A pathogenic variant in CHEK2 shows a founder effect in Portuguese Roma patients with thyroid cancer

Purpose Germline mutations in DNA repair-related genes have been recently reported in cases with familial non-medullary thyroid carcinoma (FNMTC). A Portuguese family from the Roma ethnic group with four members affected with papillary thyroid carcinoma (PTC), and three members with multinodular goiter (MNG) was identified. The aim of this study was to investigate the involvement of DNA repair-related genes in the etiology of FNMTC in this family and in the Roma ethnic group. Methods Ninety-four hereditary cancer predisposition genes were analyzed through next-generation sequencing. Sanger sequencing was used for variant confirmation and screening. Twelve polymorphic markers were genotyped for haplotype analysis in the CHEK2 locus. Results A germline pathogenic frameshift variant in the CHEK2 gene [c.596dupA, p.(Tyr199Ter)] was detected in homozygosity in the proband (PTC) and in his brother (MNG), being heterozygous in his mother (PTC), two sisters (PTC), and one nephew (MNG). This variant was absent in 100 general population controls. The screening of the CHEK2 variant was extended to other Roma individuals, being detected in 2/33 Roma patients with thyroid cancer, and in 1/15 Roma controls. Haplotype segregation analysis identified a common ancestral core haplotype (Hcac), covering 10 Mb in the CHEK2 locus, shared by affected CHEK2 variant carriers. Analysis of 62 individuals CHEK2 wild-type indicated that none presented the Hcac haplotype. The estimated age for this variant suggested that it was transmitted by a relatively recent common ancestor. Conclusions We identified a founder CHEK2 pathogenic variant, which is likely to underlie thyroid cancer and other cancer manifestations in the Roma population.