Background: Brachygnathia, cardiomegaly and renal hypoplasia syndrome (BCRHS, OMIA 001595â??9940) is a previously\nreported recessively inherited disorder in Australian Poll Merino/Merino sheep. Affected lambs are stillborn with various\ncongenital defects as reflected in the name of the disease, as well as short stature, a short and broad cranium, a small\nthoracic cavity, thin ribs and brachysternum. The BCRHS phenotype shows similarity to certain human short stature\nsyndromes, in particular the human 3M syndrome-2. Here we report the identification of a likely disease-causing variant\nand propose an ovine model for human 3M syndrome-2.\nResults: Eight positional candidate genes were identified among the 39 genes in the approximately 1 Mb interval to\nwhich the disease was mapped previously. Obscurin like cytoskeletal adaptor 1 (OBSL1) was selected as a strong\npositional candidate gene based on gene function and the resulting phenotypes observed in humans with mutations\nin this gene. Whole genome sequencing of an affected lamb (BCRHS3) identified a likely causal variant\nENSOARG00000020239:g.220472248delC within OBSL1. Sanger sequencing of seven affected, six obligate carrier, two\nphenotypically unaffected animals from the original flock and one unrelated control animal validated the variant. A\ngenotyping assay was developed to genotype 583 animals from the original flock, giving an estimated allele frequency\nof 5%.\nConclusions: The identification of a likely disease-causing variant resulting in a frameshift (p.(Val573Trpfs*119)) in the\nOBSL1 protein has enabled improved breeding management of the implicated flock. The opportunity for an ovine\nmodel for human 3M syndrome and ensuing therapeutic research is promising given the availability of carrier ram\nsemen for BCRHS.
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