Institute of Genetics, Vetsuisse Faculty, University of Bern, Bremgartenstrasse 109a, Bern, 3012, Switzerland.
Clinic for Ruminants, Vetsuisse Faculty, University of Bern, Bremgartenstrasse 109a, Bern, 3012, Switzerland.
Acta Vet Scand. 2024 Jul 4;66(1):29. doi: 10.1186/s13028-024-00752-y.
Chiari malformation type II (CMII) was originally reported in humans as a rare disorder characterized by the downward herniation of the hindbrain and towering cerebellum. The congenital brain malformation is usually accompanied by spina bifida, a congenital spinal anomaly resulting from incomplete closure of the dorsal aspect of the spinal neural tube, and occasionally by other lesions. A similar disorder has been reported in several animal species, including cattle, particularly as a congenital syndrome. A cause of congenital syndromic Chiari-like malformation (CSCM) in cattle has not been reported to date. We collected a series of 14 CSCM-affected Holstein calves (13 purebred, one Red Danish Dairy F1 cross) and performed whole-genome sequencing (WGS). WGS was performed on 33 cattle, including eight cases with parents (trio-based; group 1), three cases with one parent (group 2), and three single cases (solo-based; group 3).
Sequencing-based genome-wide association study of the 13 Holstein calves with CSCM and 166 controls revealed no significantly associated genome region. Assuming a single Holstein breed-specific recessive allele, no region of shared homozygosity was detected suggesting heterogeneity. Subsequent filtering for protein-changing variants that were only homozygous in the genomes of the individual cases allowed the identification of two missense variants affecting different genes, SHC4 in case 4 in group 1 and WDR45B in case 13 in group 3. Furthermore, these two variants were only observed in Holstein cattle when querying WGS data of > 5,100 animals. Alternatively, potential de novo mutational events were assessed in each case. Filtering for heterozygous private protein-changing variants identified one DYNC1H1 frameshift variant as a candidate causal dominant acting allele in case 12 in group 3. Finally, the presence of larger structural DNA variants and chromosomal abnormalities was investigated in all cases. Depth of coverage analysis revealed two different partial monosomies of chromosome 2 segments in cases 1 and 7 in group 1 and a trisomy of chromosome 12 in the WDR45B homozygous case 13 in group 3.
This study presents for the first time a detailed genomic evaluation of CSCM in Holstein cattle and suggests an unexpected genetic and allelic heterogeneity considering the mode of inheritance, as well as the type of variant. For the first time, we propose candidate causal variants that may explain bovine CSCM in a certain proportion of affected calves. We present cattle as a large animal model for human CMII and propose new genes and genomic variants as possible causes for related diseases in both animals and humans.
Chiari 畸形 II 型（CMII）最初在人类中被报道为一种罕见的疾病，其特征是后脑和高耸的小脑向下疝出。这种先天性脑畸形通常伴有脊柱裂，这是一种由于脊柱神经管背侧不完全闭合而导致的先天性脊柱异常，偶尔还伴有其他病变。在包括牛在内的几种动物物种中也报告了类似的疾病，特别是作为一种先天性综合征。迄今为止，尚未报道牛先天性综合征性 Chiari 样畸形（CSCM）的病因。我们收集了一系列 14 例 CSCM 受影响的荷斯坦小牛（13 例纯种，1 例红丹麦奶牛 F1 杂交），并进行了全基因组测序（WGS）。对包括 8 例有父母的病例（基于三联体；第 1 组）、3 例有 1 个父母的病例（第 2 组）和 3 例单病例（基于独奏体；第 3 组）在内的 33 头牛进行了 WGS。
对 13 例荷斯坦 CSCM 小牛和 166 例对照进行基于测序的全基因组关联研究，未发现显著相关的基因组区域。假设单一荷斯坦品种特异性隐性等位基因，在个体病例的基因组中未检测到共享纯合区域，提示存在异质性。随后对仅在个体病例基因组中纯合的致病变异进行过滤，可鉴定出影响不同基因的两个错义变异，第 1 组的第 4 例中的 SHC4 和第 3 组的第 13 例中的 WDR45B。此外，当查询 >5100 只动物的 WGS 数据时，仅在荷斯坦牛中观察到这两个变体。或者，在每个病例中评估了潜在的新生突变事件。对杂合性私有致病变异进行过滤，在第 3 组的第 12 例中鉴定出一个 DYNC1H1 移码变异作为候选致病显性作用等位基因。最后，对所有病例均进行了较大结构 DNA 变异和染色体异常的检测。深度覆盖分析显示，第 1 组的第 1 例和第 7 例存在 2 号染色体片段的不同部分单体性，第 3 组的 WDR45B 纯合子第 13 例存在 12 号染色体三体性。
本研究首次对荷斯坦牛 CSCM 进行了详细的基因组评估，并考虑到遗传方式和变异类型，提出了令人惊讶的遗传和等位基因异质性。首次提出了可能在一定比例受影响小牛中解释牛 CSCM 的候选致病变异。我们提出牛是人类 CMII 的大型动物模型，并提出了新的基因和基因组变异作为动物和人类相关疾病的可能原因。
