Is a heterozygous missense variant in SGSH the cause of a syndromic form of congenital amastia in an Original Braunvieh calf?

A 5-days-old female purebred Original Braunvieh female calf was referred owing to a congenital absence of teats and cleft palate. Gross pathology revealed the entire absence of the udder including teats, complete palatoschisis affecting both soft and hard palate, hepatomegaly, corneal opacity and an open vulva (Figure S1). Whole genome sequencing (WGS) was performed using genomic DNA obtained from ear tissue from the calf. Reads were mapped to the ARS-UCD1.2 assembly (Rosen et al., 2020), resulting in an average read depth of 14.7×. The WGS data were evaluated as previously described (Jacinto et al., 2021). Variant filtering did not reveal any private homozygous protein-changing variants present in the genome of the affected calf, making a possible recessive inheritance unlikely. Assuming that a spontaneous mutation affecting a protein-coding gene is the cause, filtering for private heterozygous coding variants present in the calf’s genome allowed the identification of six variants with a predicted moderate or high impact (Table S1). These variants were confirmed as true by visual inspection with the integrative genomes viewer software (Robinson et al., 2017). These variants were absent from a total of 5365 controls and a single variant affects SGSH, a putative candidate gene for the observed congenital anomaly. This heterozygous variant at chr19:52427490C>T represents a missense variant in SGSH exon 4 (NM_001102189.2: c.425C>T) (Figure S2). We suspected that the identified variant in SGSH either occurred post-zygotically in the developing embryo or was inherited from a mosaic parent. Unfortunately, no biological samples were available from the parents. The encoded amino acid of SGSH is predicted to be altered at codon 142 (NP_001095659.2: p.Thr142Met) located in the N-sulphoglucosamine sulphohydrolase domain. The substitution of threonine to methionine affects an amino acid that is highly conserved in all species (Figure S2) and has been predicted to be harmful using three different tools (Provean, −4.729; PhD-SNP, 50%; SIFT, 79%).