A homozygote mutation in RPA2 associated with bone marrow failure, immunodeficiency, and telomere biology disorder

Telomere biology disorders (TBDs) are characterized by bone marrow failure (BMF) and dysfunctional telomeres. So far, inherited mutations in 18 genes have been identified in TBDs. Here, we describe a child presenting with early BMF, immunodeficiency, and severely short and defective telomeres, carrying a homozygous splicing mutation (c.409-2 A > G; p.Q136_K138del) in RPA2 - a known replication factor and telomerase accessory factor. The Q136_K138del mutation is predicted to compromise the binding of RPA2 to the single-stranded telomeric DNA. Sequencing of single telomeres revealed that telomere variant repeats (TVRs), present also in healthy individuals, became more prominent in the short telomeres of the patient. Such TVRs may aggravate the telomere dysfunction due to lower affinity to the shelterin proteins. The severe telomere shortening and the activation of DNA damage response at telomeres indicate that this RPA2 mutation causes TBD in a similar manner to other known mutations and should be considered in patients displaying clinical TBD features.