P6029 Congenital cataract formation in Holstein Friesian cattle.

Congenital cataracts are opacities of the lens present from birth. Affected individuals suffer from loss of vision differing from moderately impaired up to total blindness. Until today, more than 255 genes have been described to harbor causative mutations for hereditary cataracts in humans. Identified mutations mostly affect genes coding for lens crystallins, but also membrane, cytoskeleton, and gap junction proteins, beaded filaments, growth, and transcriptional factors. Cataracts in cattle have been observed in different breeds as Holstein Friesian, Jersey, Hereford, Aberdeen Angus, Shorthorn, Ayrshire, and Romagnola. However, the genetic basis of cataract formation remained unknown in most cases. We investigated 31 cases of bilateral congenital cataract in Holstein Friesian cattle. Pedigree analysis revealed that 26 of 31 cases were paternal half siblings. 28 of 31 cases shared one common ancestor on the dam and sire site of the pedigree three to five generations earlier. A case-control study was performed using genotyping data of 26 cases and 88 controls to check for associations with the cataract phenotype. A genome-wide analysis using the Illumina BovineSNP50v2 BeadChip revealed an association on bovine chromosome 7 (BTA7) at position 12.4 Mb (Bonferroni-adjusted p-value: 1.85 × 10–32) and 6.2 Mb (p-value: 5.44 × 10–30). Regarding the proposed autosomal recessive inheritance, we searched for regions of extended homozygosity in cases. A 7.4 Mb interval from 5,675,621 to 13,146,547 on BTA7 (UMD_3.1) was detected covered by 80 single nucleotide polymorphism (SNP) loci, and does not contain any genes previously described as cataract causing. To assess the population frequency, the region was phased (Beagle v. 3.3.2) and inferred for the putative disease related haplotype. The frequency of carriers deduced from haplotyping was ∼0.4% in 25,000 randomly tested Holstein Friesian cattle. Within and around the region of extended homozygosity, we searched for positional-functional candidate genes. Four potential functional candidates strongly linked to lens development (NOTCH3, NXNL1, SMARCA4, DNMT1) were identified and analyzed by Sanger sequencing. Furthermore, 21 positional candidates solely based on their location and four genes weakly linked to eye development were selected. Nevertheless, all these genes had to be excluded as potentially disease causing, because none of the detected variants were unambiguously associated with the phenotype, and/or the detected variants had no effect on the amino acid sequence. Due to the lack of further candidate genes in the associated region, additional studies, such as whole genome resequencing of affected and related cattle, are planned to elucidate the disease-causing mutation.