Exploring skeletal disorders in cattle and sheep: a WGS-based framework for diagnosis and classification.

Background Genetic skeletal disorders are a heterogeneous group of syndromic or non-syndromic diseases characterized by abnormal bone, joint or cartilage development. These disorders generally occur sporadically in ruminants. Although a genetic etiology is often suspected, only a limited number of causal variants have been identified and no comprehensive genetic analyses of a cohort of bovine and ovine skeletal developmental defects have been published. The aims of our study were (1) to propose a nosology of genetic skeletal disorders in cattle and sheep and (2) to contribute to the nosology with a number of novel genomically characterized cases. Results Based on a literature review, the proposed nosology of skeletal disorders in cattle and sheep with a confirmed molecular cause was found to comprise 43 different disorders associated with 45 different genes. In addition, horn traits were also included. The disorders were grouped into 21 categories based on the human medical nosology. Thirty novel bovine and nine ovine cases of congenital skeletal disorders were investigated. These represented 19 different disorders, which were grouped into 9 categories. Whole-genome sequencing (WGS) data were generated based on sample availability for either complete trios, affected paternal halfsiblings or isolated single cases. We identified 21 SNVs or small indels for 12 skeletal disorders. Of these, 17 were considered candidate variants affecting 16 different genes, including 11 that were classified as pathogenic and six as likely pathogenic. Additionally, the remaining 4 SNVs were of uncertain significance. Two aneuploidies (trisomy and partial monosomy) were the cause of two different disorders. For eight cases affected by six disorders no variant could be identified. Different modes of inheritance were detected, including spontaneous dominant de novo mutations, autosomal recessive alleles, an X-linked dominant allele, as well as aneuploidies. The overall molecular genetic diagnostic rate was 64%. Conclusions Genomic analysis revealed considerable heterogeneity of the described phenotypes in terms of mode of inheritance, affected genes, and variant type. We propose, for the first time in veterinary medicine, a nosology of genetic skeletal disorders in ruminants that may be useful for more precise differential clinicopathological diagnosis. We emphasize the potential of WGS to enhance genetic disease diagnosis and the importance of adopting a nosology for disease categorization.