominant causative variant for CMO affecting splicing of SLC37A2 has been reported so far only in three Terrier breeds. The purpose of this study was to identify further possible causative genetic variants associated with CHS in an American Staffordshire Terrier, as well as CMO in seven affected dogs of different breeds. We investigated their whole-genome sequences (WGS) and filtered variants using 584 unrelated genomes, which revealed no variants shared across all affected dogs. However, filtering for private variants of each case separately yielded plausible dominantly inherited candidate variants in three of the eight cases. In an Australian Terrier, a heterozygous missense variant in the COL1A1 gene (c.1786G>A; p.(Val596Ile)) was discovered. A pathogenic missense variant in COL1A1 was previously reported in humans with infantile cortical hyperostosis, or Caffey disease, resembling canine CMO. Furthermore, in a Basset Hound, a heterozygous most likely pathogenic splice site variant was found in SLC37A2 (c.1446+1G>A), predicted to lead to exon skipping as shown before in SLC37A2-associated canine CMO of Terriers. Lastly, in a Weimaraner, a heterozygous frameshift variant in SLC35D1 (c.1021_1024delTCAG; p.(Ser341ArgfsTer22)) might cause CMO due to the critical role of SLC35D1 in chondrogenesis and skeletal development. Our study indicates allelic and locus heterogeneity for canine CMO and illustrates the current possibilities and limitations of WGS-based precision medicine in dogs.