Copy of (Template) [Gene name] Gene Curation

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
Inheritance	Semidominant
Prevalence Possible sources 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 ideopathic pulmonary fibrosis. 2 POINTS AD CASE Gln1165Profs22 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.(Gln1211Glyfs57) 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.A1121Lfs6) 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 Classifications (pts) Definitive (12pts) Strong (12pts) Moderate (7-11pts) Limited (0.1-6pts) No genetic evidence Refuted Disputed
Molecular Mechanism Mechanisms 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 options Complete (100%) High (≥80%) Moderate (<80% and >20%) Low (≤20%) (list source/PMID)	Source:
Age of Onset options Congenital Pediatric Adolescent Adulthood Late adulthood (list source/PMID)
Severity Options 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.
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 Examples - 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

Copy of (Template) [Gene name] Gene Curation

RTEL1 related disorders