Deleterious Mutations in the TPO Gene Associated with Familial Thyroid Follicular Cell Carcinoma in Dutch German Longhaired Pointers

Familial thyroid cancer originating from follicular cells accounts for 5-15% of all the thyroid carcinoma cases in humans. Previously, we described thyroid follicular cell carcinomas in a large number of the Dutch German longhaired pointers (GLPs) with a likely autosomal recessive inheritance pattern. Here, we investigated the genetic causes of the disease using a combined approach of genome-wide association study and runs of homozygosity (ROH) analysis based on 170k SNP array genotype data and whole-genome sequences. A region 0-5 Mb on chromosome 17 was identified to be associated with the disease. Whole-genome sequencing revealed many mutations fitting the recessive inheritance pattern in this region including two deleterious mutations in the TPO gene, chr17:800788G>A (686F>V) and chr17:805276C>T (845T>M). These two SNP were subsequently genotyped in 186 GLPs (59 affected and 127 unaffected) and confirmed to be highly associated with the disease. The recessive genotypes had higher relative risks of 16.94 and 16.64 compared to homozygous genotypes for the reference alleles, respectively. This study provides novel insight into the genetic causes leading to the familial thyroid follicular cell carcinoma, and we were able to develop a genetic test to screen susceptible dogs.

Automated summary

This study identified genetic causes leading to familial thyroid follicular cell carcinoma, including deleterious mutations in chromosome 17, and successfully developed a genetic test to screen susceptible dogs.