Abstract
BackgroundBovine frontonasal dysplasias like arhinencephaly, synophthalmia, cyclopia and anophthalmia are sporadic congenital facial malformations. In this study, computed tomography, necropsy, histopathological examinations and whole genome sequencing on an Illumina NextSeq500 were performed to characterize a stillborn Limousin calf with frontonasal dysplasia. In order to identify private genetic and structural variants, we screened whole genome sequencing data of the affected calf and unaffected relatives including parents, a maternal and paternal halfsibling.ResultsThe stillborn calf exhibited severe craniofacial malformations. Nose and maxilla were absent, mandibles were upwardly curved and a median cleft palate was evident. Eyes, optic nerve and orbital cavities were not developed and the rudimentary orbita showed hypotelorism. A defect centrally in the front skull covered with a membrane extended into the intracranial cavity. Aprosencephaly affected telencephalic and diencephalic structures and cerebellum. In addition, a shortened tail was seen. Filtering whole genome sequencing data revealed a private frameshift variant within the candidate gene ZIC2 in the affected calf. This variant was heterozygous mutant in this case and homozygous wild type in parents, half-siblings and controls.ConclusionsWe found a novel ZIC2 frameshift mutation in an aprosencephalic Limousin calf. The origin of this variant is most likely due to a de novo mutation in the germline of one parent or during very early embryonic development. To the authors’ best knowledge, this is the first identified mutation in cattle associated with bovine frontonasal dysplasia.
Highlights
Bovine frontonasal dysplasias like arhinencephaly, synophthalmia, cyclopia and anophthalmia are sporadic congenital facial malformations
The absence of the olfactory tract, partial fusion, complete fusion or the total absence of ocular globes are phenotypes of Frontonasal dysplasias (FND) found in cattle [1]
Phenotype The stillborn male Limousin calf had a weight of 52 kg and the crest-rump length was 103 cm (40.55 in.)
Summary
Bovine frontonasal dysplasias like arhinencephaly, synophthalmia, cyclopia and anophthalmia are sporadic congenital facial malformations. In this study, computed tomography, necropsy, histopathological examinations and whole genome sequencing on an Illumina NextSeq500 were performed to characterize a stillborn Limousin calf with frontonasal dysplasia. Frontonasal dysplasias (FND) comprise a heterogeneous group of disorders with congenital polymalformations caused by abnormal median facial development. The absence of the olfactory tract (arhinencephaly), partial fusion (synophthalmia), complete fusion (cyclopia) or the total absence (anopthalmia) of ocular globes are phenotypes of FND found in cattle [1]. The spectrum of Aristaless-Like Homeoboxprotein (ALX) related FNDs involves recessively inherited loss-offunction mutations in the ALX1, ALX3, and ALX4 genes [7]. Sporadic cases of different types of cyclopia and FND occur in cattle [1, 9–17], buffalo [18– 20], sheep [21–23] and goats [24] (Table 1). Whole genome scans for FND were not yet performed in ruminants
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