Disease | (includes Hoyeraal-Hreidarsson syndrome, dyskeratosis congenita, and telomere-related idiopathic pulmonary fibrosis and/or bone marrow failure syndrome) |
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Inheritance | Semidominant |
Prevalence | Source: |
Rapid or full curation? | |
ClinGen / GenCC / BabySeq / HGMD / OMIM | ClinGen - no curation yet from interstitial lung disease GCEP. GenCC - Strong curations for AD pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3 from Ambry and Invitae. Strong curation for AR dyskeratosis congenita from Invitae. |
Clinical Validity Scoring Notes and points | Scoring LOF variants NM_032957.5: c.2992C>T; p.R998* PMID: 36655009 - 39 yo male with dyspnea, h/o pancytopenia, cirrhotic liver with some history of drinking and smoking and mold exposure, fibrotic hypersensitivity pneumonitis. Heterozygous for c.2920C > T (p. Arg974Ter) and subsequently diagnosed with Dyskeratosis congenita. AD DC LOF CASE, 2 POINTS PMID: 30995915 - this variant is found in both family 90 (AR family) and F001. Its confusing as to whether they are het or hom in F001. Family 90 has DC and is biallelic - the father and one sister have the R998* variant and presented short telomeres. Family F001 has pulmonary fibrosis per table 1, and thre analyzed relatives with the variant all had short telomeres. In the supplement they show the Sanger chromatogram for this variant and label it as patient 90 and F001 but unclear if both individuals are truly het as shown. At least scoring 2 POINTS FOR AR DC CASE (family 90) PMID: 23329068 - Family NCI-180: Proband comp het with Gln853Pro and ARg998X confirmed in trans. The mother and brother also have short telomeres and are het for the missense variant. Brother has telomeres significantly below first percentilE for his age and hypocellular bone marrow tih a cytogenetic clone. AD AND AR FAMILY - 2 POINTS FOR LOF AR VARIANT
NM_032957.5: c.3028C>T p.R1010* 23329068 - Family NCI-164. Arg1010X in two brothers with HH, inherited from healthy mother with short telomeres. Authors propose anticipation to explain this, but it seems possible they may have just missed the 2nd variant. testing performed via WES. Not sure how to really score this one. PMID: 27128385 - aka R986X. Comp het with Q1042H in a patient with HHS. 2 POINTS AR CASE. PMID: 30523160 - Aka Arg986X in family I, het only in proband with hypersensitivity pneumonitis and parent with ideopathic idiopathic pulmonary fibrosis. 2 POINTS AD CASE
Gln1165Profs*22 c.3631_3634delCAGA p.(Gln1211Glyfs*57) c.2387delT; p.Val796AlafsX4 Other papers I reviewed: PMID: 23329068 - Some evidence for both AD and AR. Family NCI-164. Arg1010X in two brothers with HH, inherited from healthy mother with short telomeres. Authors propose anticipation to explain this, but it seems possible they may have just missed the 2nd variant. testing performed via WES. Not sure how to really score this one. NCI-238-1 - a DC-like patient with Ala645Thr. They have short telomeres and BMF. AD CASE 0.5 POINTS
PMID: 37354000 - distribution of telomere band size (kb) versus the percentage of bands in patients was significantly different than that of the RTEL1 relatives and the controls - see fig 1. The difference in telomere length was also statistically significant for monoallelic RTEL1 carriers compared to controls (see fig 4). SUPPORTS THAT HET “CARRIERS” ARE AFFECTED per supplement: Family NCI-297. proband with c.3361delG (p.A1121Lfs*6) and c.1338+3 A>G, confirmed in trans. The father, who was het only for the c.1338+3 A>G variant, developed BMF. 2 POINTS AR CASE, 0.5 POINT FOR AD FATHER. but he is the only individual to develop TBD-related clinical manifestations.
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Clinical Validity Points Total | AD CASES: At least 8 points for LOF variants AR CASES: At least 8 points for LOF variants Source: 36655009, 30995915, 23329068, 30523160, 23329068, 37354000 |
Clinical Validity Classification | Expand |
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| title | Classifications (pts) |
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| Definitive (12pts) Strong (12pts) Moderate (7-11pts) Limited (0.1-6pts) No genetic evidence Refuted Disputed |
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Molecular Mechanism | Expand |
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| Loss of function Gain of function Dominant negative Unknown Other |
| Loss of function for both AD and AR See clinical validity scoring for variants PMID: 36655009, 30995915, 23329068, 30523160, 23329068, 37354000 |
Penetrance | Expand |
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| Complete (100%) High (≥80%) Moderate (<80% and >20%) Low (≤20%) |
(list source/PMID) | Source: |
Age of Onset | Expand |
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| Congenital Pediatric Adolescent Adulthood Late adulthood |
(list source/PMID) | |
Severity | Expand |
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| Embryonic lethal - presence of a pathogenic variant or variants is not compatible with life. The penetrance must be complete.
Severe - presence of a pathogenic variant or variant(s) results in significantly reduced fitness. The penetrance must be complete or high.
Moderate - significant morbidity or mortality due to clinical features, but fitness may not be reduced, or penetrance is reduced.
Mild - Presence of a variant or variant(s) is not associated with reduced fitness, no significant morbidity or mortality, and/or penetrance is low.
None - presence of a variant results in no phenotype. An example is recessive disorders in which no phenotype is reported in carriers. |
| GENE The RTEL1 gene is associated with RTEL1-related disorders, a spectrum of disease that include Hoyeraal-Hreidarsson syndrome, dyskeratosis congenita, and telomere-related idiopathic pulmonary fibrosis and/or bone marrow failure syndrome. It is semidominant with a molecular mechanism of loss-of-function. Individuals with biallelic variants are more likely to present with the earlier onset, and more severe Hoyeraal-Hreidarsson syndrome or dyskeratosis congenita (PMID: 30995915, 23329068, 27128385, 37354000). Individuals with single heterozygous variants are at risk for idiopathic pulmonary fibrosis and/or bone marrow failure syndrome; however, some individuals have also been reported to present with dyskeratosis congenita (PMID: 36655009, 30523160, 28507545, 37354000). Furthermore, some heterozygous carriers have been reported to be unaffected but may have shortened telomeres, indicating that there may be reduced penetrance for heterozygous individuals (PMID: 23329068, 37354000, 23329068). These disorders have overlapping clinical features. Features of Hoyeraal-Hreidarsson syndrome include cerebellar hypoplasia, enteropathy, severe immunodeficiency, bone marrow failure, developmental delay, and short telomeres. Features of dyskeratosis congenita include dysplastic nails, lacy reticular pigmentation of the upper chest and/or neck, oral leukoplakia, and increased risk of bone marrow failure, myelodysplastic syndrome, pulmonary fibrosis, and short telomeres (PMID: 20301779). Features of idiopathic pulmonary fibrosis and/or bone marrow failure syndrome also include shortened telomeres, pulmonary fibrosis, familial interstitial pneumonia, increased risk of bone marrow failure or myelodysplastic syndrome and typically presents in adulthood (PMID: 30523160). |
Clinical Features | Sources: |
HPO Terms https://hpo.jax.org/app/ | |
Gene SOPs & Notes | LINK if SOP is a long document. Short notes if it is easy to digest. eg. Last known truncating variant |
Curation Summary | Expand |
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| - The @GENE@ is associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs). - Variable expression or severity:
The severity and expressivity of the disorder is highly variable, even within families.
- If multiple conditions associated with the gene:
It has also been associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs). - Limited evidence gene: The PCNA gene has been reported in individuals with early onset autosomal recessive ataxia (PMID: 33426167, 24911150), however, evidence supporting this gene-dIsease relationship is limited |
| The RTEL1 gene is associated with RTEL1-related disorders, which encompass a spectrum of phenotypes that include Hoyeraal-Hreidarsson syndrome, dyskeratosis congenita |
Case ID, Curator name, Date, Jira ticket link | Andrea Oza, SDSM-CDT 12.26.24 |