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RTEL1 Gene Curation

RTEL1 Gene Curation

Owned by Andrea Oza
Last updated: 2024-12-26
6 min read

Precuration from interstitial lung disease GCEP - appears this has been fully reviewed but not published yet per Marina. Couldn’t access the slides and info in the GCI is limited - “Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism or inheritance pattern. Additionally, there is significant phenotypic overlap between the OMIM assertions for RTEL1 which is supported in the literature by the prevalence of shortened telomeres found along with RTEL1 variants as well as phenotypes involving damage in highly proliferative tissues or tissues that typically receive high levels of environmental insult. Therefore, the following disease entities have been lumped into one disease entity.”

Gene-disease assertions not curated here (add link or write note):

Disease

RTEL1-related disorders

(includes Hoyeraal-Hreidarsson syndrome, dyskeratosis congenita, and telomere-related idiopathic pulmonary fibrosis and/or bone marrow failure syndrome)

Disease

RTEL1-related disorders

(includes Hoyeraal-Hreidarsson syndrome, dyskeratosis congenita, and telomere-related idiopathic pulmonary fibrosis and/or bone marrow failure syndrome)

Inheritance

Semidominant

Prevalence

Orphanet

Medline Plus Genetics

 

Source:

Rapid or full curation?

Rapid
Full

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 idiopathic pulmonary fibrosis. 2 POINTS AD CASE

Gln1165Profs*22

  • PMID: 30523160 - IN family D, het only in patient with idiopathic pulmonary fibrosis and in their mother with interstitial pneumonia with autoimmune features. 2 POINTS AD CASE AND 1 AD SEG

c.3631_3634delCAGA p.(Gln1211Glyfs*57)

  • PMID: 30523160 - AKA c.3556_3559delAGAC in family H with proband w/ idiopathic pulmonary fibrosis. 2 POINTS AD CASE

 

c.2387delT; p.Val796AlafsX4

  • PMID: 28507545 - het only in a patient with DC. 2 POINTS LOF AD DC CASE

 

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.

 

 

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

Definitive (12pts)

Strong (12pts)

Moderate (7-11pts)

Limited (0.1-6pts)

No genetic evidence

Refuted

Disputed

 

Molecular Mechanism

Loss of function

Gain of function

Dominant negative

Unknown

Other

Loss of function for both AD and AR

  • Semidominant disease

See clinical validity scoring for variants

PMID: 36655009, 30995915, 23329068, 30523160, 23329068, 37354000

 

Penetrance

Complete (100%)

High (≥80%)

Moderate  (<80% and >20%)

Low (≤20%)

(list source/PMID)

 

Source:

Age of Onset

Congenital

Pediatric

Adolescent

Adulthood

Late adulthood

(list source/PMID)

 

Severity

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

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