A de novo variant in the bovine ADAMTSL4 gene in an Original Braunvieh calf with congenital cataract.

Inherited forms of cataract are a heterogeneous group of eye disorders known in livestock species. Clinicopathological analysis of a single case of impaired vision in a newborn Original Braunvieh calf revealed nuclear cataract. Whole-genome sequencing of the parent-offspring trio revealed a de novo mutation of ADAMTSL4 in this case. The heterozygous p.Arg776His missense variant affects a conserved residue of the ADAMTSL4 gene that encodes a secreted glycoprotein expressed in the lens throughout embryonic development. In humans, ADAMTSL4 genetic variants cause recessively inherited forms of subluxation of the lens. Given that ADAMTSL4 is a functional candidate gene for inherited disorders of the lens, we suggest that heterozygosity for the identified missense variant may have caused the congenital cataract in the affected calf. Cattle populations should be monitored for unexplained cataract cases, with subsequent DNA sequencing a hypothesized pathogenic effect of heterozygous ADAMTSL4 variants could be confirmed.

CNGB3 Missense Variant Causes Recessive Achromatopsia in Original Braunvieh Cattle.

Sporadic occurrence of inherited eye disorders has been reported in cattle but so far pathogenic variants were found only for rare forms of cataract but not for retinopathies. The aim of this study was to characterize the phenotype and the genetic aetiology of a recessive form of congenital day-blindness observed in several cases of purebred Original Braunvieh cattle. Electroretinography in an affected calf revealed absent cone-mediated function, whereas the rods continue to function normally. Brain areas involved in vision were morphologically normal. When targeting cones by immunofluorescence, a decrease in cone number and an accumulation of beta subunits of cone cyclic-nucleotide gated channel (CNGB3) in the outer plexiform layer of affected animals was obvious. Achromatopsia is a monogenic Mendelian disease characterized by the loss of cone photoreceptor function resulting in day-blindness, total color-blindness, and decreased central visual acuity. After SNP genotyping and subsequent homozygosity mapping with twelve affected cattle, we performed whole-genome sequencing and variant calling of three cases. We identified a single missense variant in the bovine CNGB3 gene situated in a ~2.5 Mb homozygous genome region on chromosome 14 shared between all cases. All affected cattle were homozygous carriers of the p.Asp251Asn mutation that was predicted to be deleterious, affecting an evolutionary conserved residue. In conclusion, we have evidence for the occurrence of a breed-specific novel CNGB3-related form of recessively inherited achromatopsia in Original Braunvieh cattle which we have designated OH1 showing an allele frequency of the deleterious allele of ~8%. The identification of carriers will enable selection against this inherited disorder. The studied cattle might serve as an animal model to further elucidate the function of CNGB3 in mammals.

APOB-associated cholesterol deficiency in Holstein cattle is not a simple recessive disease.

In 2015, cholesterol deficiency (CD) was reported for the first time as a new recessive defect in Holstein cattle. After GWAS mapping and identification of a disease-associated haplotype, a causative loss-of-function variant in APOB was identified. CD-clinically affected APOB homozygotes showed poor development, intermittent diarrhea and hypocholesterolemia and, consequently, a limited life expectation. Herein, we present a collection of 18 cases clinically diagnosed as CD-affected APOB heterozygotes. CD-clinically affected heterozygotes show reduced cholesterol and triglyceride blood concentrations. The differences in total blood cholesterol and triglycerides between nine CD-clinically affected and 36 non-affected heterozygotes were significant. As only some APOB heterozygotes show the clinical CD phenotype, we assume that the penetrance is reduced in heterozygotes compared to the fully penetrant effect observed in homozygotes. We conclude that APOB-associated CD represents most likely an incomplete dominant inherited metabolic disease with incomplete penetrance in heterozygotes.

A de novo germline mutation of DLX3 in a Brown Swiss calf with tricho-dento-osseus-like syndrome.

OBJECTIVE: A novel congenital disorder affecting a calf was observed, and its phenotype and genetic mutation identified. ANIMAL: A six-month-old female Brown Swiss calf. METHODS: Diagnostic investigation and whole genome sequencing of a case parent trio was performed. RESULTS: The calf had a dull kinky coat with mild hypotrichosis, and teeth with brown staining and enamel defects. Histological examination of skin biopsies was compatible with a follicular dysplasia. Radiography and computed tomography revealed thickening of the skull bones and large pulp cavities with a marked thinning of enamel affecting all teeth. A de novo germline mutation affecting the distal-less homeobox gene (DLX3) was identified. The 10 bp frameshift mutation in exon 3 of the bovine DLX3 gene is predicted to replace the second C-terminal transactivation domain of the wild-type protein by a recoded peptide of 99 amino acids without any sequence similarity. CONCLUSION AND CLINICAL IMPORTANCE: A causative mutation for a sporadic phenotype resembling human tricho-dento-osseous syndrome was identified after detection of a de novo germline mutation in the DLX3 gene.