title: A recessive founder mutation in regulator of telomere elongation helicase 1, RTEL1, underlies severe immunodeficiency and features of Hoyeraal Hreidarsson syndrome.
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.
authors.affiliation: Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, United States of America.
authors.forename: Bari J
authors.initials: BJ
authors.lastname: Ballew
authors.forename: Vijai
authors.initials: V
authors.lastname: Joseph
authors.forename: Saurav
authors.initials: S
authors.lastname: De
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Sarek
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Vannier
authors.forename: Travis
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authors.lastname: Stracker
authors.forename: Kasmintan A
authors.initials: KA
authors.lastname: Schrader
authors.forename: Trudy N
authors.initials: TN
authors.lastname: Small
authors.forename: Richard
authors.initials: R
authors.lastname: O'Reilly
authors.forename: Chris
authors.initials: C
authors.lastname: Manschreck
authors.forename: Megan M
authors.initials: MM
authors.lastname: Harlan Fleischut
authors.forename: Liying
authors.initials: L
authors.lastname: Zhang
authors.forename: John
authors.initials: J
authors.lastname: Sullivan
authors.forename: Kelly
authors.initials: K
authors.lastname: Stratton
authors.forename: Meredith
authors.initials: M
authors.lastname: Yeager
authors.forename: Kevin
authors.initials: K
authors.lastname: Jacobs
authors.forename: Neelam
authors.initials: N
authors.lastname: Giri
authors.forename: Blanche P
authors.initials: BP
authors.lastname: Alter
authors.forename: Joseph
authors.initials: J
authors.lastname: Boland
authors.forename: Laurie
authors.initials: L
authors.lastname: Burdett
authors.forename: Kenneth
authors.initials: K
authors.lastname: Offit
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Boulton
authors.forename: Sharon A
authors.initials: SA
authors.lastname: Savage
authors.forename: John H J
authors.initials: JH
authors.lastname: Petrini
mesh_terms: D000328:Adult; D004265:DNA Helicases / Q000235:genetics*; D019871:Dyskeratosis Congenita / Q000209:etiology / Q000235:genetics* / Q000473:pathology*; D005260:Female; D005317:Fetal Growth Retardation / Q000209:etiology / Q000235:genetics* / Q000473:pathology*; D005808:Genes, Recessive; D018095:Germ-Line Mutation; D006720:Homozygote; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics / Q000473:pathology*; D008607:Intellectual Disability / Q000209:etiology / Q000235:genetics* / Q000473:pathology*; D007585:Jews; D008831:Microcephaly / Q000209:etiology / Q000235:genetics* / Q000473:pathology*; D008969:Molecular Sequence Data; D009154:Mutation; D010641:Phenotype; D019098:Telomerase / Q000235:genetics; D016615:Telomere / Q000235:genetics
chemical_list: D019098:Telomerase; C532890:RTEL1 protein, human; D004265:DNA Helicases