A Recessive Founder Mutation in Regulator of Telomere Elongation Helicase 1, RTEL1, Underlies Severe Immunodeficiency and Features of Hoyeraal Hreidarsson Syndrome

Bari J Ballew,Kenneth Offit,Simon J Boulton,Kasmintan A Schrader,Blanche P Alter,Laurie Burdett,Sharon A Savage,Megan M Harlan Fleischut,Saurav De,Kelly Stratton,Vijai Joseph,Chris Manschreck,John Sullivan,Grzegorz Sarek,Liying Zhang,Trudy N Small,Meredith Yeager,Neelam Giri,Kevin B Jacobs ,Joseph F Boland ,Richard O’reilly ,Jean Baptiste Vannier ,Travis H Stracker ,John H.j Petrini

doi:10.1371/journal.pgen.1003695

Abstract

Dyskeratosis congenita (DC) is a heterogeneous inherited bone marrow failure and cancer predisposition syndrome in which germline mutations in telomere biology genes account for approximately one-half of known families. Hoyeraal Hreidarsson syndrome (HH) is a clinically severe variant of DC in which patients also have cerebellar hypoplasia and may present with severe immunodeficiency and enteropathy. We discovered a germline autosomal recessive mutation in RTEL1, a helicase with critical telomeric functions, in two unrelated families of Ashkenazi Jewish (AJ) ancestry. The affected individuals in these families are homozygous for the same mutation, R1264H, which affects three isoforms of RTEL1. Each parent was a heterozygous carrier of one mutant allele. Patient-derived cell lines revealed evidence of telomere dysfunction, including significantly decreased telomere length, telomere length heterogeneity, and the presence of extra-chromosomal circular telomeric DNA. In addition, RTEL1 mutant cells exhibited enhanced sensitivity to the interstrand cross-linking agent mitomycin C. The molecular data and the patterns of inheritance are consistent with a hypomorphic mutation in RTEL1 as the underlying basis of the clinical and cellular phenotypes. This study further implicates RTEL1 in the etiology of DC/HH and immunodeficiency, and identifies the first known homozygous autosomal recessive disease-associated mutation in RTEL1.

Highlights

Hoyeraal Hreidarsson syndrome (HH) is a clinically severe variant of the telomere biology disorder dyskeratosis congenita (DC) [1]
DC and HH are caused by defects in telomere biology; improperly maintained telomeres are thought to be a major contributor to carcinogenesis
By studying families affected by DC for whom a causative mutation has not yet been identified, we have discovered a homozygous germline mutation in Regulator of Telomere Elongation Helicase 1 (RTEL1), a telomere maintenance gene that, if mutated, can result in HH

Summary

Introduction

Hoyeraal Hreidarsson syndrome (HH) is a clinically severe variant of the telomere biology disorder dyskeratosis congenita (DC) [1]. DC is a heterogeneous inherited bone marrow failure syndrome (IBMFS) diagnosed by the presence of the classic triad of dysplastic nails, abnormal skin pigmentation, and oral leukoplakia. Substantial clinical heterogeneity has been observed and the phenotype may include pulmonary fibrosis, liver disease, esophageal, urethral, or lacrimal duct stenosis, developmental delay, and/or other complications. Individuals with DC are at very high risk of bone marrow failure (BMF), myelodysplastic syndrome, and cancer [2]. The clinical consequences of DC manifest at variable ages and in different patterns, even within the same family. Independent of the classic triad, lymphocyte telomere lengths less than the first percentile for age are diagnostic of DC

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Conclusion