Brachygnathia, cardiomegaly and renal hypoplasia syndrome (BCRHS, OMIA 001595–9940 ) is a previously reported recessively inherited disorder in Australian Poll Merino/Merino sheep. Affected lambs are stillborn with various congenital defects as reflected in the name of the disease, as well as short stature, a short and broad cranium, a small thoracic cavity, thin ribs and brachysternum. The BCRHS phenotype shows similarity to certain human short stature syndromes, in particular the human 3M syndrome-2. Here we report the identification of a likely disease-causing variant and propose an ovine model for human 3M syndrome-2. Eight positional candidate genes were identified among the 39 genes in the approximately 1 Mb interval to which the disease was mapped previously. Obscurin like cytoskeletal adaptor 1 (OBSL1) was selected as a strong positional candidate gene based on gene function and the resulting phenotypes observed in humans with mutations in this gene. Whole genome sequencing of an affected lamb (BCRHS3) identified a likely causal variant ENSOARG00000020239:g.220472248delC within OBSL1. Sanger sequencing of seven affected, six obligate carrier, two phenotypically unaffected animals from the original flock and one unrelated control animal validated the variant. A genotyping assay was developed to genotype 583 animals from the original flock, giving an estimated allele frequency of 5%. The identification of a likely disease-causing variant resulting in a frameshift (p.(Val573Trpfs*119)) in the OBSL1 protein has enabled improved breeding management of the implicated flock. The opportunity for an ovine model for human 3M syndrome and ensuing therapeutic research is promising given the availability of carrier ram semen for BCRHS.

中文翻译：

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人类3M综合征2的新绵羊模型的分子基础。

Brachygnathia，心脏肥大和肾发育不全综合征（BCRHS，OMIA 001595–9940）是澳大利亚民意调查美利奴羊/美利奴绵羊的一种隐性遗传病。患病的羔羊死胎，具有各种先天性缺陷，如疾病名称所示，以及身材矮小，颅骨短而宽，胸腔小，肋骨薄和胸骨短。BCRHS表型显示出与某些人类矮身材综合征，特别是人类3M综合征2相似。在这里，我们报告鉴定可能的致病变异，并提出人类3M综合征2的绵羊模型。在该疾病先前定位的大约1 Mb间隔中，在39个基因中鉴定出8个位置候选基因。基于基因功能和在具有该基因突变的人类中观察到的表型，选择了类似Obscurin的细胞骨架衔接子1（OBSL1）作为强位置候选基因。受影响的羔羊的全基因组测序（BCRHS3）在OBSL1中鉴定出可能的因果变体ENSOARG00000020239：g.220472248delC。Sanger测序的七只患病，六只专心携带者，两只来自原始群的表型未受影响的动物和一只无关的对照动物验证了该变体。进行了基因分型分析，以对来自原始羊群的583只动物进行基因分型，得出等位基因频率估计为5％。鉴定可能的致病变体导致OBSL1蛋白发生移码（p。（Val573Trpfs * 119）），已使相关鸡群的育种管理得以改善。