Suspected parental gonadal/gonadosomatic mosaicism for a TINF2 mutation in two sisters with dyskeratosis congenita

Dyskeratosis congenita (DC; OMIM: 127550) is a rare inherited bone marrow failure syndrome. TINF2 mutations are the second most common genetic cause of DC, and most cases arise from de novo mutations. Although the TINF2 p.Thr284Pro variant has been reported in isolated cases, its pathogenic role has not been functionally validated, and its potential association with suspected parental gonadal/gonadosomatic mosaicism has not been previously described.

To evaluate the functional impact of the TINF2 p.Thr284Pro variant and explore its association with suspected parental gonadal/gonadosomatic mosaicism in a DC pedigree in which two affected sisters were born to clinically unaffected parents. The findings may provide evidence for improved molecular diagnosis and genetic counseling in DC.

Clinical and genetic investigations were performed in a family suspected of DC. Multi-tissue sequencing was conducted in the parents and the proband. To evaluate the functional consequences of the variant, wild-type and p.Thr284Pro mutant TINF2 overexpression plasmids were constructed and transfected into HEK293T cells. TINF2 protein expression was analyzed by Western blotting. Cell proliferation was assessed using the CCK-8 assay, telomere length was measured by quantitative PCR, and cellular senescence was evaluated using SA-β-galactosidase staining.

Both affected sisters exhibited an incomplete classical DC phenotype, characterized primarily by pancytopenia and nail dystrophy. Genetic analysis identified the same heterozygous TINF2 c.850A>C (p.Thr284Pro) variant in both patients. This variant was absent in peripheral blood and other parental tissues (oral mucosa and hair follicles), suggesting an apparently de novo occurrence in the siblings and raising the possibility of suspected parental gonadal/gonadosomatic mosaicism. Functional assays provided preliminary supportive evidence that the mutant construct was associated with lower detected TINF2 protein levels compared with wild type (P = 0.01), decreased cellular proliferation suggestive of impaired proliferative capacity, a reduced relative telomere length signal (P < 0.001), and increased senescence-associated β-galactosidase activity. These findings provide preliminary evidence regarding the potential functional impact of the TINF2 p.Thr284Pro variant.

This study provides the first clinical-genetic evidence for suspected parental gonadal/gonadosomatic mosaicism of the TINF2 p.Thr284Pro variant, along with exploratory in vitro data supporting its potential functional impact. The affected sisters exhibited an incomplete classical DC phenotype (nail dystrophy without reticular skin pigmentation or oral leukoplakia), thereby expanding the clinical spectrum of DC and highlighting important implications for genetic counseling.