Figure 2.

Identification and validation of genetic variants in MUTYH and OGG1 genes in the germline of three families with SI-NETs. Whole-exome sequencing results (panels A, B, C and G, H, I) with corresponding Sanger sequencing validations (panels D, E, F and J, K, L) of heterozygous variants MUTYH p.(Gly396Asp) and OGG1 p.(Arg46Gln) in the germline of subjects with familial history of SI-NETs. NGS data are presented using the Integrative Genomics Viewer – IGV software, Broad Institute. Variant MUTYH p.(Gly396Asp) was initially detected in two families with history of SI-NETs; families O and No. The sequenced subject from family O, (subject O1 (panels A and D)), is a carrier of this variant. The same substitution was also detected in one of the two sequenced subjects of family No, i.e. No1 (panels B and E). The variant was not identified in the other affected subject of the same family, No2 (panels C and F). Panels G to L illustrate the presence of variant OGG1 p.(Arg46Gln) in two subjects of family M (M1 (panels G and J) and M3 (panels I and L)). Subject M1 was diagnosed with the disease at the age of 66 years, while his younger brother M3 is considered to be a healthy carrier, since his son M2 (panels H and K) was diagnosed with SI-NET at the age of 43 years. M2 did not show any OGG1 mutation, but he is a carrier of heterozygous alleles TERT p.(Ala279Thr) and SDHB p.(Ser163Pro) (Fig. 1, Tables 2 and 3).