Identification of a novel CTR9 germline mutation in a family with Wilms tumor

Germline mutations in the WT1 gene have been identified in some families with Wilms tumor. Recently, the CTR9 gene was found to be mutated in three families with Wilms tumor, thus representing a novel predisposition gene for this disease. We identified a family with a history of Wilms tumor characterized by three affected siblings, one of them presenting an aggressive bilateral tumor.Here we investigated the involvement of WT1 and CTR9 genes in this family with Wilms tumor. The involvement of WT1 was first evaluated by Next generation sequencing in leukocytes DNA from one affected family member. Subsequently, the CTR9 gene was analyzed by Sanger sequencing in DNA and RNA from patients’ leukocytes and/or tumor. No mutations were detected in WT1. However, we identified a novel CTR9 germline variant, located in a consensus splice acceptor site, which was found to segregate with Wilms tumor in this family. We found that this variant leads to the skipping of the entire exon 9 in the mRNA, which is predicted to encode a truncated CTR9 protein, strongly suggesting that it is pathogenic. Additionally, we also detected loss of heterozygosity in the index case tumor, which is consistent with CTR9 being a tumor suppressor gene, confirming also its contribution to familial Wilms tumor etiology.The identification of a novel CTR9 germline mutation will improve the present knowledge on the molecular basis of familial Wilms tumor. Importantly, it will help in the genetic counselling and may also lead to earlier diagnosis in other family members and future generations.