Undiagnosed Hackathon Ends Diagnostic Odyssey in a Patient With DNA2-Related Rothmund-Thomson Syndrome.

Abstract

Rothmund-Thomson syndrome (RTS) is an ultra-rare, genetically heterogeneous autosomal recessive genodermatosis characterized by poikiloderma, sparse hair and eyebrows, photosensitivity, and short stature. The recently described RTS type 4 (RTS-4), caused by biallelic variants in the DNA2 gene, is associated with additional distinctive features such as microphthalmia, corneal opacity, congenital cataracts (rather than juvenile), and hypothyroidism. To date, eight individuals with RTS-4 have been reported, all carrying a deep intronic variant in DNA2 (ENST00000358410.8:c.588-2214A>G) and originating from Brazilian or Portuguese ethnic backgrounds. We present the first patient with RTS-4 outside these ethnic backgrounds, harboring the same deep intronic DNA2 variant (ENST00000358410.8:c.588-2214A>G) in combination with a novel pathogenic variant (ENST00000358410.8:c.2519 T>C, Leu840Pro). This patient expands the molecular spectrum of RTS-4 and underscores the critical role of genome sequencing in identifying pathogenic deep intronic variants. Additionally, the patient's response to recombinant human growth hormone treatment is described. Finally, this patient, undiagnosed for several years, was solved through an international effort at the 2024 Undiagnosed Hackathon, highlighting the value of international cooperation and resource sharing toward ensuring that no patient remains undiagnosed.