Congenital hydrocephalus in a Belgian draft horse associated with a nonsense mutation in B3GALNT2

Abstract

Congenital hydrocephalus has been reported for a number of horse breeds, and for Friesian horses this condition has been associated with a nonsense mutation of B3GALNT2. We report the first case of congenital hydrocephalus associated with the said mutation in a Belgian draft horse. Genetic testing and consideration of the testing results in breeding programs are warranted.

Congenital hydrocephalus (CH) is a birth defect characterized by the accumulation of cerebrospinal fluid in the ventricles of the brain, which results in a marked increase in cranial cavity volume (1). While CH in horses is not a common occurrence, 0.6 foals per 1000 births are estimated to be affected (2); it does result in the abortion or stillbirth of affected foals and can be a cause of dystocia. Congenital hydrocephalus has been reported for a number of horse breeds including the American Quarter Horse (3), American Miniature Horse (4), Friesian horse (1), Standardbred (5), Hanoverian Warmblood (6), and Thoroughbred (7). In Friesian horses, CH has an autosomal recessive mode of inheritance which is associated with a nonsense mutation in the B3GALNT2 gene (8). Interestingly, the same nonsense mutation of the B3GALNT2 gene has been reported in a human patient with muscular dystrophy suffering from hydrocephalus (9). Eight of 83 (9.6%) randomly selected Friesian stallions in Mexico were heterozygous for the nonsense mutation of the B3GALNT2 gene (10), while 8 of 60 (13.3%) Friesian stallions, and 139 of 805 (17.3%) Friesian broodmares screened in the Netherlands were carriers of the mutated allele (8).

We report here the first case of congenital hydrocephalus associated with the aforementioned mutation of B3GALNT2 in a Belgian draft horse. In the fall of 2016, a Belgian draft mare aborted a fetus during the 7th month of gestation. Upon visual inspection, the fetus had an enlarged and abnormally shaped skull (Figure 1). The dam’s daughter, which had been bred to the same stallion, also aborted a fetus with hydrocephalus during the third trimester around day 300 of gestation. Samples, including those of the dam and sire, were submitted to a commercial laboratory to determine the presence and zygosity of the B3GALNT2 nonsense mutation (Animal Genetics, Tallahassee, Florida, USA). Both parents were revealed to be carriers, i.e., heterozygous, for the mutation. Following the Mendelian laws of inheritance, the mating of heterozygous carriers results in a 25% chance of obtaining a foal that is homozygous for the mutation and will be affected by hydrocephalus (Figure 2).

Figure 1.

Enlarged and abnormally shaped skull of the aborted fetus.

Figure 2.

Diagram depicting Mendel’s laws of inheritance when mating 2 heterozygous carriers. B — unmutated allele; b — mutated allele.

The seemingly high prevalence rate for heterozygosity in the Friesian horse population of greater than 10% (8) is likely attributable to the high inbreeding rate which was computed to be 1.5% using pedigree data (11), and exceeds the limit of 1% as recommended by the Food and Agriculture Organization (FAO) (12). Inbreeding data are not available for the Belgian draft breed, but given that it is a small population, a higher than average inbreeding rate can be expected.

The identification of the nonsense mutation of B3GALNT2 in a breed other than the Friesian horse emphasizes the importance of genetic testing in cases of CH and the consideration of results for future matings. Ideally, only individuals not carrying the mutated allele should be paired. Realizing that this is not always practical, it is strongly recommended to have only one of the parents be a heterozygous carrier for the mutated allele to avoid the risk of CH in the resulting offspring. Should the mating of 2 heterozygous carriers be pursued, preimplantation genetic testing is a viable solution to manage the risk of CH in the resulting foal. Following breeding, the blastocyst is recovered and a trophectoderm biopsy is obtained after which the embryo is cryopreserved. Following genetic testing of the biopsied material confirming the absence of the B3GALNT2 mutation, the cryopreserved embryo can be transferred to a recipient mare (13,14). CVJ