FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2588832503> ?p ?o ?g. }

• W2588832503 abstract "Abstract Abstract 515 Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome that results from impaired telomere maintenance. The classic triad (dysplastic nails, skin pigmentation, and oral leukoplakia) is diagnostic of DC but significant clinical heterogeneity can exist, even within a family. Leukocyte telomere lengths less than the first percentile for age are diagnostic of DC. Patients with DC are at high risk of bone marrow failure (BMF), myelodysplastic syndrome, cancer, pulmonary fibrosis, liver disease and other complications. Currently, germline mutations in 1 of 8 telomere biology genes (DKC1, TERC, TERT, TINF2, NOP10, NHP2, WRAP53, and CTC1) are known to cause ∼50–60% of DC cases. Our longitudinal cohort study conducts detailed medical record review and clinical examinations of patients with DC and their family members. DC is diagnosed based on the presence of the diagnostic triad or 1 of the triad plus BMF. All DC patients had telomeres <1st percentile. Patients are classified as DC-like if they have telomeres <1st percentile and other features, such as BMF or family history, suggestive of DC. All participants in this study were negative for mutations in the known DC genes. We performed whole exome sequencing (WES) on two DC families using an enriched multiplexed sequencing library (Nimblegen v2) and sequenced on an Illumina HiSeq™. Variants were removed from analyses if they did not pass quality control filters or were present more than 3 times in publically available databases (1000Genomes, ESP, Kaviar, and dbSNP). Since DC can be inherited in autosomal dominant, autosomal recessive, and X-linked manners, we evaluated all inheritance models in our families. Additionally, if healthy family members had very short telomeres, they were also evaluated as potential silent carriers, since this approach has facilitated the identification of other DC genes. Nonsynonymous variants were considered deleterious if SIFT, PolyPhen 2, and Condel predictions were consistent. Family 1 has 2 siblings with the Hoyeraal Hreidarsson syndrome (HH) variant of DC, which includes features of DC plus cerebellar hypoplasia. In that family, WES revealed autosomal dominant inheritance of a nonsense mutation in RTEL1 (Regulator of Telomere Elongation Helicase 1), p.Arg1010Stop. Their mother, who has lymphocyte telomere lengths at the 1st percentile, is a clinically silent carrier of this mutation; the severe phenotypes present in her children are likely an example of genetic anticipation. In family 2, we found 2 RTEL1 mutations, a nonsense (p.Arg998Stop) and a deleterious missense (p.Glu615Asp) mutation, that were inherited from the father and mother, respectively. One clinically healthy child inherited only the missense mutation, but has telomeres <1st percentile. The other child has HH and extremely short telomeres; he is a compound heterozygote, having inherited both the missense and nonsense mutations in RTEL1. We subsequently performed targeted sequencing of the entire RTEL1 gene in all of our mutation-negative DC (n=11) and DC-like (n=14) families. We identified missense mutations in RTEL1 in 2 additional families. Family 3 has 2 DC-like siblings, but only the proband's DNA was available for sequencing. He was heterozygous for a deleterious missense mutation (p.Ala645Thr) in a conserved helicase domain of RTEL1. In family 4, a mutation was inherited in an autosomal recessive manner by a proband with HH. This mutation is intronic except for a read-through transcript of RTEL1-TNFRSF6B, which utilizes an alternative exon 34. If translated, this variant results in the amino acid change p.Arg1264His, which is likely deleterious; if not, this mutation may affect nonsense-mediated decay or induce a regulatory change in RTEL1 expression. RTEL1 is an essential, evolutionarily conserved DNA helicase that is important for DNA replication and telomere elongation. Depletion of mRTEL1 from mouse embryonic stem cells results in telomeric loss and chromosomal instability. All individuals with germline RTEL1 mutations in this study have short telomeres, which underscores the functional importance of RTEL1 in human telomere maintenance. In summary, by employing WES followed by targeted sequencing, we discovered mutations in RTEL1 in 4 DC families, indicating that dysfunctional RTEL1 is a biologically plausible cause of DC. Disclosures: No relevant conflicts of interest to declare." @default.
• W2588832503 created "2017-02-24" @default.
• W2588832503 creator A5000991321 @default.
• W2588832503 creator A5006363663 @default.
• W2588832503 creator A5045246519 @default.
• W2588832503 creator A5067533895 @default.
• W2588832503 creator A5073008351 @default.
• W2588832503 creator A5083582714 @default.
• W2588832503 creator A5083815833 @default.
• W2588832503 creator A5086610185 @default.
• W2588832503 creator A5087166167 @default.
• W2588832503 creator A5088697436 @default.
• W2588832503 date "2012-11-16" @default.
• W2588832503 modified "2023-10-13" @default.
• W2588832503 title "Germline Mutations in RTEL1 cause Dyskeratosis Congenita" @default.
• W2588832503 doi "https://doi.org/10.1182/blood.v120.21.515.515" @default.
• W2588832503 hasPublicationYear "2012" @default.
• W2588832503 type Work @default.
• W2588832503 sameAs 2588832503 @default.
• W2588832503 citedByCount "0" @default.
• W2588832503 crossrefType "journal-article" @default.
• W2588832503 hasAuthorship W2588832503A5000991321 @default.
• W2588832503 hasAuthorship W2588832503A5006363663 @default.
• W2588832503 hasAuthorship W2588832503A5045246519 @default.
• W2588832503 hasAuthorship W2588832503A5067533895 @default.
• W2588832503 hasAuthorship W2588832503A5073008351 @default.
• W2588832503 hasAuthorship W2588832503A5083582714 @default.
• W2588832503 hasAuthorship W2588832503A5083815833 @default.
• W2588832503 hasAuthorship W2588832503A5086610185 @default.
• W2588832503 hasAuthorship W2588832503A5087166167 @default.
• W2588832503 hasAuthorship W2588832503A5088697436 @default.
• W2588832503 hasConcept C104317684 @default.
• W2588832503 hasConcept C109159458 @default.
• W2588832503 hasConcept C16671776 @default.
• W2588832503 hasConcept C177336024 @default.
• W2588832503 hasConcept C2779285011 @default.
• W2588832503 hasConcept C2780525284 @default.
• W2588832503 hasConcept C28328180 @default.
• W2588832503 hasConcept C501734568 @default.
• W2588832503 hasConcept C54355233 @default.
• W2588832503 hasConcept C71924100 @default.
• W2588832503 hasConcept C86803240 @default.
• W2588832503 hasConceptScore W2588832503C104317684 @default.
• W2588832503 hasConceptScore W2588832503C109159458 @default.
• W2588832503 hasConceptScore W2588832503C16671776 @default.
• W2588832503 hasConceptScore W2588832503C177336024 @default.
• W2588832503 hasConceptScore W2588832503C2779285011 @default.
• W2588832503 hasConceptScore W2588832503C2780525284 @default.
• W2588832503 hasConceptScore W2588832503C28328180 @default.
• W2588832503 hasConceptScore W2588832503C501734568 @default.
• W2588832503 hasConceptScore W2588832503C54355233 @default.
• W2588832503 hasConceptScore W2588832503C71924100 @default.
• W2588832503 hasConceptScore W2588832503C86803240 @default.
• W2588832503 hasLocation W25888325031 @default.
• W2588832503 hasOpenAccess W2588832503 @default.
• W2588832503 hasPrimaryLocation W25888325031 @default.
• W2588832503 hasRelatedWork W1849849028 @default.
• W2588832503 hasRelatedWork W1995667263 @default.
• W2588832503 hasRelatedWork W2029860584 @default.
• W2588832503 hasRelatedWork W2058969871 @default.
• W2588832503 hasRelatedWork W2076622465 @default.
• W2588832503 hasRelatedWork W2089842428 @default.
• W2588832503 hasRelatedWork W2095313936 @default.
• W2588832503 hasRelatedWork W2107042037 @default.
• W2588832503 hasRelatedWork W2164323697 @default.
• W2588832503 hasRelatedWork W2171657219 @default.
• W2588832503 hasRelatedWork W2300742375 @default.
• W2588832503 hasRelatedWork W2411004362 @default.
• W2588832503 hasRelatedWork W2416758706 @default.
• W2588832503 hasRelatedWork W2549255458 @default.
• W2588832503 hasRelatedWork W2564879378 @default.
• W2588832503 hasRelatedWork W2579265792 @default.
• W2588832503 hasRelatedWork W2806913944 @default.
• W2588832503 hasRelatedWork W2899622243 @default.
• W2588832503 hasRelatedWork W2974624687 @default.
• W2588832503 hasRelatedWork W2736491966 @default.
• W2588832503 isParatext "false" @default.
• W2588832503 isRetracted "false" @default.
• W2588832503 magId "2588832503" @default.
• W2588832503 workType "article" @default.