Table 1.

Description of 27 patients with RTEL1 variants

Patient IDAge/sexTL*RTEL1 variantsOther germline variantsRTEL1 ACGMHematologic diagnosisSomatic anomalies and other clinical featuresFamily historyOutcome
Heterozygous pathogenic or likely pathogenic variants
 KCH-136/M<1stR974X, c.2920 C>T§TERT, R756C c.2266 C>TPathogenicFamilial hypoMDSAbnormal lung function: TLCOc 72%Brother has hypoMDSResponded to cyclosporine
 KCH-325/M<1stR974X, c.2920 C>T§NonePathogenicHypoMDSSuspected to have inherited diseaseFH of cancerNo treatment
 KCH-829/F<1stc.301+1G>ANoneLPICUS: neutropeniaBicuspid aortic valve, high arched palatePedigree (Figure 3)Treated with G-CSF
 KCH-1031/F<1stR986X, c.2956 C>T§NonePathogenicICUS: neutropeniaDystrophic nails, neutropenia for 16 yNoneTreated with G-CSF
 KCH-1154/F<10thR986X, c.2956 C>T§Not testedPathogenicMacrocytosis, hypocellular BMDystrophic nailPedigree (Figure 3)No treatment
 KCH-1530/F<1stc.301+1G>ANoneLPAA/PNHNoneNoneTreated with IST, LTFU
 NIH-431/FNormalM652T, c.1955 T>CSLX4, T750M c.2249 C>TLPICUS: neutropeniaNormal BM cellularityNoneNo treatment
Biallelic pathogenic or likely pathogenic variants
 NIH-132/M<1stD719N, c.2155 G>A P871L, c.2612 C>TNoneLPMAALiver cirrhosis, pulmonary fibrosisPedigree (Figure 3)Responded to androgen (danazol)
LB
 NIH-26/F<1stG951, c.2851 G>A F1262L, c.3786 C>GNoneLPSAAProlonged thrombocytopeniaPedigree (Figure 3)Awaiting HSCT
Pathogenic
Variants of uncertain significance
 KCH-271/M<10thV178A, c.533 T>CNoneUSMDS (RAEB1)Laryngeal squamous cell cancer, age of 60 y; small cell lung cancer, age of 66 yFH of cancerTreated with 5-azacitidine, progressed to AML, died
 KCH-437/M<1stA549T, c.1645 G>ANoneUSHypoMDSReticulate skin pigmentation, skin warts, liver fibrosis, portal hypertension, esophageal varicesFH of cancerNo treatment
 KCH-533/F<10thQ397E, c.1189 C>GNoneUSICUSNoneNoneEvolved to hypoMDS
 KCH-919/F<1stD220N, c.658 G>ATERT, A1062T c.3184 G>AUSMAAShort stature, reticulate skin pigmentation, dystrophic nails, Lichen planus, epiphoraPedigree (Figure 3)No treatment
 KCH-1233/M<10thA990V, c.2969 C>TNoneUSBMFS, ICUSLearning difficulties, epilepsy, urogenital anomalies, hyperostosis cranium, occult spina bifidaNoneG-CSF, died lymphoma
 KCH-1373/M<1stP992L, c.2975 C>TNoneUSCMML1NoneFH of cancerNo treatment
 KCH-1453/F<1stQ397E, c.1189 C>GNoneUSThrombocytopenia/MAAShort statureFH of cancer, brother has short TLPartial response to IST, relapsed
 KCH-1629/F<1stP824S, c.2470 C>TNoneUSMAAPresented in pregnancyNoneNo treatment
 KCH-1738/M<1stV402A, c.1205 T>CNoneUSHypoMDSNoneNoneNo treatment
 KCH-1963/M<1stD942N, c.2824 G>ANoneUSAMLNoneNoneChemotherapy, MUD HSCT, died GVHD
 NIH-317/MNormalP884L, c.2651 C>TNoneUSSAANoneFH of cancerTreated with IST/EPAG and evolved to −7/MDS
 NIH-563/FNormalP82L, c.245 C>TNoneUSMAAMitral valve prolapsePedigree (Figure 3)Progressed to SAA on EPAG and evolved to MDS/AML; died following HSCT of relapsed AML
 NIH-732/F<1stA902G, c.2705 C>GTERC, r.287 C>G§USMAAFrequent miscarriages, early graying of hairMaternal early graying of hair, MDS in maternal uncle, BMF in paternal grandmotherNo treatment
Likely benign variants
 KCH-652/M<1stM320T, c.959 T>CTERT, A279T c.835 G>ALBHypoMDSCeliac disease, hepatosplenomegaly, abnormal lung functionNoneMUD HSCT; complete response
 KCH-738/F<10thP867L, c.2600 C>TNoneLBMacrocytosisShort stature, normal BM cellularityNoneNo treatment
 KCH-1873/MNormalM320T, c.959 T>CNoneLBMDS (RAEB2)NoneNoneBest supportive care; died
 NIH-623/FNormalP867L, c.2672 C>TTERT, R537C c.1609 C>TLBMAAEczemaFather and brother with early graying of hair, mother with macrocytic anemiaNo treatment
 NIH-847/MNormalP996H, c.2987 C>ANoneLBhypoMDSNoneSister with SLE, paternal grandfather with polycythemia veraResponded to EPAG
  • The RTEL1 variants identified in our study were annotated using the isoform 3 (1300 aa; NM_001283009.1).

  • CMML, chronic myelomonocytic leukemia; EPAG, eltrombopag; F, female; FH, family history; GVHD, graft-versus-host disease; HSCT, hematopoietic stem cell transplantation; ID, identification; IST, immunosuppressive therapy with antithymocyte globulin and cyclosporine; LTFU, loss to follow-up; M, male; MAA, moderate aplastic anemia; MUD, matched unrelated donor; PNH, paroxysmal nocturnal hemoglobinuria; RAEB, MDS with refractory anemia with excess blasts; SAA, severe AA; SLE, systemic lupus erythematosus; TLCO, transfer factor of the lung for carbon monoxide.

  • * <1st, TL below the first percentile of age matched controls (very short telomeres); <10th, TL below tenth percentile (short telomeres).

  • For the KCH cohort, the targeting next-generation sequencing panel had 12 candidate genes. For the NIH cohort, the targeting next-generation sequencing panel had 49 candidate genes.

  • ACMG consensus criteria.

  • § Variants previously reported as pathogenic.