Simultaneous Occurrence of Hypospadias and Bilateral Cleft Lip and Jaw in a Crossbred Calf: Clinical, Computer Tomographic, and Genomic Characterization

Abstract

Congenital abnormalities in animals, including abnormalities of the cleft lip and jaw and hypospadias have been reported in all domesticated species. They are a major concern for breeders due to the increased economic loss they entail. In this article, we described a congenital bilateral cheilognathoschisis (cleft lip and jaw) with campylognathia in association with penile hypospadias and preputial hypoplasia with failure of preputial fusion in a Bos taurus crossbred Piedmontese × Wagyu calf. Clinical examination, computed tomography, and whole genome sequencing were performed to describe and identify a possible cause of the abnormalities. Clinical examination revealed a bilateral cheilognathoschisis of approximately 4 cm in length and 3 cm in width in the widest part, with computer tomography analyses confirming the bilateral absence of the processus nasalis of the incisive bone and the lateral deviation of the processus palatinus towards the left side. Genomic data analyses identified 13 mutations with a high impact on the products of the following overlapped genes: ACVR1, ADGRA2, BHMT2, BMPR1B, CCDC8, CDH1, EGF, F13A1, GSTP1, IRF6, MMP14, MYBPHL, and PHC2 with ADGRA2, EGF, F13A1, GSTP1, and IRF6 having mutations in a homozygous state. The whole genome investigation indicates the involvement of multiple genes in the birth defects observed in this case.

Epigenetic regulation of craniofacial development and disease

“…Zebrafish ring1b mutants do not develop cranial cartilage or bone due to impaired chondrocyte differentiation. Other PRC proteins, PHC1 and PHC2, are important in NCC formation and patterning craniofacial skeletal elements by regulating Hox expression (Isono et al, 2005; Marc et al, 2023). These two factors have also been associated with congenital diseases including CATCH‐22 syndrome (PHC1) as well as patients presenting with DiGeorge syndrome‐like phenotypes (PHC1) and nonsyndromic cleft lip and palate (PHC2; Marc et al, 2023; Shirai et al, 2002; Takihara et al, 1997; Wilson et al, 1993).…”

“…Other PRC proteins, PHC1 and PHC2, are important in NCC formation and patterning craniofacial skeletal elements by regulating Hox expression (Isono et al, 2005; Marc et al, 2023). These two factors have also been associated with congenital diseases including CATCH‐22 syndrome (PHC1) as well as patients presenting with DiGeorge syndrome‐like phenotypes (PHC1) and nonsyndromic cleft lip and palate (PHC2; Marc et al, 2023; Shirai et al, 2002; Takihara et al, 1997; Wilson et al, 1993). ASXL proteins (Additional sex combs‐like) ASXL1/2/3, which serve as scaffolds in the PRC complex, have important roles in early neural crest development, from generation of neural crest to delamination and emigration (Lichtig et al, 2020; Matheus et al, 2019).…”