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Germline mutations of regulator of telomere elongation helicase 1, RTEL1, in Dyskeratosis congenita

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Dyskeratosis congenita (DC) is an inherited bone marrow failure and cancer predisposition syndrome caused by aberrant telomere biology. The classic triad of dysplastic nails, abnormal skin pigmentation, and oral leukoplakia is diagnostic of DC, but substantial clinical heterogeneity exists; the clinically severe variant Hoyeraal Hreidarsson syndrome (HH) also includes cerebellar hypoplasia, severe immunodeficiency, enteropathy, and intrauterine growth retardation. Germline mutations in telomere biology genes account for approximately one-half of known DC families. Using exome sequencing, we identified mutations in RTEL1, a helicase with critical telomeric functions, in two families with HH. In the first family, two siblings with HH and very short telomeres inherited a premature stop codon from their mother who has short telomeres. The proband from the second family has HH and inherited a premature stop codon in RTEL1 from his father and a missense mutation from his mother, who also has short telomeres. In addition, inheritance of only the missense mutation led to very short telomeres in the proband’s brother. Targeted sequencing identified a different RTEL1 missense mutation in one additional DC proband who has bone marrow failure and short telomeres. Both missense mutations affect the helicase domain of RTEL1, and three in silico prediction algorithms suggest that they are likely deleterious. The nonsense mutations both cause truncation of the RTEL1 protein, resulting in loss of the PIP box; this may abrogate an important protein–protein interaction. These findings implicate a new telomere biology gene, RTEL1, in the etiology of DC.

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We thank all of the study participants for their valuable contributions. Lisa Leathwood, RN and Maureen Risch, RN, Westat, Inc., provided excellent study support.

This study was funded by the intramural research program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health and by contracts N02-CP-91026, N02-CP-11019, and HHSN261200655001C with Westat, Inc.

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Correspondence to Sharon A. Savage.

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Supplementary material 1 (PDF 13 kb)Online Resource 1: Exome coverage statistics. Exome coverage, off-target and on-target bases are indicated for two DC families


Supplementary material 2 (PDF 15 kb)Online Resource 2: Exome variant filtering strategy. Variants were sequentially filtered by the criteria described


Supplementary material 3 (PDF 29 kb)Online Resource 3: Variants found in RTEL1 by targeted sequencing. Targeted sequencing of RTEL1 exons revealed variants that were common (MAF > 1 %), synonymous, or predicted to be benign


Supplementary material 4 (PDF 15 kb)Online Resource 4: Primers for the RTEL1 locus used in IonTorrent sequencing. These primers were used for targeted sequencing of the RTEL1 exons

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Ballew, B.J., Yeager, M., Jacobs, K. et al. Germline mutations of regulator of telomere elongation helicase 1, RTEL1, in Dyskeratosis congenita. Hum Genet 132, 473–480 (2013).

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