Categories: Cardiovascular system phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 217095 (trait) , 601656 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal dominant

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2022

Species-specific description: Besnard et al. (2022) monitored “sire-family calf mortality within the French and Walloon Holstein populations, and ... [used] this information to detect genetic defects that might have been overlooked by lack of specific symptoms. … After outlining the 5 worst bulls per category, [the authors] ... paid particular attention to the bulls Mo and Pa, because they were half-brothers. Using a battery of approaches, including necropsies, karyotyping, genetic mapping, and whole-genome sequencing, [the authors] ... described 2 new independent genetic defects in their progeny and their molecular etiology. … Pa was found to be mosaic for a dominant de novo nonsense mutation of GATA 6 binding protein (GATA6), causing severe cardiac malformations.”

Mapping: Besnard et al. (2022) "analyzed SNP array genotypes of 14 progeny that died during the preweaning period ... and 189 half-sib controls .... via transmission disequilibrium test. [The authors] ... mapped the TA [truncus arteriosus] locus on BTA24 between positions 19,505,558 (rs453420861) and 37,877,878 (rs723126921) bp on the ARS-UCD1 assembly."

Molecular basis: Whole genome sequencing of an affected animal and comparison to control animals identified "a thymine-to-adenine substitution in exon 2 of GATA6 predicted to introduce a premature stop codon (chr24: g.34,187,181T > A; GATA6 p.K417X)" as likely causal variant (Besnard et al., 2022). The variant was validated in additional animals and "2 orthologous human truncating mutations located closest to the present bovine nonsense variant (pS418fs and pG441X) have been reported to cause exactly the same phenotype" (Besnard et al.; 2022).

Clinical features: Besnard et al. (2022): "8 [affected calves] showed symptoms compatible with severe heart defects either leading to premature death or justifying euthanasia on humane grounds."

Pathology: Besnard et al. (2022): "Autopsies gave results strikingly similar to the systematic observation of a persistent truncus arteriosus ... , sometimes associated with additional heart septation defects ...."

Breed: Holstein Friesian (Cattle) (VBO_0000239).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: