<scp> <i>TG</i> </scp> Nonsense Variant in Dwarf Rottweiler Dogs

We identified a dwarfism syndrome in six Rottweiler dogs characterized by reduced height and body weight; limb deformities, shortening of the tail and abnormally thick skin in puppies; developmental delays, pain and non-goitrous hypothyroidism. Histological examination of the thyroid gland revealed severe chronic diffuse bilateral atrophy with loss of thyroid follicles and lack of colloid. Pedigree analysis suggested an autosomal recessive transmission. Whole genome sequencing of an affected dog and filtering for private variants against 1539 control genomes identified a homozygous nonsense variant in the TG gene encoding thyroglobulin, NM_001048104.1:c.3694C>T. The variant was predicted to introduce a premature stop codon truncating 55% of the wild-type open reading frame, NP_001041569.1:p.(Arg1232*). The TG glycoprotein is the precursor to the thyroid hormones triiodothyronine (T3) and tetraiodothyronine (T4). TG deficiency leads to comparable phenotypes in human patients, cattle and goats. Genotyping six affected and 87 control Rottweiler dogs confirmed the expected genotype-phenotype association, with all affected dogs being homozygous for the mutant allele and control dogs being either heterozygous or homozygous wild-type. All four obligate carriers were heterozygous and among the 74 unrelated control dogs without known relationships to cases we found a 5.4% carrier frequency. Correct co-segregation in the available families was also observed. Taken together, this study provides an initial clinical and pathological characterization of an inherited dwarfism syndrome in Rottweilers and identifies a TG variant as a causal genetic defect. The results enable genetic testing to avoid unintentional risk matings.