First Evidence of Familial Transmission of Hereditary Gastrointestinal Polyposis Associated with Germline APC Variant in Jack Russell Terriers

SIMPLE SUMMARY: Hereditary gastrointestinal (GI) polyposis in Jack Russell terriers (JRTs) is a recently discovered disease caused by an identical germline variant in the adenomatous polyposis coli (APC) gene. To date, intrafamilial transmission of this disease has not been demonstrated, mainly due to the difficulty in tracing the family members of household dogs. In this study, we found three unrelated JRT lineages in which hereditary GI polyposis was transmitted across successive generations in association with the germline APC variant. ABSTRACT: Jack Russell terriers (JRTs) with gastrointestinal (GI) neoplastic polyps have been recently reported to harbor an identical germline variant in the adenomatous polyposis coli (APC) gene, c.[462_463delinsTT], in the heterozygous state, which indicates that this disease is an autosomal dominant hereditary disorder. Many individual cases of this disease have been observed in clinical practice; however, familial transmission has not been demonstrated due to the difficulty in tracing the family members of household dogs, especially after the disease’s onset in adulthood. Recently, we encountered two cases of GI polyposis in maternal half sisters. These two cases facilitated the identification of additional relatives spanning three generations, including parents, full and half siblings of the dam (aunt and uncle), littermate and non-littermate siblings, and a nephew. Genetic analysis revealed that 11 of the 14 examined JRTs in this family carried the heterozygous germline APC variant, and eight dogs with the variant already had a current and/or past medical history of GI neoplastic polyps. Some cases in the family showed significantly more severe disease phenotypes than those initially reported, suggesting that the severity of this disease can vary considerably among individuals. Moreover, familial aggregation of severe cases suggested that the genetic modifier involved in increasing severity may have been transmitted in this family in addition to the germline APC variant. Furthermore, in addition to this family, we reported two other families of JRTs affected by hereditary GI polyposis that consisted of five full and half siblings and a mother–daughter pair, respectively. These findings unequivocally establish the transgenerational transmission of hereditary GI polyposis associated with the germline APC variant in JRT lineages.