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Hoyeraal Hreidarsson syndrome, a severe variant of dyskeratosis congenita, caused by biallelic mutations in TPP1

Monday, September 22, 2014 — Poster Session II

4:00 p.m. – 6:00 p.m.

FAES Academic Center




  • B.J. Ballew
  • H. Kocak
  • K. Bisht
  • J.F. Boland
  • B.D. Hicks
  • L. Burdett
  • A. Vogt
  • A.A. Hutchinson
  • N. Giri
  • B.P. Alter
  • M. Yeager
  • C. Keegan
  • J. Nandakumar
  • S.A. Savage


Dyskeratosis congenita (DC) is an inherited telomere biology disorder resulting in bone marrow failure and cancer. Causative mutations remain unknown in ~30% of DC; gene discovery confirms diagnosis and assists family planning. DC genes provide insight into cancer susceptibility loci: polymorphisms in 6 DC genes are associated with cancer risk. We performed whole exome sequencing on mutation-negative DC families in our cohort. We identified extremely rare variants and filtered by family structure, examining all plausible inheritance models. We highlighted variants in genes associated with DC-related phenotypes, and analyzed variants’ impact using in silico techniques. This led to the discovery of novel mutations in TPP1, part of the shelterin complex, in a DC family. The proband (diagnosed with the severe DC variant Hoyeraal Hreidarsson syndrome), sister, and father have telomeres <1st percentile for age; all three harbor a single-amino acid deletion in the TEL patch of TPP1. The proband also has a missense TPP1 mutation in the TIN2-binding domain; his mother is a silent carrier of this mutation. Functional analyses demonstrated that the deletion compromises telomerase processivity and recruitment, while the missense mutation reduces TPP1-TIN2 binding. These data demonstrate that compound heterozygous inheritance of these alleles results in clinically severe DC.

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