Categories: Neoplasm

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 606765 (gene) , 603386 (trait) , 188550 (trait) , 605642 (trait)

Mendelian trait/disorder: unknown

Mode of inheritance: Probably autosomal recessive

Disease-related: yes

Species-specific description: Yu et al. (2021) described familial thyroid follicular cell carcinomas in Dutch German longhaired pointers (GLPs). Yu et al. (2021) "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."

Inheritance: Yu et al (2021): "45 of 54 histopathologically confirmed cases are closely related to a pair of first-half cousins in the past, indicating a familial disease. In addition, genetics contributed more to the thyroid follicular cell carcinoma than other factors by an estimated heritability of 0.62 based on pedigree. ... We observed a significant higher pedigree-based inbreeding coefficient in the affected dogs (mean F 0.23) compared to unaffected dogs (mean F 0.14), suggesting the contribution of inbreeding to tumour development."

Mapping: Yu et al. (2021): "A region 0-5 Mb on chromosome 17 was identified to be associated with the disease."

Molecular basis: Yu et al. (2021): "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." Yu et al. (2022; BMC Genomics) "comprehensively investigated the somatic mutations that potentially contribute to the inherited tumor formation and progression using high depth whole-genome sequencing. A GNAS p.A204D missense mutation was identified in 4 out of 7 FCC tumors by whole-genome sequencing and in 20 out of 32 dogs' tumors by targeted sequencing."

Clinical features: Yu et al. (2021): "The age of diagnosis ranged between 4.5 and 13.5 years, and 76% of cases were diagnosed before 10 years of age, implying an early onset of disease."

Breed: German Longhaired Pointer (Dog) (VBO_0200570).
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: