Deep Phenotyping of Patients with Trichothiodystrophy or Xeroderma Pigmentosum

Authors

• SG Khan
• J Pugh
• R Bembry
• ER Heller
• D Tamura
• M Scheibye-Knudsen
• G Nelson
• JJ DiGiovanna
• KH Kraemer

Abstract

Trichothiodystrophy (TTD) and xeroderma pigmentosum (XP) are two rare, autosomal recessive disorders with defects in genes involved in transcription and in DNA nucleotide excision repair. TTD patients have a wide spectrum of developmental abnormalities without increased risk of skin cancer. In contrast, XP patients have a10,000-fold increased skin cancer risk. We performed deep phenotyping to better understand the relationship of the clinical features to the disease processes and molecular defects. Structured history and clinical information from direct NIH evaluation, NIH medical record systems (CRIS and BTRIS), outside medical records and results of DNA sequencing of candidate genes were entered into a 350 item database. We are employing hierarchical clustering and scoring algorithms together with principal component analysis to pinpoint key features associated with these diseases. We are initially analyzing a cohort of 25 TTD, 13 XP/TTD and 29 XP patients all with mutations in the ERCC2 (XPD) gene. Molecular analysis in conjunction with deep phenotyping of clinical data may help identify distinct phenotypes that can guide therapy, inform prognosis, and provide insights into the pathological mechanisms of these diseases.

Scientific Focus Area: Genetics and Genomics

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