de novo TINF2 C.845G>A: Pathogenic Variant in Patient with Dyskeratosis Congenita

Dyskeratosis congenita (DC) is a clinically and genetically heterogeneous, multisystem inherited syndrome with a very high risk for bone marrow failure (BMF) and cancer predisposition. The classical clinical form of DC is characterized by abnormal skin pigmentation, nail dystrophy, and oral leukoplakia. Bone marrow failure is considered to be an important and major complication of DC and the leading cause of death which develops in around 85% of cases. A number of genes involved in telomere maintenance are associated with DC, such as genes that encode the components of the telomerase complex (TERT, DKC1, TERC, NOP10, and NHP2), T-loop assembly protein (RTEL1), telomere capping (CTC1), telomere shelterin complex (TINF2), and telomerase trafficking protein (TCAB1). Mutations in TINF2 have been reported in 11–20% of all patients with DC and have been associated with bone marrow failure. Here we report on a 19-month old boy with very early presentation of bone marrow failure as a first clinical manifestation of DC. Upon first admission, the patient presented with thrombocytopenia and macrocytic anemia. Soon after, his blood counts deteriorated with the development of pancytopenia and aplastic anemia. Four months later, he developed nail dystrophy and skin hyperpigmentation. A de novo heterozygous pathogenic variant c.845G>A, p.(Arg282His) was located in exon 6 of TINF2 gene and was identified via clinical exome sequencing. The findings confirmed the diagnosis of DC. This is the first case with DC due to TINF2 pathogenic variant reported in North Macedonia.