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

Area of Science:

• Genetics
• Dermatology
• Ophthalmology

Background:

• Rothmund-Thomson syndrome (RTS) is an ultra-rare genodermatosis with genetic heterogeneity.
• RTS type 4 (RTS-4) is caused by DNA2 gene variants and presents with unique features like microphthalmia and congenital cataracts.
• Previously reported RTS-4 cases involved a specific deep intronic DNA2 variant in individuals of Brazilian/Portuguese descent.

Observation:

• A novel patient with RTS-4 was identified outside of previously described ethnic groups.
• This patient carried the known deep intronic DNA2 variant (ENST00000358410.8:c.588-2214A>G) along with a new pathogenic variant (ENST00000358410.8:c.2519T>C, Leu840Pro).
• The patient's clinical course, including response to recombinant human growth hormone, was documented.

Findings:

• This case expands the known molecular spectrum of RTS-4.
• Genome sequencing was crucial for identifying the deep intronic pathogenic variant.
• The patient remained undiagnosed for several years, underscoring diagnostic challenges.

Implications:

• This finding broadens the ethnic and molecular landscape of RTS-4.
• Highlights the essential role of advanced genetic sequencing in diagnosing rare diseases.
• Emphasizes the value of international collaboration and data sharing in undiagnosed disease research.