Nine male and eight female calves born to a Normande artificial insemination bull named “Ly” were referred to the French National Observatory of Bovine Abnormalities for multiple fractures, shortened gestation, and stillbirth or perinatal mortality. Using Illumina BovineSNP50 array genotypes from affected calves and 84 half-sib controls, the associated locus was mapped to a 6.5-Mb interval on chromosome 19, assuming autosomal inheritance with germline mosaicism. Subsequent comparison of the whole-genome sequences of one case and 5116 control genomes, followed by genotyping in the affected pedigree, identified a de novo missense substitution within the NC1 domain of the COL1A1 gene (Chr19 g.36,473,965G > A; p.D1412N) as unique candidate variant. Interestingly, the affected residue was completely conserved among 243 vertebrate orthologs, and the same substitution in humans has been reported to cause type II osteogenesis imperfecta (OI), a connective tissue disorder that is characterized primarily by bone deformity and fragility. Moreover, three COL1A1 mutations have been described to cause the same syndrome in cattle. Necropsy, computed tomography, radiology, and histology confirmed the diagnosis of type II OI, further supporting the causality of this variant. In addition, a detailed analysis of gestation length and perinatal mortality in 1387 offspring of Ly and more than 160,000 progeny of 63 control bulls allowed us to statistically confirm in a large pedigree the association between type II OI and preterm delivery, which is probably due to premature rupture of fetal membranes and has been reported in several isolated cases of type II OI in humans and cattle. Finally, analysis of perinatal mortality rates and segregation distortion supported a low level of germ cell mosaicism in Ly, with an estimate of 4.5% to 7.7% of mutant sperm and thus 63 to 107 affected calves born. These numbers contrast with the 17 cases reported and raise concerns about the underreporting of congenital defects to heredo-surveillance platforms, even for textbook genetic syndromes. In conclusion, we describe a large animal model for a recurrent substitution in COL1A1 that is responsible for type II OI in humans. More generally, this study highlights the utility of such datasets and large half-sib families available in livestock species to characterize sporadic genetic defects.

中文翻译：

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COL1A1 中反复发生的从头错义突变导致诺曼底牛 II 型成骨不全症和早产


一头名为“Ly”的诺曼德人工授精公牛所生的九头雄性和八头雌性小牛因多处骨折、妊娠缩短、死产或围产期死亡率被转交给法国国家牛异常观察站。使用来自受影响小牛和 84 个半同胞对照的 Illumina BovineSNP50 阵列基因型，相关基因座被映射到 19 号染色体上的 6.5 Mb 间隔，假设具有种系嵌合的常染色体遗传。随后对 1 个病例和 5116 个对照基因组的全基因组序列进行比较，然后对受影响的家系进行基因分型，发现 COL1A1 基因 NC1 结构域内存在从头错义替换 (Chr19 g.36,473,965G > A; p.D1412N ）作为独特的候选变体。有趣的是，受影响的残基在 243 个脊椎动物直向同源物中完全保守，并且据报道，在人类中相同的替换会导致 II 型成骨不全症 (OI)，这是一种主要以骨畸形和脆弱为特征的结缔组织疾病。此外，三种 COL1A1 突变已被描述可在牛身上引起相同的综合征。尸检、计算机断层扫描、放射学和组织学证实了 II 型 OI 的诊断，进一步支持了这种变异的因果关系。此外，对 1387 个 Ly 后代和 63 头对照公牛的 160,000 多个后代的妊娠长度和围产期死亡率进行了详细分析，使我们能够在一个大型谱系中统计证实 II 型 OI 与早产之间的关联，这可能是由于胎膜早破，在人类和牛的几起孤立的 II 型成骨不全病例中已有报道。 最后，对围产期死亡率和分离扭曲的分析表明，Ly 的生殖细胞嵌合体水平较低，估计有 4.5% 至 7.7% 的突变精子，因此出生了 63 至 107 头受影响的小牛。这些数字与报告的 17 例病例形成鲜明对比，并引发了人们对遗传缺陷监测平台漏报的担忧，甚至是教科书遗传综合征的漏报。总之，我们描述了一个大型动物模型，用于研究导致人类 II 型 OI 的 COL1A1 反复替换。更一般地说，这项研究强调了牲畜物种中可用的此类数据集和大型半同胞家族在表征散发性遗传缺陷方面的效用。