Dyskeratosis congenita (DC) is a rare inherited multisystem telomere biology disorder (TBD) caused by impaired telomere maintenance resulting in abnormally short or dysfunctional telomeres. Classic DC is defined by a mucocutaneous triad of dysplastic nails, lacy reticular skin pigmentation, and oral leukoplakia, and is complicated by progressive bone marrow failure, predisposition to myelodysplastic syndrome / acute myeloid leukemia and squamous cell carcinoma, and pulmonary and hepatic fibrosis. DC sits at the early-onset, classic end of the broader telomere biology disorder spectrum, with Hoyeraal-Hreidarsson syndrome (with cerebellar hypoplasia) and Revesz syndrome (with exudative retinopathy) representing severe variants. Pathogenic germline variants in at least 16 genes spanning the telomerase core (TERT, TERC), the H/ACA snoRNP (DKC1, NHP2, NOP10, NAF1), telomerase trafficking (WRAP53), the shelterin complex (TINF2, ACD, POT1), the CST replication complex (CTC1, STN1, RPA1), the RTEL1 helicase, and RNA-processing factors (PARN, ZCCHC8) cause DC, with X-linked, autosomal dominant, and autosomal recessive inheritance depending on the gene. Diagnosis relies on multicolor flow-FISH lymphocyte telomere length testing (very short telomeres, often below the 1st percentile for age) and germline genetic testing, which identifies a pathogenic variant in approximately 80% of clinically diagnosed individuals.
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name: Dyskeratosis Congenita
creation_date: "2026-06-05T12:00:00Z"
category: Mendelian
description: >-
Dyskeratosis congenita (DC) is a rare inherited multisystem telomere biology
disorder (TBD) caused by impaired telomere maintenance resulting in abnormally
short or dysfunctional telomeres. Classic DC is defined by a mucocutaneous triad
of dysplastic nails, lacy reticular skin pigmentation, and oral leukoplakia, and
is complicated by progressive bone marrow failure, predisposition to
myelodysplastic syndrome / acute myeloid leukemia and squamous cell carcinoma,
and pulmonary and hepatic fibrosis. DC sits at the early-onset, classic end of
the broader telomere biology disorder spectrum, with Hoyeraal-Hreidarsson
syndrome (with cerebellar hypoplasia) and Revesz syndrome (with exudative
retinopathy) representing severe variants. Pathogenic germline variants in at
least 16 genes spanning the telomerase core (TERT, TERC), the H/ACA snoRNP
(DKC1, NHP2, NOP10, NAF1), telomerase trafficking (WRAP53), the shelterin
complex (TINF2, ACD, POT1), the CST replication complex (CTC1, STN1, RPA1), the
RTEL1 helicase, and RNA-processing factors (PARN, ZCCHC8) cause DC, with
X-linked, autosomal dominant, and autosomal recessive inheritance depending on
the gene. Diagnosis relies on multicolor flow-FISH lymphocyte telomere length
testing (very short telomeres, often below the 1st percentile for age) and
germline genetic testing, which identifies a pathogenic variant in approximately
80% of clinically diagnosed individuals.
disease_term:
preferred_term: Dyskeratosis Congenita
term:
id: MONDO:0015780
label: dyskeratosis congenita
parents:
- Bone Marrow Failure
- Inherited Bone Marrow Failure Syndrome
- Telomere Biology Disorder
references:
- reference: PMID:20301779
title: "Dyskeratosis Congenita and Related Telomere Biology Disorders."
tags:
- GeneReviews
inheritance:
- name: X-linked recessive inheritance
inheritance_term:
preferred_term: X-linked recessive inheritance
term:
id: HP:0001419
label: X-linked recessive inheritance
description: >-
X-linked recessive inheritance applies to DKC1, the gene encoding dyskerin and
historically the most common and most severe form of classic DC.
evidence:
- reference: PMID:20301779
reference_title: "Dyskeratosis Congenita and Related Telomere Biology Disorders."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The mode of inheritance of DC/TBD varies by gene: X-linked: DKC1."
explanation: GeneReviews assigns X-linked inheritance specifically to DKC1.
- name: Autosomal dominant inheritance
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
description: >-
Autosomal dominant inheritance applies to NAF1, RPA1, TERC, TINF2, and ZCCHC8,
and is the most frequent mode in adult-onset (cryptic) TBD.
evidence:
- reference: PMID:20301779
reference_title: "Dyskeratosis Congenita and Related Telomere Biology Disorders."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Autosomal dominant: NAF1, RPA1, TERC, TINF2, and ZCCHC8."
explanation: GeneReviews lists the autosomal dominant DC/TBD genes.
- reference: PMID:38066848
reference_title: "Clinical manifestations of telomere biology disorders in adults."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "TBD genetic etiology includes all modes of inheritance, with autosomal dominant the most frequent in adult-onset disease."
explanation: Autosomal dominant inheritance predominates in adult-onset TBD.
- name: Autosomal recessive inheritance
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
description: >-
Autosomal recessive inheritance applies to CTC1, NHP2, NOP10, POT1, STN1, and
WRAP53; ACD, PARN, RTEL1, and TERT can be inherited as either dominant or
recessive.
evidence:
- reference: PMID:20301779
reference_title: "Dyskeratosis Congenita and Related Telomere Biology Disorders."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Autosomal recessive: CTC1, NHP2, NOP10, POT1, STN1, and WRAP53."
explanation: GeneReviews lists the autosomal recessive DC/TBD genes.
prevalence:
- population: Global
prevalence_class: RARE
percentage: Rare
notes: >-
DC is consistently described as an ultra-rare/rare inherited bone marrow
failure syndrome. Reported prevalence estimates range from approximately 1 per
1,000,000 to 1-9 per 1,000,000.
evidence:
- reference: PMID:37593443
reference_title: "Dyskeratosis congenita: natural history of the disease through the study of a cohort of patients diagnosed in childhood."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Dyskeratosis congenita (DC) is a multisystem and ultra-rare hereditary disease characterized by somatic involvement, bone marrow failure, and predisposition to cancer."
explanation: Characterizes DC as an ultra-rare hereditary multisystem disease.
progression:
- phase: Onset
age_range: Childhood
notes: >-
Classic DC typically presents in childhood with mucocutaneous features and
early bone marrow failure, whereas cryptic/adult-onset TBD may present in mid-
or late adulthood with isolated pulmonary, hepatic, hematologic disease, or
cancer.
evidence:
- reference: PMID:37593443
reference_title: "Dyskeratosis congenita: natural history of the disease through the study of a cohort of patients diagnosed in childhood."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Fourteen patients were diagnosed with DC between the ages of 3 and 17 years (median, 8.5 years). They all had hematologic manifestations at diagnosis"
explanation: Childhood-diagnosed cohort with median diagnosis age 8.5 years and universal hematologic manifestations.
- reference: PMID:38066848
reference_title: "Clinical manifestations of telomere biology disorders in adults."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Adult-onset TBDs are often cryptic with isolated pulmonary, liver, or hematologic disease, or cancer, and may lack the classic disease-defining triad"
explanation: Adult-onset TBD presents cryptically and may lack the triad.
- phase: Bone marrow failure
notes: >-
The majority of children with classic DC progress to bone marrow failure,
typically in the first or second decade of life.
evidence:
- reference: PMID:37593443
reference_title: "Dyskeratosis congenita: natural history of the disease through the study of a cohort of patients diagnosed in childhood."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Thirteen progressed to bone marrow failure at a median age of 8 years"
explanation: 13/14 children progressed to bone marrow failure at median age 8 years.
has_subtypes:
- name: DKC1
display_name: X-linked DC (DKC1, dyskerin)
description: >-
X-linked recessive DC caused by pathogenic variants in DKC1 encoding dyskerin,
a core component of the H/ACA small nucleolar ribonucleoprotein required for
pseudouridylation and for stability of the telomerase RNA component. DKC1
disease is historically the most common and most severe classic DC form,
including Hoyeraal-Hreidarsson syndrome.
inheritance:
- name: X-linked recessive inheritance
inheritance_term:
preferred_term: X-linked recessive inheritance
term:
id: HP:0001419
label: X-linked recessive inheritance
genes:
- preferred_term: DKC1
term:
id: hgnc:2890
label: DKC1
evidence:
- reference: PMID:20301779
reference_title: "Dyskeratosis Congenita and Related Telomere Biology Disorders."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The mode of inheritance of DC/TBD varies by gene: X-linked: DKC1."
explanation: GeneReviews assigns X-linked inheritance to DKC1.
- name: TERT
display_name: Telomerase reverse transcriptase (TERT)
description: >-
DC caused by variants in TERT, the catalytic protein subunit of telomerase.
TERT-associated disease can be inherited as autosomal dominant or autosomal
recessive and is a common cause of adult-onset/cryptic TBD with pulmonary or
hepatic fibrosis.
inheritance:
- name: Autosomal dominant inheritance
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
- name: Autosomal recessive inheritance
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
genes:
- preferred_term: TERT
term:
id: hgnc:11730
label: TERT
evidence:
- reference: PMID:20301779
reference_title: "Dyskeratosis Congenita and Related Telomere Biology Disorders."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Autosomal dominant or autosomal recessive: ACD, PARN, RTEL1, and TERT."
explanation: GeneReviews lists TERT as dominant or recessive DC/TBD.
- name: TERC
display_name: Telomerase RNA component (TERC)
description: >-
Autosomal dominant DC caused by variants in TERC, the RNA template subunit of
telomerase. Frequently underlies later-onset disease with pulmonary fibrosis.
inheritance:
- name: Autosomal dominant inheritance
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
genes:
- preferred_term: TERC
term:
id: hgnc:11727
label: TERC
evidence:
- reference: PMID:20301779
reference_title: "Dyskeratosis Congenita and Related Telomere Biology Disorders."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Autosomal dominant: NAF1, RPA1, TERC, TINF2, and ZCCHC8."
explanation: GeneReviews lists TERC as autosomal dominant DC/TBD.
- name: TINF2
display_name: Shelterin TINF2 (TIN2)
description: >-
Autosomal dominant DC caused by variants in TINF2 encoding the shelterin
component TIN2. TINF2 disease is often severe and early-onset, and is enriched
for severe variants including Revesz syndrome and progression to liver disease.
inheritance:
- name: Autosomal dominant inheritance
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
genes:
- preferred_term: TINF2
term:
id: hgnc:11824
label: TINF2
evidence:
- reference: PMID:37184208
reference_title: "Progression of liver disease and portal hypertension in dyskeratosis congenita and related telomere biology disorders."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "those with heterozygous TINF2 DC were significantly younger, predominantly male, and more likely to have DC-associated mucocutaneous triad features and severe bone marrow failure"
explanation: TINF2 DC patients are younger with severe triad features and bone marrow failure.
- name: RTEL1
display_name: Regulator of telomere elongation helicase 1 (RTEL1)
description: >-
DC caused by variants in RTEL1, a DNA helicase that dismantles telomeric
T-loops and supports telomere replication. RTEL1 disease can be autosomal
dominant or recessive and includes Hoyeraal-Hreidarsson syndrome.
inheritance:
- name: Autosomal dominant inheritance
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
- name: Autosomal recessive inheritance
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
genes:
- preferred_term: RTEL1
term:
id: hgnc:15888
label: RTEL1
evidence:
- reference: PMID:20301779
reference_title: "Dyskeratosis Congenita and Related Telomere Biology Disorders."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Autosomal dominant or autosomal recessive: ACD, PARN, RTEL1, and TERT."
explanation: GeneReviews lists RTEL1 as dominant or recessive DC/TBD.
- name: CTC1
display_name: CST complex CTC1
description: >-
Autosomal recessive DC caused by variants in CTC1, a component of the
CTC1-STN1-TEN1 (CST) complex that supports telomere C-strand replication and
interacts with DNA polymerase alpha-primase. CTC1 disease overlaps with Coats
plus syndrome.
inheritance:
- name: Autosomal recessive inheritance
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
genes:
- preferred_term: CTC1
term:
id: hgnc:26169
label: CTC1
evidence:
- reference: PMID:20301779
reference_title: "Dyskeratosis Congenita and Related Telomere Biology Disorders."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Autosomal recessive: CTC1, NHP2, NOP10, POT1, STN1, and WRAP53."
explanation: GeneReviews lists CTC1 as autosomal recessive DC/TBD.
- name: RPA1
display_name: Replication protein A1 (RPA1)
description: >-
Autosomal dominant DC caused by variants in RPA1, a single-stranded
DNA-binding protein involved in telomere replication.
inheritance:
- name: Autosomal dominant inheritance
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
genes:
- preferred_term: RPA1
term:
id: hgnc:10289
label: RPA1
evidence:
- reference: PMID:20301779
reference_title: "Dyskeratosis Congenita and Related Telomere Biology Disorders."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Autosomal dominant: NAF1, RPA1, TERC, TINF2, and ZCCHC8."
explanation: GeneReviews lists RPA1 as autosomal dominant DC/TBD.
- name: ACD
display_name: Shelterin ACD (TPP1)
description: >-
DC caused by variants in ACD encoding the shelterin protein TPP1, which
recruits and stimulates telomerase. ACD disease can be autosomal dominant or
recessive.
inheritance:
- name: Autosomal dominant inheritance
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
- name: Autosomal recessive inheritance
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
genes:
- preferred_term: ACD
term:
id: hgnc:25070
label: ACD
evidence:
- reference: PMID:20301779
reference_title: "Dyskeratosis Congenita and Related Telomere Biology Disorders."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Autosomal dominant or autosomal recessive: ACD, PARN, RTEL1, and TERT."
explanation: GeneReviews lists ACD as dominant or recessive DC/TBD.
- name: NHP2
display_name: H/ACA snoRNP NHP2
description: >-
Autosomal recessive DC caused by variants in NHP2, an H/ACA
ribonucleoprotein component required for telomerase RNA stability.
inheritance:
- name: Autosomal recessive inheritance
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
genes:
- preferred_term: NHP2
term:
id: hgnc:14377
label: NHP2
evidence:
- reference: PMID:20301779
reference_title: "Dyskeratosis Congenita and Related Telomere Biology Disorders."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Autosomal recessive: CTC1, NHP2, NOP10, POT1, STN1, and WRAP53."
explanation: GeneReviews lists NHP2 as autosomal recessive DC/TBD.
- name: NOP10
display_name: H/ACA snoRNP NOP10
description: >-
Autosomal recessive DC caused by variants in NOP10, an H/ACA
ribonucleoprotein component required for telomerase RNA stability.
inheritance:
- name: Autosomal recessive inheritance
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
genes:
- preferred_term: NOP10
term:
id: hgnc:14378
label: NOP10
evidence:
- reference: PMID:20301779
reference_title: "Dyskeratosis Congenita and Related Telomere Biology Disorders."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Autosomal recessive: CTC1, NHP2, NOP10, POT1, STN1, and WRAP53."
explanation: GeneReviews lists NOP10 as autosomal recessive DC/TBD.
- name: PARN
display_name: Poly(A)-specific ribonuclease (PARN)
description: >-
DC caused by variants in PARN, a deadenylase required for maturation of the
telomerase RNA component (TERC). PARN disease can be autosomal dominant or
recessive and is associated with pulmonary fibrosis.
inheritance:
- name: Autosomal dominant inheritance
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
- name: Autosomal recessive inheritance
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
genes:
- preferred_term: PARN
term:
id: hgnc:8609
label: PARN
evidence:
- reference: PMID:20301779
reference_title: "Dyskeratosis Congenita and Related Telomere Biology Disorders."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Autosomal dominant or autosomal recessive: ACD, PARN, RTEL1, and TERT."
explanation: GeneReviews lists PARN as dominant or recessive DC/TBD.
- name: WRAP53
display_name: WRAP53 (TCAB1)
description: >-
Autosomal recessive DC caused by variants in WRAP53 (TCAB1), which traffics
telomerase to Cajal bodies for recruitment to telomeres.
inheritance:
- name: Autosomal recessive inheritance
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
genes:
- preferred_term: WRAP53
term:
id: hgnc:25522
label: WRAP53
evidence:
- reference: PMID:20301779
reference_title: "Dyskeratosis Congenita and Related Telomere Biology Disorders."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Autosomal recessive: CTC1, NHP2, NOP10, POT1, STN1, and WRAP53."
explanation: GeneReviews lists WRAP53 as autosomal recessive DC/TBD.
- name: POT1
display_name: Shelterin POT1
description: >-
Autosomal recessive DC caused by variants in POT1, a shelterin component that
binds telomeric single-stranded DNA. Novel POT1 variants expanding the DC
allelic series reduce binding to telomeric ssDNA.
inheritance:
- name: Autosomal recessive inheritance
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
genes:
- preferred_term: POT1
term:
id: hgnc:17284
label: POT1
evidence:
- reference: PMID:39198715
reference_title: "The evolving genetic landscape of telomere biology disorder dyskeratosis congenita."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "we have also identified several novel variants in POT1 and ZCCHC8 in multiple cases from different families expanding the allelic series of DC and DCL phenotypes."
explanation: Novel POT1 variants expand the DC allelic series.
- name: NAF1
display_name: Nuclear assembly factor 1 (NAF1)
description: >-
Autosomal dominant DC/TBD caused by variants in NAF1, an H/ACA
ribonucleoprotein assembly factor required for biogenesis and stability of the
telomerase RNA component.
inheritance:
- name: Autosomal dominant inheritance
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
genes:
- preferred_term: NAF1
term:
id: hgnc:25126
label: NAF1
evidence:
- reference: PMID:20301779
reference_title: "Dyskeratosis Congenita and Related Telomere Biology Disorders."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Autosomal dominant: NAF1, RPA1, TERC, TINF2, and ZCCHC8."
explanation: GeneReviews lists NAF1 as autosomal dominant DC/TBD.
- name: STN1
display_name: CST complex STN1
description: >-
Autosomal recessive DC/TBD caused by variants in STN1, a component of the CST
(CTC1-STN1-TEN1) complex that supports telomere replication and C-strand fill-in.
inheritance:
- name: Autosomal recessive inheritance
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
genes:
- preferred_term: STN1
term:
id: hgnc:26200
label: STN1
evidence:
- reference: PMID:20301779
reference_title: "Dyskeratosis Congenita and Related Telomere Biology Disorders."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Autosomal recessive: CTC1, NHP2, NOP10, POT1, STN1, and WRAP53."
explanation: GeneReviews lists STN1 as autosomal recessive DC/TBD.
- name: ZCCHC8
display_name: ZCCHC8 (nuclear exosome targeting complex)
description: >-
Autosomal dominant DC/TBD caused by variants in ZCCHC8, a component of the
nuclear exosome targeting (NEXT) complex involved in processing/quality control
of the telomerase RNA component.
inheritance:
- name: Autosomal dominant inheritance
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
genes:
- preferred_term: ZCCHC8
term:
id: hgnc:25265
label: ZCCHC8
evidence:
- reference: PMID:20301779
reference_title: "Dyskeratosis Congenita and Related Telomere Biology Disorders."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Autosomal dominant: NAF1, RPA1, TERC, TINF2, and ZCCHC8."
explanation: GeneReviews lists ZCCHC8 as autosomal dominant DC/TBD.
pathophysiology:
- name: Impaired Telomere Maintenance
description: >-
The unifying upstream defect in DC is impaired telomere maintenance. Germline
pathogenic variants in genes encoding telomerase (TERT catalytic subunit, TERC
RNA template), the H/ACA snoRNP that stabilizes TERC (DKC1/dyskerin, NHP2,
NOP10, NAF1), telomerase trafficking factors (WRAP53/TCAB1), the shelterin
complex (TINF2, ACD/TPP1, POT1), the CST replication complex (CTC1, STN1, RPA1),
and the RTEL1 helicase reduce the cell's ability to replenish telomeric repeats.
Telomeres are nucleoprotein caps that prevent activation of the DNA damage
response at chromosome ends.
cell_types:
- preferred_term: Hematopoietic stem cell
term:
id: CL:0000037
label: hematopoietic stem cell
biological_processes:
- preferred_term: Telomere maintenance
term:
id: GO:0000723
label: telomere maintenance
modifier: DECREASED
- preferred_term: Telomere maintenance via telomerase
term:
id: GO:0007004
label: telomere maintenance via telomerase
modifier: DECREASED
cellular_components:
- preferred_term: Telomerase holoenzyme complex
term:
id: GO:0005697
label: telomerase holoenzyme complex
molecular_functions:
- preferred_term: Telomerase RNA binding
term:
id: GO:0070034
label: telomerase RNA binding
genes:
- preferred_term: DKC1
term:
id: hgnc:2890
label: DKC1
- preferred_term: TERT
term:
id: hgnc:11730
label: TERT
- preferred_term: TERC
term:
id: hgnc:11727
label: TERC
- preferred_term: TINF2
term:
id: hgnc:11824
label: TINF2
- preferred_term: RTEL1
term:
id: hgnc:15888
label: RTEL1
- preferred_term: CTC1
term:
id: hgnc:26169
label: CTC1
- preferred_term: RPA1
term:
id: hgnc:10289
label: RPA1
- preferred_term: ACD
term:
id: hgnc:25070
label: ACD
- preferred_term: NHP2
term:
id: hgnc:14377
label: NHP2
- preferred_term: NOP10
term:
id: hgnc:14378
label: NOP10
- preferred_term: PARN
term:
id: hgnc:8609
label: PARN
- preferred_term: WRAP53
term:
id: hgnc:25522
label: WRAP53
- preferred_term: POT1
term:
id: hgnc:17284
label: POT1
- preferred_term: POLA1
term:
id: hgnc:9173
label: POLA1
- preferred_term: NAF1
term:
id: hgnc:25126
label: NAF1
- preferred_term: STN1
term:
id: hgnc:26200
label: STN1
- preferred_term: ZCCHC8
term:
id: hgnc:25265
label: ZCCHC8
evidence:
- reference: PMID:20301779
reference_title: "Dyskeratosis Congenita and Related Telomere Biology Disorders."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Dyskeratosis congenita and related telomere biology disorders (DC/TBD) are caused by impaired telomere maintenance resulting in short or very short telomeres."
explanation: Establishes impaired telomere maintenance as the unifying cause of DC.
- reference: PMID:36151328
reference_title: "Genetics of human telomere biology disorders."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Mendelian defects in several of these factors can result in abnormally short or dysfunctional telomeres"
explanation: Mendelian defects in telomere factors produce short or dysfunctional telomeres.
downstream:
- target: Critically Short Telomeres and Replicative Senescence
- name: Critically Short Telomeres and Replicative Senescence
description: >-
Defective maintenance leads to progressive telomere attrition until telomeres
become critically short or dysfunctional. Critically short telomeres are sensed
as DNA damage, activating the p53/p21 DNA damage response and driving affected
cells into replicative senescence or apoptosis, thereby limiting the replicative
capacity of the tissue. Very short telomeres (often below the 1st percentile for
age) are the diagnostic hallmark of DC.
cell_types:
- preferred_term: Hematopoietic stem cell
term:
id: CL:0000037
label: hematopoietic stem cell
biological_processes:
- preferred_term: Replicative senescence
term:
id: GO:0090399
label: replicative senescence
modifier: INCREASED
- preferred_term: Apoptotic process
term:
id: GO:0006915
label: apoptotic process
modifier: INCREASED
- preferred_term: p53-mediated DNA damage response
term:
id: GO:0030330
label: DNA damage response, signal transduction by p53 class mediator
modifier: INCREASED
evidence:
- reference: PMID:39371255
reference_title: "Inherited Telomere Biology Disorders: Pathophysiology, Clinical Presentation, Diagnostics, and Treatment."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "telomeres shorten continuously with each cell division until critically short telomeres prevent further proliferation whereby cells undergo terminal differentiation, senescence, or apoptosis."
explanation: Critically short telomeres halt proliferation and trigger senescence or apoptosis.
- reference: PMID:40215293
reference_title: "Loss of Ten1 in mice induces telomere shortening and models human dyskeratosis congenita."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Molecular analyses revealed a reduction of proliferating cells, increased apoptosis, and stem cell depletion with activation of the p53/p21 signaling pathway."
explanation: Ten1-knockout mouse model demonstrates p53/p21 activation, apoptosis, and stem cell depletion from telomere dysfunction.
downstream:
- target: Stem Cell Exhaustion in High-Turnover Tissues
- name: Stem Cell Exhaustion in High-Turnover Tissues
description: >-
Because telomere reserve restricts replicative capacity, tissues with high
proliferative demand are preferentially affected. Premature replicative
exhaustion of stem and progenitor cells in the bone marrow, immune system,
skin and mucosa, liver, and lung produces the characteristic multisystem
phenotype: bone marrow failure, mucocutaneous changes, and hepatic and
pulmonary fibrosis. Genomic instability from dysfunctional telomeres also
underlies the predisposition to myelodysplastic syndrome, leukemia, and
squamous cell carcinoma.
cell_types:
- preferred_term: Hematopoietic stem cell
term:
id: CL:0000037
label: hematopoietic stem cell
- preferred_term: Hematopoietic precursor cell
term:
id: CL:0008001
label: hematopoietic precursor cell
- preferred_term: Pulmonary alveolar type 2 cell
term:
id: CL:0002063
label: pulmonary alveolar type 2 cell
evidence:
- reference: PMID:39371255
reference_title: "Inherited Telomere Biology Disorders: Pathophysiology, Clinical Presentation, Diagnostics, and Treatment."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "altered telomere maintenance as observed in TBDs typically results in premature replicative cellular exhaustion in the respective organ systems eventually leading to life-threatening complications such as bone marrow failure (BMF), pulmonary fibrosis, and liver cirrhosis."
explanation: Premature replicative exhaustion in high-turnover organs causes bone marrow failure, pulmonary fibrosis, and liver cirrhosis.
downstream:
- target: Bone marrow failure
description: Exhaustion of hematopoietic stem and progenitor cells produces progressive bone marrow failure.
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
evidence:
- reference: PMID:39371255
reference_title: "Inherited Telomere Biology Disorders: Pathophysiology, Clinical Presentation, Diagnostics, and Treatment."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "premature replicative cellular exhaustion in the respective organ systems eventually leading to life-threatening complications such as bone marrow failure (BMF), pulmonary fibrosis, and liver cirrhosis."
explanation: The review explicitly links premature cellular exhaustion in affected organs to bone marrow failure.
- target: Pulmonary fibrosis
description: Exhaustion of proliferative lung epithelial compartments contributes to telomere-biology-disorder pulmonary fibrosis.
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
evidence:
- reference: PMID:39371255
reference_title: "Inherited Telomere Biology Disorders: Pathophysiology, Clinical Presentation, Diagnostics, and Treatment."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "premature replicative cellular exhaustion in the respective organ systems eventually leading to life-threatening complications such as bone marrow failure (BMF), pulmonary fibrosis, and liver cirrhosis."
explanation: The review explicitly links premature cellular exhaustion in affected organs to pulmonary fibrosis.
- target: Hepatic fibrosis and portal hypertension
description: Telomere-driven cellular exhaustion in liver tissue predisposes to fibrotic/cirrhotic liver disease.
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
evidence:
- reference: PMID:39371255
reference_title: "Inherited Telomere Biology Disorders: Pathophysiology, Clinical Presentation, Diagnostics, and Treatment."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "premature replicative cellular exhaustion in the respective organ systems eventually leading to life-threatening complications such as bone marrow failure (BMF), pulmonary fibrosis, and liver cirrhosis."
explanation: The review explicitly links premature cellular exhaustion in affected organs to liver cirrhosis, supporting the hepatic fibrosis/cirrhosis branch.
phenotypes:
- category: Integumentary
name: Nail dystrophy
description: >-
Dysplastic, dystrophic nails are a component of the classic DC mucocutaneous
triad.
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Nail dystrophy
term:
id: HP:0008404
label: Nail dystrophy
evidence:
- reference: PMID:20301779
reference_title: "Dyskeratosis Congenita and Related Telomere Biology Disorders."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Classic DC is characterized by a triad of dysplastic nails, lacy reticular pigmentation of the upper chest and/or neck, and oral leukoplakia"
explanation: Dysplastic nails are part of the diagnostic DC triad.
- reference: ORPHA:1775
supports: SUPPORT
snippet: "HP:0008404 | Nail dystrophy | Very frequent (99-80%)"
explanation: Orphanet classifies nail dystrophy as very frequent in dyskeratosis congenita.
- category: Integumentary
name: Reticular skin pigmentation
description: >-
Lacy/reticulated abnormal skin pigmentation, typically of the upper chest
and/or neck, is a component of the classic DC mucocutaneous triad.
phenotype_term:
preferred_term: Reticulated skin pigmentation
term:
id: HP:0007427
label: Reticulated skin pigmentation
evidence:
- reference: PMID:20301779
reference_title: "Dyskeratosis Congenita and Related Telomere Biology Disorders."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "a triad of dysplastic nails, lacy reticular pigmentation of the upper chest and/or neck, and oral leukoplakia"
explanation: Lacy reticular pigmentation is part of the diagnostic DC triad.
- reference: ORPHA:1775
supports: SUPPORT
snippet: "classic triad of nail dysplasia, skin pigmentary changes, and oral leukoplakia"
explanation: Orphanet's definition supports pigmentary skin change as part of the classic DC triad.
- category: Oral
name: Oral leukoplakia
description: >-
Oral leukoplakia is a component of the classic DC mucocutaneous triad and a
site of increased risk for squamous cell carcinoma.
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Oral leukoplakia
term:
id: HP:0002745
label: Oral leukoplakia
evidence:
- reference: PMID:20301779
reference_title: "Dyskeratosis Congenita and Related Telomere Biology Disorders."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "a triad of dysplastic nails, lacy reticular pigmentation of the upper chest and/or neck, and oral leukoplakia"
explanation: Oral leukoplakia is part of the diagnostic DC triad.
- reference: ORPHA:1775
supports: SUPPORT
snippet: "HP:0002745 | Oral leukoplakia | Very frequent (99-80%)"
explanation: Orphanet classifies oral leukoplakia as very frequent in dyskeratosis congenita.
- category: Hematologic
name: Bone marrow failure
description: >-
Progressive bone marrow failure is a hallmark complication of DC and the
leading cause of early mortality. Most children with classic DC progress to
bone marrow failure.
phenotype_term:
preferred_term: Aplastic anemia
term:
id: HP:0001915
label: Aplastic anemia
clinical_course: PROGRESSIVE
evidence:
- reference: PMID:20301779
reference_title: "Dyskeratosis Congenita and Related Telomere Biology Disorders."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "People with DC/TBD are at increased risk for progressive bone marrow failure (BMF)"
explanation: Progressive bone marrow failure is a defining complication of DC.
- reference: PMID:37593443
reference_title: "Dyskeratosis congenita: natural history of the disease through the study of a cohort of patients diagnosed in childhood."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Thirteen progressed to bone marrow failure at a median age of 8 years"
explanation: 13/14 children progressed to bone marrow failure at median age 8 years.
- category: Hematologic
name: Bone marrow hypocellularity
description: >-
Bone marrow hypocellularity reflects hematopoietic stem cell exhaustion from
telomere dysfunction.
phenotype_term:
preferred_term: Bone marrow hypocellularity
term:
id: HP:0005528
label: Bone marrow hypocellularity
evidence:
- reference: PMID:39371255
reference_title: "Inherited Telomere Biology Disorders: Pathophysiology, Clinical Presentation, Diagnostics, and Treatment."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "altered telomere maintenance as observed in TBDs typically results in premature replicative cellular exhaustion in the respective organ systems eventually leading to life-threatening complications such as bone marrow failure (BMF)"
explanation: Replicative exhaustion of marrow precursors leads to bone marrow failure and hypocellularity.
- reference: ORPHA:1775
supports: SUPPORT
snippet: "HP:0005528 | Bone marrow hypocellularity | Frequent (79-30%)"
explanation: Orphanet classifies bone marrow hypocellularity as frequent in dyskeratosis congenita.
- category: Respiratory
name: Pulmonary fibrosis
description: >-
Pulmonary fibrosis / interstitial lung disease occurs in a substantial minority
of DC patients and may be the presenting feature of cryptic adult-onset disease.
Diagnostic surgical lung biopsy and empirical immunosuppression carry increased
risk in unrecognized DC-associated pulmonary fibrosis.
phenotype_term:
preferred_term: Pulmonary fibrosis
term:
id: HP:0002206
label: Pulmonary fibrosis
evidence:
- reference: PMID:20301779
reference_title: "Dyskeratosis Congenita and Related Telomere Biology Disorders."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "increased risk for progressive bone marrow failure (BMF), myelodysplastic syndrome or acute myelogenous leukemia, solid tumors (usually squamous cell carcinoma of the head/neck or anogenital cancer), and pulmonary fibrosis."
explanation: Pulmonary fibrosis is a recognized DC complication.
- reference: PMID:34479523
reference_title: "Pulmonary fibrosis in dyskeratosis congenita: a case report with a PRISMA-compliant systematic review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "PF caused by DC should be kept in mind by clinicians in the differential diagnosis of patients with unexplained PF and should be excluded before diagnostic surgical lung biopsy is undertaken or empirical immunosuppression therapy is prescribed."
explanation: DC-associated pulmonary fibrosis should be excluded before lung biopsy or immunosuppression.
- category: Hepatic
name: Hepatic fibrosis and portal hypertension
description: >-
Liver involvement is common in DC, typically with a cholestatic pattern of
liver enzyme elevation; a subset progresses to clinically significant liver
disease and portal hypertension, especially in recessive or TINF2-associated DC.
phenotype_term:
preferred_term: Periportal fibrosis
term:
id: HP:0001405
label: Periportal fibrosis
evidence:
- reference: PMID:37184208
reference_title: "Progression of liver disease and portal hypertension in dyskeratosis congenita and related telomere biology disorders."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Liver abnormality (defined at baseline assessment by laboratory and/or radiological findings) was present in 72.4% of patients with predominantly cholestatic pattern of liver enzyme elevation."
explanation: Liver abnormality was present in 72.4% of DC/TBD patients with cholestatic pattern.
- reference: PMID:37184208
reference_title: "Progression of liver disease and portal hypertension in dyskeratosis congenita and related telomere biology disorders."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Clinically significant liver disease and portal hypertension developed in 17.2% of patients during the 6-year follow-up; this progression was mainly seen in patients with recessive or TINF2 -associated DC."
explanation: 17.2% progressed to clinically significant liver disease and portal hypertension.
- category: Neoplasm
name: Predisposition to myelodysplastic syndrome and acute myeloid leukemia
description: >-
DC carries an increased risk of myelodysplastic syndrome and acute myeloid
leukemia due to genomic instability and clonal evolution in the failing marrow.
phenotype_term:
preferred_term: Myelodysplasia
term:
id: HP:0002863
label: Myelodysplasia
evidence:
- reference: PMID:20301779
reference_title: "Dyskeratosis Congenita and Related Telomere Biology Disorders."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "increased risk for progressive bone marrow failure (BMF), myelodysplastic syndrome or acute myelogenous leukemia"
explanation: DC predisposes to myelodysplastic syndrome and acute myeloid leukemia.
- category: Neoplasm
name: Predisposition to squamous cell carcinoma
description: >-
DC patients are at increased risk of solid tumors, usually squamous cell
carcinoma of the head and neck or anogenital region.
phenotype_term:
preferred_term: Squamous cell carcinoma
term:
id: HP:0002860
label: Squamous cell carcinoma
evidence:
- reference: PMID:20301779
reference_title: "Dyskeratosis Congenita and Related Telomere Biology Disorders."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "solid tumors (usually squamous cell carcinoma of the head/neck or anogenital cancer)"
explanation: DC predisposes to squamous cell carcinoma of the head/neck or anogenital region.
- category: Immunologic
name: Immunodeficiency
description: >-
Immune dysfunction can occur in DC, reflecting telomere-driven exhaustion of
the lymphoid compartment.
phenotype_term:
preferred_term: Immunodeficiency
term:
id: HP:0002721
label: Immunodeficiency
evidence:
- reference: PMID:39371255
reference_title: "Inherited Telomere Biology Disorders: Pathophysiology, Clinical Presentation, Diagnostics, and Treatment."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "a sufficient telomere reserve is particularly important in cells with high proliferative activity (e.g., hematopoiesis, immune cells, intestinal cells, liver, lung, and skin)."
explanation: Immune cells require telomere reserve; telomere depletion compromises immune function.
- category: Neurologic
name: Cerebellar hypoplasia (Hoyeraal-Hreidarsson syndrome)
description: >-
Cerebellar hypoplasia defines Hoyeraal-Hreidarsson syndrome, a severe
early-onset DC variant.
phenotype_term:
preferred_term: Cerebellar hypoplasia
term:
id: HP:0001321
label: Cerebellar hypoplasia
evidence:
- reference: PMID:20301779
reference_title: "Dyskeratosis Congenita and Related Telomere Biology Disorders."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "additional findings include cerebellar hypoplasia (Hoyeraal Hreidarsson syndrome)"
explanation: Cerebellar hypoplasia defines the Hoyeraal-Hreidarsson severe DC variant.
- category: Ophthalmologic
name: Exudative retinopathy (Revesz syndrome)
description: >-
Bilateral exudative retinopathy (a Coats-like retinal vascular exudation
process) with intracranial calcifications defines Revesz syndrome, a severe DC
variant. Mapped to HP:0030490 (Exudative vitreoretinopathy), which captures the
retinal vascular exudation underlying this phenotype more accurately than serous
retinal detachment.
phenotype_term:
preferred_term: Exudative retinopathy
term:
id: HP:0030490
label: Exudative vitreoretinopathy
evidence:
- reference: PMID:20301779
reference_title: "Dyskeratosis Congenita and Related Telomere Biology Disorders."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "bilateral exudative retinopathy and intracranial calcifications (Revesz syndrome"
explanation: Bilateral exudative retinopathy defines the Revesz severe DC variant.
genetic:
- name: DKC1
gene_term:
preferred_term: DKC1
term:
id: hgnc:2890
label: DKC1
relationship_type: CAUSATIVE
variant_origin: GERMLINE
inheritance:
- name: X-linked recessive inheritance
inheritance_term:
preferred_term: X-linked recessive inheritance
term:
id: HP:0001419
label: X-linked recessive inheritance
subtype: DKC1
notes: >-
DKC1 encodes dyskerin, an H/ACA snoRNP pseudouridine synthase required for
stability of the telomerase RNA component; X-linked recessive, classically the
most common and severe DC form.
evidence:
- reference: PMID:20301779
reference_title: "Dyskeratosis Congenita and Related Telomere Biology Disorders."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "ACD, CTC1, DKC1, NAF1, NHP2, NOP10, PARN, POT1, RPA1, RTEL1, STN1, TERC, TERT, TINF2, WRAP53, and ZCCHC8 are the genes in which pathogenic variants are known to cause DC/TBD"
explanation: GeneReviews lists DKC1 among the 16 genes causing DC/TBD.
- name: TERT
gene_term:
preferred_term: TERT
term:
id: hgnc:11730
label: TERT
relationship_type: CAUSATIVE
variant_origin: GERMLINE
inheritance:
- name: Autosomal dominant inheritance
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
- name: Autosomal recessive inheritance
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
subtype: TERT
notes: >-
TERT encodes the catalytic protein subunit of telomerase; variants cause DC and
cryptic adult-onset TBD with pulmonary/hepatic fibrosis.
evidence:
- reference: PMID:20301779
reference_title: "Dyskeratosis Congenita and Related Telomere Biology Disorders."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "ACD, CTC1, DKC1, NAF1, NHP2, NOP10, PARN, POT1, RPA1, RTEL1, STN1, TERC, TERT, TINF2, WRAP53, and ZCCHC8 are the genes in which pathogenic variants are known to cause DC/TBD"
explanation: GeneReviews lists TERT among the 16 genes causing DC/TBD.
- name: TERC
gene_term:
preferred_term: TERC
term:
id: hgnc:11727
label: TERC
relationship_type: CAUSATIVE
variant_origin: GERMLINE
inheritance:
- name: Autosomal dominant inheritance
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
subtype: TERC
notes: >-
TERC encodes the telomerase RNA template subunit; autosomal dominant DC/TBD.
evidence:
- reference: PMID:20301779
reference_title: "Dyskeratosis Congenita and Related Telomere Biology Disorders."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "ACD, CTC1, DKC1, NAF1, NHP2, NOP10, PARN, POT1, RPA1, RTEL1, STN1, TERC, TERT, TINF2, WRAP53, and ZCCHC8 are the genes in which pathogenic variants are known to cause DC/TBD"
explanation: GeneReviews lists TERC among the 16 genes causing DC/TBD.
- name: TINF2
gene_term:
preferred_term: TINF2
term:
id: hgnc:11824
label: TINF2
relationship_type: CAUSATIVE
variant_origin: GERMLINE
inheritance:
- name: Autosomal dominant inheritance
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
subtype: TINF2
notes: >-
TINF2 encodes shelterin TIN2; autosomal dominant, often severe early-onset DC.
evidence:
- reference: PMID:20301779
reference_title: "Dyskeratosis Congenita and Related Telomere Biology Disorders."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "ACD, CTC1, DKC1, NAF1, NHP2, NOP10, PARN, POT1, RPA1, RTEL1, STN1, TERC, TERT, TINF2, WRAP53, and ZCCHC8 are the genes in which pathogenic variants are known to cause DC/TBD"
explanation: GeneReviews lists TINF2 among the 16 genes causing DC/TBD.
- name: RTEL1
gene_term:
preferred_term: RTEL1
term:
id: hgnc:15888
label: RTEL1
relationship_type: CAUSATIVE
variant_origin: GERMLINE
inheritance:
- name: Autosomal dominant inheritance
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
- name: Autosomal recessive inheritance
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
subtype: RTEL1
notes: >-
RTEL1 encodes a telomere-replication helicase; dominant or recessive DC,
including Hoyeraal-Hreidarsson syndrome.
evidence:
- reference: PMID:20301779
reference_title: "Dyskeratosis Congenita and Related Telomere Biology Disorders."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "ACD, CTC1, DKC1, NAF1, NHP2, NOP10, PARN, POT1, RPA1, RTEL1, STN1, TERC, TERT, TINF2, WRAP53, and ZCCHC8 are the genes in which pathogenic variants are known to cause DC/TBD"
explanation: GeneReviews lists RTEL1 among the 16 genes causing DC/TBD.
- name: CTC1
gene_term:
preferred_term: CTC1
term:
id: hgnc:26169
label: CTC1
relationship_type: CAUSATIVE
variant_origin: GERMLINE
inheritance:
- name: Autosomal recessive inheritance
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
subtype: CTC1
notes: >-
CTC1 encodes a CST-complex subunit supporting telomere C-strand replication;
autosomal recessive DC overlapping Coats plus.
evidence:
- reference: PMID:20301779
reference_title: "Dyskeratosis Congenita and Related Telomere Biology Disorders."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "ACD, CTC1, DKC1, NAF1, NHP2, NOP10, PARN, POT1, RPA1, RTEL1, STN1, TERC, TERT, TINF2, WRAP53, and ZCCHC8 are the genes in which pathogenic variants are known to cause DC/TBD"
explanation: GeneReviews lists CTC1 among the 16 genes causing DC/TBD.
- name: RPA1
gene_term:
preferred_term: RPA1
term:
id: hgnc:10289
label: RPA1
relationship_type: CAUSATIVE
variant_origin: GERMLINE
inheritance:
- name: Autosomal dominant inheritance
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
subtype: RPA1
notes: >-
RPA1 encodes a single-stranded DNA-binding protein involved in telomere
replication; autosomal dominant DC/TBD.
evidence:
- reference: PMID:20301779
reference_title: "Dyskeratosis Congenita and Related Telomere Biology Disorders."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "ACD, CTC1, DKC1, NAF1, NHP2, NOP10, PARN, POT1, RPA1, RTEL1, STN1, TERC, TERT, TINF2, WRAP53, and ZCCHC8 are the genes in which pathogenic variants are known to cause DC/TBD"
explanation: GeneReviews lists RPA1 among the 16 genes causing DC/TBD.
- name: ACD
gene_term:
preferred_term: ACD
term:
id: hgnc:25070
label: ACD
relationship_type: CAUSATIVE
variant_origin: GERMLINE
inheritance:
- name: Autosomal dominant inheritance
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
- name: Autosomal recessive inheritance
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
subtype: ACD
notes: >-
ACD encodes shelterin TPP1, which recruits and stimulates telomerase; dominant
or recessive DC.
evidence:
- reference: PMID:20301779
reference_title: "Dyskeratosis Congenita and Related Telomere Biology Disorders."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "ACD, CTC1, DKC1, NAF1, NHP2, NOP10, PARN, POT1, RPA1, RTEL1, STN1, TERC, TERT, TINF2, WRAP53, and ZCCHC8 are the genes in which pathogenic variants are known to cause DC/TBD"
explanation: GeneReviews lists ACD among the 16 genes causing DC/TBD.
- name: NHP2
gene_term:
preferred_term: NHP2
term:
id: hgnc:14377
label: NHP2
relationship_type: CAUSATIVE
variant_origin: GERMLINE
inheritance:
- name: Autosomal recessive inheritance
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
subtype: NHP2
notes: >-
NHP2 encodes an H/ACA snoRNP component required for telomerase RNA stability;
autosomal recessive DC.
evidence:
- reference: PMID:20301779
reference_title: "Dyskeratosis Congenita and Related Telomere Biology Disorders."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "ACD, CTC1, DKC1, NAF1, NHP2, NOP10, PARN, POT1, RPA1, RTEL1, STN1, TERC, TERT, TINF2, WRAP53, and ZCCHC8 are the genes in which pathogenic variants are known to cause DC/TBD"
explanation: GeneReviews lists NHP2 among the 16 genes causing DC/TBD.
- name: NOP10
gene_term:
preferred_term: NOP10
term:
id: hgnc:14378
label: NOP10
relationship_type: CAUSATIVE
variant_origin: GERMLINE
inheritance:
- name: Autosomal recessive inheritance
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
subtype: NOP10
notes: >-
NOP10 encodes an H/ACA snoRNP component required for telomerase RNA stability;
autosomal recessive DC.
evidence:
- reference: PMID:20301779
reference_title: "Dyskeratosis Congenita and Related Telomere Biology Disorders."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "ACD, CTC1, DKC1, NAF1, NHP2, NOP10, PARN, POT1, RPA1, RTEL1, STN1, TERC, TERT, TINF2, WRAP53, and ZCCHC8 are the genes in which pathogenic variants are known to cause DC/TBD"
explanation: GeneReviews lists NOP10 among the 16 genes causing DC/TBD.
- name: PARN
gene_term:
preferred_term: PARN
term:
id: hgnc:8609
label: PARN
relationship_type: CAUSATIVE
variant_origin: GERMLINE
inheritance:
- name: Autosomal dominant inheritance
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
- name: Autosomal recessive inheritance
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
subtype: PARN
notes: >-
PARN encodes a deadenylase required for TERC maturation; dominant or recessive
DC, associated with pulmonary fibrosis.
evidence:
- reference: PMID:20301779
reference_title: "Dyskeratosis Congenita and Related Telomere Biology Disorders."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "ACD, CTC1, DKC1, NAF1, NHP2, NOP10, PARN, POT1, RPA1, RTEL1, STN1, TERC, TERT, TINF2, WRAP53, and ZCCHC8 are the genes in which pathogenic variants are known to cause DC/TBD"
explanation: GeneReviews lists PARN among the 16 genes causing DC/TBD.
- name: WRAP53
gene_term:
preferred_term: WRAP53
term:
id: hgnc:25522
label: WRAP53
relationship_type: CAUSATIVE
variant_origin: GERMLINE
inheritance:
- name: Autosomal recessive inheritance
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
subtype: WRAP53
notes: >-
WRAP53 (TCAB1) traffics telomerase to Cajal bodies; autosomal recessive DC.
evidence:
- reference: PMID:20301779
reference_title: "Dyskeratosis Congenita and Related Telomere Biology Disorders."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "ACD, CTC1, DKC1, NAF1, NHP2, NOP10, PARN, POT1, RPA1, RTEL1, STN1, TERC, TERT, TINF2, WRAP53, and ZCCHC8 are the genes in which pathogenic variants are known to cause DC/TBD"
explanation: GeneReviews lists WRAP53 among the 16 genes causing DC/TBD.
- name: POT1
gene_term:
preferred_term: POT1
term:
id: hgnc:17284
label: POT1
relationship_type: CAUSATIVE
variant_origin: GERMLINE
inheritance:
- name: Autosomal recessive inheritance
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
subtype: POT1
notes: >-
POT1 encodes a shelterin protein binding telomeric single-stranded DNA;
pathogenic variants reduce ssDNA binding and expand the DC allelic series.
evidence:
- reference: PMID:39198715
reference_title: "The evolving genetic landscape of telomere biology disorder dyskeratosis congenita."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "we have also identified several novel variants in POT1 and ZCCHC8 in multiple cases from different families expanding the allelic series of DC and DCL phenotypes."
explanation: Novel POT1 variants expand the DC allelic series.
- name: POLA1
gene_term:
preferred_term: POLA1
term:
id: hgnc:9173
label: POLA1
relationship_type: CAUSATIVE
variant_origin: GERMLINE
inheritance:
- name: X-linked recessive inheritance
inheritance_term:
preferred_term: X-linked recessive inheritance
term:
id: HP:0001419
label: X-linked recessive inheritance
notes: >-
POLA1 (DNA polymerase alpha catalytic subunit) was newly implicated as an
X-linked DC gene in 2024; pathogenic variants disrupt protein-protein
interactions with primase, the CST complex, and shelterin that are critical for
telomere maintenance.
evidence:
- reference: PMID:39198715
reference_title: "The evolving genetic landscape of telomere biology disorder dyskeratosis congenita."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "This led us to identify several novel pathogenic variants within known genetic loci and in the novel X-linked gene, POLA1."
explanation: POLA1 is a newly identified X-linked DC gene.
- reference: PMID:39198715
reference_title: "The evolving genetic landscape of telomere biology disorder dyskeratosis congenita."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Functional characterisation of novel POLA1 and POT1 variants, revealed pathogenic effects on protein-protein interactions with primase, CTC1-STN1-TEN1 (CST) and shelterin subunit complexes, that are critical for telomere maintenance."
explanation: Functional studies show POLA1 variants disrupt CST/shelterin/primase interactions required for telomere maintenance.
- name: NAF1
gene_term:
preferred_term: NAF1
term:
id: hgnc:25126
label: NAF1
relationship_type: CAUSATIVE
variant_origin: GERMLINE
inheritance:
- name: Autosomal dominant inheritance
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
subtype: NAF1
notes: >-
NAF1 encodes an H/ACA ribonucleoprotein assembly factor required for biogenesis
and stability of the telomerase RNA component (TERC).
evidence:
- reference: PMID:20301779
reference_title: "Dyskeratosis Congenita and Related Telomere Biology Disorders."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "ACD, CTC1, DKC1, NAF1, NHP2, NOP10, PARN, POT1, RPA1, RTEL1, STN1, TERC, TERT, TINF2, WRAP53, and ZCCHC8 are the genes in which pathogenic variants are known to cause DC/TBD"
explanation: GeneReviews lists NAF1 among the 16 genes causing DC/TBD.
- name: STN1
gene_term:
preferred_term: STN1
term:
id: hgnc:26200
label: STN1
relationship_type: CAUSATIVE
variant_origin: GERMLINE
inheritance:
- name: Autosomal recessive inheritance
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
subtype: STN1
notes: >-
STN1 encodes a subunit of the CST (CTC1-STN1-TEN1) complex required for telomere
replication and C-strand fill-in synthesis.
evidence:
- reference: PMID:20301779
reference_title: "Dyskeratosis Congenita and Related Telomere Biology Disorders."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "ACD, CTC1, DKC1, NAF1, NHP2, NOP10, PARN, POT1, RPA1, RTEL1, STN1, TERC, TERT, TINF2, WRAP53, and ZCCHC8 are the genes in which pathogenic variants are known to cause DC/TBD"
explanation: GeneReviews lists STN1 among the 16 genes causing DC/TBD.
- name: ZCCHC8
gene_term:
preferred_term: ZCCHC8
term:
id: hgnc:25265
label: ZCCHC8
relationship_type: CAUSATIVE
variant_origin: GERMLINE
inheritance:
- name: Autosomal dominant inheritance
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
subtype: ZCCHC8
notes: >-
ZCCHC8 encodes a component of the nuclear exosome targeting (NEXT) complex
involved in processing and quality control of the telomerase RNA component.
evidence:
- reference: PMID:20301779
reference_title: "Dyskeratosis Congenita and Related Telomere Biology Disorders."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "ACD, CTC1, DKC1, NAF1, NHP2, NOP10, PARN, POT1, RPA1, RTEL1, STN1, TERC, TERT, TINF2, WRAP53, and ZCCHC8 are the genes in which pathogenic variants are known to cause DC/TBD"
explanation: GeneReviews lists ZCCHC8 among the 16 genes causing DC/TBD.
- reference: PMID:39198715
reference_title: "The evolving genetic landscape of telomere biology disorder dyskeratosis congenita."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "we have also identified several novel variants in POT1 and ZCCHC8 in multiple cases from different families expanding the allelic series of DC and DCL phenotypes."
explanation: Novel ZCCHC8 variants expand the DC allelic series.
treatments:
- name: Hematopoietic stem cell transplantation
description: >-
Hematopoietic cell transplantation is the only curative treatment for bone
marrow failure and leukemia in DC, but historically has poor long-term outcome
due to treatment toxicity. Radiation- and alkylator-reduced conditioning is
favored, and related donors carrying the familial variant should be avoided.
treatment_term:
preferred_term: hematopoietic stem cell transplantation
term:
id: MAXO:0000747
label: hematopoietic stem cell transplantation
therapeutic_modality: CELL_THERAPY
evidence:
- reference: PMID:20301779
reference_title: "Dyskeratosis Congenita and Related Telomere Biology Disorders."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Hematopoietic cell transplantation (HCT) is the only curative treatment for BMF and leukemia, but long-term outcome has historically been poor due to treatment toxicity"
explanation: HCT is the only curative treatment for DC marrow failure/leukemia but is toxicity-limited.
target_mechanisms:
- target: Stem Cell Exhaustion in High-Turnover Tissues
treatment_effect: MODULATES
description: >-
HSCT replaces the dysfunctional short-telomere hematopoietic stem cell
pool with donor-derived cells, rescuing hematopoiesis and reducing
leukemia risk; it does not correct the underlying telomere maintenance
defect in non-hematopoietic tissues.
- name: Androgen therapy (danazol)
description: >-
Androgen therapy (e.g., danazol, oxymetholone) can improve blood counts and may
be considered for bone marrow failure when a suitable transplant donor is not
available. The combination of androgens with granulocyte colony-stimulating
factor should be avoided because it has been associated with splenic rupture;
monitoring of CBC, liver function, and liver ultrasound is recommended.
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: danazol
term:
id: CHEBI:4315
label: danazol
- preferred_term: oxymetholone
term:
id: CHEBI:7864
label: oxymetholone
therapeutic_modality: SMALL_MOLECULE
evidence:
- reference: PMID:20301779
reference_title: "Dyskeratosis Congenita and Related Telomere Biology Disorders."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "if a suitable donor is not available, androgen therapy may be considered for BMF."
explanation: Androgen therapy is an option for bone marrow failure when transplant is not available.
- reference: PMID:20301779
reference_title: "Dyskeratosis Congenita and Related Telomere Biology Disorders."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "the combination of androgens and granulocyte colony-stimulating factor in treatment of BMF (has been associated with splenic rupture)"
explanation: GeneReviews Agents/Circumstances to Avoid - androgen plus G-CSF risks splenic rupture.
target_mechanisms:
- target: Impaired Telomere Maintenance
treatment_effect: MODULATES
description: >-
Androgens (danazol, oxymetholone) upregulate TERT expression, boosting
telomerase activity in hematopoietic progenitors and partially reversing
the telomere maintenance defect.
- target: Critically Short Telomeres and Replicative Senescence
treatment_effect: MODULATES
description: >-
By stimulating TERT, androgen therapy can slow the rate of telomere
attrition in bone marrow progenitors, delaying progression to replicative
senescence and improving blood counts.
- name: Lung transplantation
description: >-
Treatment of pulmonary fibrosis is primarily supportive, although lung
transplantation may be considered for end-stage disease.
treatment_term:
preferred_term: organ transplantation
term:
id: MAXO:0010039
label: organ transplantation
therapeutic_modality: SURGERY
evidence:
- reference: PMID:20301779
reference_title: "Dyskeratosis Congenita and Related Telomere Biology Disorders."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Treatment of pulmonary fibrosis is primarily supportive, although lung transplantation may be considered."
explanation: Lung transplantation may be considered for DC-associated pulmonary fibrosis.
target_mechanisms:
- target: Stem Cell Exhaustion in High-Turnover Tissues
treatment_effect: MODULATES
description: >-
Lung transplantation replaces end-stage fibrotic lung tissue; it does not
address the underlying telomere biology defect and DC patients face
elevated post-transplant risks from impaired regenerative capacity in
other high-turnover tissues.
- name: Cancer surveillance and supportive care
description: >-
Surveillance is central to DC management, including annual CBC and bone marrow
evaluation, monthly oral/head/neck self-examination with annual otolaryngology
and dermatology screening, and annual pulmonary function tests. Of note, cancer
therapy may pose an increased risk of prolonged cytopenias and pulmonary and
hepatic toxicity, and non-irradiated/leukodepleted blood products should be used.
treatment_term:
preferred_term: supportive care
term:
id: MAXO:0000950
label: supportive care
evidence:
- reference: PMID:20301779
reference_title: "Dyskeratosis Congenita and Related Telomere Biology Disorders."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "cancer therapy may pose an increased risk for prolonged cytopenias as well as pulmonary and hepatic toxicity."
explanation: GeneReviews notes increased risk from cancer therapy, motivating surveillance and supportive care.
- name: Genetic counseling
description: >-
Genetic counseling addresses gene-specific mode of inheritance; once the
familial variant is identified, prenatal and preimplantation genetic testing
are possible. Family members should not donate blood if HCT is being considered,
and potential related donors require telomere length and/or molecular testing.
treatment_term:
preferred_term: Genetic Counseling
term:
id: NCIT:C15240
label: Genetic Counseling
evidence:
- reference: PMID:20301779
reference_title: "Dyskeratosis Congenita and Related Telomere Biology Disorders."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Once the DC/TBD-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible."
explanation: Genetic counseling enables prenatal/preimplantation testing once the variant is known.
discussions:
- discussion_id: gap_dc_unexplained_genetic_cause
prompt: >-
What accounts for the roughly 20% of clinically diagnosed dyskeratosis
congenita / telomere biology disorder cases in which no pathogenic variant is
identified in any of the 16 known DC/TBD genes?
kind: KNOWLEDGE_GAP
status: OPEN
attaches_to:
- pathophysiology#Impaired Telomere Maintenance
rationale: >-
GeneReviews reports that pathogenic variants in the 16 known DC/TBD genes are
identified in approximately 80% of individuals meeting clinical diagnostic
criteria, leaving roughly one in five clinically diagnosed patients genetically
unexplained. These cases likely harbor variants in undiscovered genes,
non-coding or structural variants in known loci, or somatic/mosaic events not
captured by standard testing. Resolving this gap would extend the mechanistic
chain (impaired telomere maintenance) to currently uncharacterized molecular
causes and improve molecular diagnosis and counseling.
evidence:
- reference: PMID:20301779
reference_title: "Dyskeratosis Congenita and Related Telomere Biology Disorders."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "in approximately 80% of individuals who meet"
explanation: >-
GeneReviews reports a genetic diagnostic yield of approximately 80%,
implying roughly 20% of clinically diagnosed DC/TBD remains genetically
unexplained.
datasets: []
Question: You are an expert researcher providing comprehensive, well-cited information.
Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies
Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.
Please provide a comprehensive research report on Dyskeratosis Congenita covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.
For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.
Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed
Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases
Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases
Search first: CTD, PubMed, PheGenI, GxE databases
Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC
For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities
For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype
Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene
Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser
Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases
Search first: CDC databases, WHO, PubMed, NHANES
Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON
Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc
Search first: Gene Ontology (GO), Reactome, KEGG, PubMed
Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold
Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA
Search first: ImmPort, Immunome Database, IEDB, Gene Ontology
Search first: PubMed, Gene Ontology, Reactome
Search first: BRENDA, UniProt, KEGG, OMIM, PubMed
Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types
Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT
Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB
Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas
Search first: OMIM, Orphanet, HPO, PubMed
Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM
Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries
Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen
For each treatment, suggest MAXO (Medical Action Ontology) terms where applicable.
Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database
Search first: CDC, WHO, behavioral intervention databases, Cochrane Library
Search first: NSGC resources, ACMG guidelines, GeneReviews
Search first: Clinical guidelines, FDA approvals, PubMed
Search first: NCBI Taxonomy
Search first: VBO (Vertebrate Breed Ontology)
Search first: NCBI Gene
Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, MAXO, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease
This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (MAXO terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details
Target disease: Dyskeratosis congenita (DC)
Category: Mendelian / inherited bone marrow failure syndrome; telomere biology disorder (TBD) / short-telomere syndrome (niewisch2023clinicalmanifestationsof pages 1-2, rolles2024inheritedtelomerebiology pages 8-9).
MONDO ID: Not available in the retrieved full-text evidence in this run (mazurek2023dyskeratosiscongenitaas pages 4-5).
Dyskeratosis congenita is an ultra-rare inherited, multisystem disorder within the telomere biology disorders spectrum, classically defined by the mucocutaneous triad of nail dystrophy, abnormal/reticulated skin pigmentation, and oral leukoplakia, and complicated by progressive bone marrow failure and increased malignancy and fibrotic organ disease risk (koldej2023dyskeratosiscongenitanatural pages 1-2, rolles2024inheritedtelomerebiology pages 8-9, niewisch2023clinicalmanifestationsof pages 1-2). Contemporary understanding frames DC as a disorder of impaired telomere maintenance, in which germline pathogenic variants across telomerase, shelterin, CST/replication, and telomerase RNA processing/trafficking pathways cause telomere shortening/dysfunction leading to stem cell exhaustion and tissue failure (revy2023geneticsofhuman pages 5-8, rolles2024inheritedtelomerebiology pages 8-9, mazurek2023dyskeratosiscongenitaas pages 1-2).
A recent 2024 high-impact genetic study expanded DC’s genetic architecture (including a newly implicated X-linked gene POLA1 and expanded allelic series in POT1 and ZCCHC8) and emphasized that a substantial fraction of clinically diagnosed cases remain genetically unresolved (tummala2024theevolvinggenetic pages 1-2, tummala2024theevolvinggenetic pages 3-5).
| Domain | Summary |
|---|---|
| Identifiers/synonyms | - Dyskeratosis congenita (DC) is also referred to as Zinsser–Cole–Engman syndrome in retrieved sources. - It is classified as a telomere biology disorder (TBD) / short-telomere syndrome. - Formal OMIM, Orphanet, ICD-10/11, MeSH, MONDO codes were not in retrieved full-text evidence. (ayas2026dyskeratosiscongenita pages 1-4, mazurek2023dyskeratosiscongenitaas pages 4-5, niewisch2023clinicalmanifestationsof pages 1-2) |
| Core definition | - DC is an ultra-rare inherited multisystem bone marrow failure syndrome caused principally by defects in telomere maintenance. - The classic diagnostic triad is nail dystrophy, abnormal/reticulated skin pigmentation, and oral leukoplakia. - Bone marrow failure and cancer predisposition are central disease-defining complications. (koldej2023dyskeratosiscongenitanatural pages 1-2, tummala2024theevolvinggenetic pages 1-2, rolles2024inheritedtelomerebiology pages 8-9, niewisch2023clinicalmanifestationsof pages 1-2) |
| Key phenotypes & frequencies | - Mucocutaneous triad frequencies reported in one 2023 review: reticulated pigmentation ~90%, nail dystrophy ~88%, leukoplakia ~80%. - Bone marrow failure is a hallmark; some sources report >90% by age 40. - Extra-hematologic disease includes pulmonary fibrosis/interstitial lung disease, liver disease/portal hypertension, premature hair graying, and cancer susceptibility; pulmonary fibrosis occurs in about 20% in one review. (mazurek2023dyskeratosiscongenitaas pages 4-5, ayas2026dyskeratosiscongenita pages 1-4, wang2021pulmonaryfibrosisin pages 1-2, vittal2023progressionofliver pages 1-2, franke2025diagnosisandmanagement pages 7-10) |
| Natural history stats | - In a pediatric cohort (n=14), diagnosis occurred at median age 8.5 years; 13/14 progressed to bone marrow failure at median age 8 years. - In the same cohort, 6/14 died, at median age 13 years; all had hematologic manifestations at diagnosis and non-hematologic manifestations accumulated over follow-up. - Adult/cryptic TBD can present later with isolated hematologic, pulmonary, or liver disease rather than the full triad. (koldej2023dyskeratosiscongenitanatural pages 1-2, niewisch2023clinicalmanifestationsof pages 1-2, franke2025diagnosisandmanagement pages 7-10) |
| Key causal genes & new 2024 findings | - Established genes in retrieved evidence include DKC1, TERC, TERT, TINF2, RTEL1, NOP10, NHP2, CTC1, ACD/TPP1, PARN, WRAP53/TCAB1, DCLRE1B, RPA1, NPM1, NAF1 and others; inheritance can be X-linked, autosomal dominant, or autosomal recessive. - A 2024 EMBO Molecular Medicine study reported that about 35% of clinically diagnosed cases remain genetically unresolved and expanded the allelic architecture with POLA1 (novel X-linked gene), plus additional POT1 and ZCCHC8 variants. - Functional data linked new variants to disrupted primase/CST/shelterin interactions, reduced POLA1 catalytic activity, reduced POT1 binding to telomeric ssDNA, and ZCCHC8 deficiency with pervasive transcription/inflammation. (tummala2024theevolvinggenetic pages 1-2, tummala2024theevolvinggenetic pages 3-5, niewisch2023clinicalmanifestationsof pages 1-2, rolles2024inheritedtelomerebiology pages 8-9) |
| Diagnostics (telomere length testing thresholds, screening yields) | - Flow-FISH lymphocyte telomere length is the current preferred functional screening test; a commonly used threshold is <1st percentile for age for strong support of TBD/DC diagnosis. - In adults, one 2023 prospective cohort used standard suspicion criteria of <10th percentile for age and an extended criterion of <6.5 kb in patients >40 years. - In 262 screened adults, shortened TL was found in 120; among standard-screened patients with NGS material, 17/76 (22.4%) had pathogenic/likely pathogenic variants and 17/76 (22.4%) had VUS; main genes were TERT, TERC, RTEL1. (rolles2024inheritedtelomerebiology pages 8-9, tometten2023identificationofadult pages 1-2, tometten2023identificationofadult pages 6-7, tometten2023identificationofadult pages 3-4, niewisch2023clinicalmanifestationsof pages 5-5) |
| Treatments (androgens, HSCT, organ transplant considerations) | - Androgens (especially danazol, also oxymetholone/nandrolone) can improve counts; reported hematologic response rates range about 50–100% short-term, with one study showing 11/12 patients gained telomere length (mean +386 bp) and 83% hematologic response at 24 months. - HSCT/allo-HCT is the only curative therapy for marrow failure/clonal evolution, but transplant morbidity is substantial; reduced-intensity and radiation-avoiding approaches are favored, and related donors carrying the familial defect should be avoided. - Organ transplantation (especially lung and liver) may be required for end-organ failure, but telomere disorders increase risk of hematologic and immunosuppression-related complications. (rolles2024inheritedtelomerebiology pages 12-14, ayas2026dyskeratosiscongenita pages 9-12, rolles2024inheritedtelomerebiology pages 10-12, glass2026telomerebiology pages 17-18) |
| Epidemiology | - DC is consistently described as ultra-rare/rare. - Retrieved prevalence estimates were approximately 1 case per 1,000,000 in one source and 1–9 per 1,000,000 in another review. - One review noted marked male predominance in historical series (male:female ~13:1), though this may reflect enrichment of X-linked DKC1 disease in some cohorts. (koldej2023dyskeratosiscongenitanatural pages 1-2, mazurek2023dyskeratosiscongenitaas pages 4-5) |
Table: This table condenses the most actionable facts on dyskeratosis congenita and related telomere biology disorders from the retrieved evidence, including definition, phenotype spectrum, genetics, diagnostics, treatment, and epidemiology. It is designed to support rapid knowledge-base curation with source-linked statements.
DC is an inherited multisystem telomere biology disorder characterized by the classic mucocutaneous triad and a high burden of bone marrow failure (BMF), with additional complications including pulmonary and liver disease and cancer predisposition (koldej2023dyskeratosiscongenitanatural pages 1-2, rolles2024inheritedtelomerebiology pages 8-9, niewisch2023clinicalmanifestationsof pages 1-2).
In the retrieved full-text evidence available for this report, specific cross-references (OMIM, Orphanet, ICD-10/ICD-11, MeSH, MONDO) were not explicitly provided, so they cannot be populated with evidence-based values here (mazurek2023dyskeratosiscongenitaas pages 4-5).
The information in this report is derived primarily from: - Aggregated disease-level resources and reviews (e.g., ASH Education Program review 2023; Transfusion Medicine and Hemotherapy review 2024; Nature Reviews Genetics 2023) (niewisch2023clinicalmanifestationsof pages 1-2, rolles2024inheritedtelomerebiology pages 8-9, revy2023geneticsofhuman pages 5-8). - Cohort studies/natural history studies (e.g., pediatric cohort natural history 2023; liver involvement cohort 2023; adult screening cohort 2023) (koldej2023dyskeratosiscongenitanatural pages 1-2, vittal2023progressionofliver pages 1-2, tometten2023identificationofadult pages 1-2).
Primary cause: Germline pathogenic variants affecting telomere maintenance (telomerase, shelterin, CST complex/replication, telomerase RNA processing/trafficking), producing critically short telomeres and telomere dysfunction (niewisch2023clinicalmanifestationsof pages 1-2, revy2023geneticsofhuman pages 5-8, rolles2024inheritedtelomerebiology pages 8-9).
Recent genetic expansion (2024): A large 2024 DC/DC-like study identified novel pathogenic variants and newly implicated the X-linked gene POLA1; it also expanded allelic series for POT1 and ZCCHC8, with functional work implicating disrupted interactions among primase, CST, and shelterin and inflammatory signatures from ZCCHC8 deficiency (tummala2024theevolvinggenetic pages 1-2, tummala2024theevolvinggenetic pages 3-5).
Direct abstract-supported quote (2024 EMBO Mol Med): the study “identify[ied]… novel pathogenic variants… and in the novel X-linked gene, POLA1” and reported functional impacts on “protein–protein interactions with primase, CST… and shelterin” (tummala2024theevolvinggenetic pages 1-2).
Environmental/clinical risk modifiers (organ progression): In a DC/TBD liver cohort, pulmonary and/or vascular disease predicted progression to clinically significant liver disease/portal hypertension, suggesting multisystem disease burden modifies organ risk (vittal2023progressionofliver pages 1-2).
No specific protective genetic variants or environmental protective factors were identified in the retrieved evidence.
Not specifically delineated for DC in the retrieved evidence; however, clinical cohorts support that systemic comorbidities (pulmonary/vascular disease) modify progression of liver complications (vittal2023progressionofliver pages 1-2).
Triad frequency data (review-level): reticulated pigmentation ~90%, nail dystrophy ~88%, leukoplakia ~80% (mazurek2023dyskeratosiscongenitaas pages 4-5).
Pediatric natural history: in a multicenter childhood-diagnosed cohort (n=14), all had hematologic manifestations at diagnosis; 13/14 progressed to BMF at median age 8 years (range 3–18) (koldej2023dyskeratosiscongenitanatural pages 1-2).
Cohort statistics (2023 Hepatology): In a DC/TBD cohort (n=58), baseline hepatic abnormality was 72.4% and 17.2% developed clinically significant liver disease/portal hypertension over follow-up (median 6 years) (vittal2023progressionofliver pages 1-2).
DC/TBDs are associated with increased malignancy risk; head and neck squamous cell carcinoma is highlighted as a frequent solid tumor in DC/TBD contexts, and leukemia/MDS risks are emphasized in reviews/chapters (ayas2026dyskeratosiscongenita pages 1-4, niewisch2023clinicalmanifestationsof pages 1-2).
Disease morbidity is described as high and multisystemic in longitudinal pediatric follow-up, but specific validated QoL instruments (e.g., SF-36, PROMIS) and quantitative QoL scores were not available in the retrieved evidence (koldej2023dyskeratosiscongenitanatural pages 1-2).
Authoritative 2023–2024 reviews and studies list DC/TBD genes spanning multiple telomere modules, including: - Telomerase core: TERT, TERC (revy2023geneticsofhuman pages 5-8, rolles2024inheritedtelomerebiology pages 8-9). - H/ACA RNP and telomerase RNA stability: DKC1, NHP2, NOP10, NAF1 (revy2023geneticsofhuman pages 5-8, niewisch2023clinicalmanifestationsof pages 1-2). - Telomerase trafficking/recruitment: WRAP53/TCAB1 and related factors (niewisch2023clinicalmanifestationsof pages 1-2, rolles2024inheritedtelomerebiology pages 8-9). - Shelterin / end protection: TINF2, POT1, ACD (TPP1) (niewisch2023clinicalmanifestationsof pages 1-2, tummala2024theevolvinggenetic pages 3-5). - Replication/CST axis: CTC1 (and CST complex context), with emerging evidence that CST–Polα/primase interactions are critical (tummala2024theevolvinggenetic pages 3-5, mazurek2023dyskeratosiscongenitaas pages 1-2). - RNA processing / additional implicated loci: PARN, ZCCHC8 (tummala2024theevolvinggenetic pages 1-2, revy2023geneticsofhuman pages 5-8).
In the 2024 EMBO Molecular Medicine cohort, variant types included predominantly missense and loss-of-function categories, plus deletions/insertions (tummala2024theevolvinggenetic pages 1-2).
Mechanistic consequences from reviews include: - Impaired telomerase activity/processivity/recruitment (TERT/TERC and recruitment factors) (niewisch2023clinicalmanifestationsof pages 1-2, revy2023geneticsofhuman pages 5-8). - Reduced telomerase RNA stability/maturation (DKC1/NHP2/NOP10 axis) (revy2023geneticsofhuman pages 5-8, niewisch2023clinicalmanifestationsof pages 1-2).
A 2024 DC/DC-like study: - Reported a novel X-linked gene POLA1 with functionally validated disease alleles and skewed X-inactivation in carrier mothers (tummala2024theevolvinggenetic pages 3-5). - Expanded the allelic series of POT1 with demonstrated reduced binding to telomeric ssDNA for pathogenic variants (tummala2024theevolvinggenetic pages 3-5). - Expanded ZCCHC8 variants associated with deficiency and inflammatory/transcriptional dysregulation signatures in blood (tummala2024theevolvinggenetic pages 1-2).
The retrieved corpus includes evidence that incomplete penetrance/variable expressivity is common in TBDs and that broader genetic context contributes to variability; specific DC-focused protective modifiers were not identified in the retrieved evidence (niewisch2023clinicalmanifestationsof pages 1-2, revy2023geneticsofhuman pages 5-8).
No specific toxins, lifestyle exposures, or infectious triggers were identified as primary causal factors for DC in the retrieved evidence. Clinical guidance emphasizes the need to recognize DC/TBD prior to potentially harmful treatments (e.g., immunosuppression in fibrotic lung disease contexts) (wang2021pulmonaryfibrosisin pages 1-2).
Suggested GO Biological Process terms consistent with the evidence: - Telomere maintenance (GO:0000723) - DNA damage response, signal transduction by p53 class mediator (GO:0030330) - Cellular senescence (GO:0090398) - Apoptotic process (GO:0006915) - Hematopoietic stem cell differentiation / hematopoiesis (e.g., GO:0030097)
A CRISPR Ten1 knockout mouse (TEN1; CST complex) provides a DC-like in vivo model: Ten1 deficiency caused telomere shortening, short lifespan, aplastic anemia, skin hyperpigmentation, and broad organ pathology with activation of p53/p21 signaling and evidence of reduced proliferation and increased apoptosis (sanzmoreno2025lossoften1 pages 1-2, sanzmoreno2025lossoften1 pages 3-6, sanzmoreno2025lossoften1 pages 2-3). This supports a causal mechanistic route from CST dysfunction → telomere attrition → p53-mediated tissue failure.
DC/TBDs show all Mendelian modes: - X-linked recessive, autosomal dominant, and autosomal recessive inheritance (niewisch2023clinicalmanifestationsof pages 1-2, tummala2024theevolvinggenetic pages 1-2).
A review reports strong male predominance (male:female ~13:1), likely reflecting enrichment of X-linked disease in some series; population-level sex ratio remains uncertain from the retrieved evidence (mazurek2023dyskeratosiscongenitaas pages 4-5).
Data gaps (not in retrieved evidence): incidence rates, carrier frequency, geographic/ancestry founder effects.
Preferred functional test: Flow-FISH telomere length measurement in leukocyte subsets; lymphocyte telomere length is described as sensitive and highly specific (rolles2024inheritedtelomerebiology pages 8-9).
Common diagnostic threshold: lymphocyte telomere length <1st percentile for age by flow-FISH strongly supports TBD/DC (rolles2024inheritedtelomerebiology pages 8-9).
Adult screening algorithm and yield (2023 prospective cohort): - Standard suspicion: <10th percentile for age; extended adult criterion: <6.5 kb in patients >40 years (tometten2023identificationofadult pages 1-2, tometten2023identificationofadult pages 3-4). - In 262 referred adults screened by flow-FISH, 120 had shortened telomeres; among standard-screened patients with NGS material, 17/76 (22.4%) had pathogenic/likely pathogenic variants and 17/76 (22.4%) had VUS (tometten2023identificationofadult pages 1-2).
Recent diagnostic pathways recommend: - Telomere length testing as prescreen, followed by targeted NGS panels and, if unresolved, WES/WGS focused on telomere maintenance genes (rolles2024inheritedtelomerebiology pages 10-12). - Recognition that a pathogenic variant is not found in all clinical cases (e.g., ~20% without identifiable cause in one review; ~35% unresolved in a 2024 DC cohort) (niewisch2023clinicalmanifestationsof pages 5-5, tummala2024theevolvinggenetic pages 1-2).
In a Spanish pediatric DC cohort (n=14): - Median diagnosis age 8.5 years; 13 progressed to bone marrow failure at median age 8 years. - 6/14 died at median age 13 years (range 6–24) (koldej2023dyskeratosiscongenitanatural pages 1-2).
Danazol and other androgens are used as non-transplant therapies for TBD/DC-related marrow failure. - A 2024 review summarizes androgen response evidence: oxymetholone hematologic responses around 69% with frequent adverse effects; danazol with fewer side effects and reported hematologic responses (some studies ~83% at 24 months) and telomere length gains in a subset (e.g., 11/12 gained TL; mean +386 bp) (rolles2024inheritedtelomerebiology pages 12-14). - A DC chapter also reports observational hematologic response ~70% and prospective danazol trial response ~80%, while noting toxicity (liver enzyme elevation, virilization) and discontinuation risk (ayas2026dyskeratosiscongenita pages 4-7).
MAXO suggestions: androgen therapy (e.g., MAXO:0000058 pharmacotherapy; more specific term depends on MAXO mapping availability).
HSCT is described as the only curative therapy for DC marrow failure/clonal evolution, but outcomes are complicated by multisystem fragility (ayas2026dyskeratosiscongenita pages 9-12).
Key implementation considerations: - Avoid related donors with the same pathogenic variant when possible (risk of graft failure and adverse outcomes) (rolles2024inheritedtelomerebiology pages 10-12). - Avoid radiation in conditioning when possible because of late pulmonary toxicity and secondary malignancy concerns (ayas2026dyskeratosiscongenita pages 9-12).
ClinicalTrials.gov implementation example: A radiation- and alkylator-free HSCT regimen trial (NCT01659606) specifies conditioning with alemtuzumab and fludarabine and post-transplant immunosuppression options (mycophenolate plus cyclosporine or tacrolimus), with eligibility including DC and related syndromes (NCT01659606 chunk 2).
MAXO suggestions: hematopoietic stem cell transplantation (MAXO:0000747), reduced-intensity conditioning (MAXO term depends on available hierarchy).
For end-stage lung or liver disease, transplantation may be required; reviews emphasize higher complication risk and the need for careful pre-transplant TBD recognition (glass2026telomerebiology pages 17-18).
Data gap: For some NCT records, phase/enrollment/status fields were not present in the retrieved text chunks; therefore they are not reported with evidence here (NCT01441037 chunk 2, NCT02162420 chunk 2).
Primary prevention of genetic DC is not generally applicable beyond reproductive options; retrieved evidence emphasizes surveillance and avoidance of harmful interventions once disease is suspected/diagnosed. - For DC-associated pulmonary fibrosis, the systematic review warns against empiric immunosuppression and diagnostic surgical lung biopsy before excluding DC/TBD (wang2021pulmonaryfibrosisin pages 1-2).
MAXO suggestions: genetic counseling (MAXO term), surveillance program (MAXO term).
No naturally occurring veterinary DC analogs were identified in the retrieved evidence.
A Ten1 (CST complex) CRISPR knockout mouse is described as a model of DC/TBD: - Phenotypes: telomere attrition, short lifespan, skin hyperpigmentation, aplastic anemia/BMF, cerebellar hypoplasia, and multi-organ pathology (sanzmoreno2025lossoften1 pages 1-2, sanzmoreno2025lossoften1 pages 2-3). - Mechanism: reduced proliferation, increased apoptosis, stem cell depletion, and activation of p53/p21 signaling (sanzmoreno2025lossoften1 pages 1-2, sanzmoreno2025lossoften1 pages 3-6).
Reviews describe use of CD34+ HSPCs and variant cell models (e.g., DKC1 variant cells), including therapeutic strategy exploration via PAPD5/7 inhibition restoring telomere length/TERC levels in specific contexts (franke2025diagnosisandmanagement pages 15-17, revy2023geneticsofhuman pages 27-30).
References
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(NCT01659606 chunk 2): Suneet Agarwal. Radiation- and Alkylator-free Bone Marrow Transplantation Regimen for Patients With Dyskeratosis Congenita. Boston Children's Hospital. 2012. ClinicalTrials.gov Identifier: NCT01659606
(ayas2026dyskeratosiscongenita pages 4-7): Mouhab Ayas and Syed Osman Ahmed. Dyskeratosis congenita. Textbook of Bone Marrow Failure, pages 267-280, Jan 2026. URL: https://doi.org/10.1007/978-3-032-02386-5_18, doi:10.1007/978-3-032-02386-5_18. This article has 8 citations.
(NCT01441037 chunk 2): Danazol for Genetic Bone Marrow and Lung Disorders. National Heart, Lung, and Blood Institute (NHLBI). 2011. ClinicalTrials.gov Identifier: NCT01441037
(NCT02162420 chunk 2): Hematopoietic Stem Cell Transplant for Dyskeratosis Congenita or Severe Aplastic Anemia. Masonic Cancer Center, University of Minnesota. 2015. ClinicalTrials.gov Identifier: NCT02162420
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