Description of 27 patients with RTEL1 variants
| Patient ID . | Age/sex . | TL* . | RTEL1 variants . | Other germline variants† . | RTEL1 ACGM‡ . | Hematologic diagnosis . | Somatic anomalies and other clinical features . | Family history . | Outcome . |
|---|---|---|---|---|---|---|---|---|---|
| Heterozygous pathogenic or likely pathogenic variants | |||||||||
| KCH-1 | 36/M | <1st | R974X, c.2920 C>T§ | TERT, R756C c.2266 C>T | Pathogenic | Familial hypoMDS | Abnormal lung function: TLCOc 72% | Brother has hypoMDS | Responded to cyclosporine |
| KCH-3 | 25/M | <1st | R974X, c.2920 C>T§ | None | Pathogenic | HypoMDS | Suspected to have inherited disease | FH of cancer | No treatment |
| KCH-8 | 29/F | <1st | c.301+1G>A | None | LP | ICUS: neutropenia | Bicuspid aortic valve, high arched palate | Pedigree (Figure 3) | Treated with G-CSF |
| KCH-10 | 31/F | <1st | R986X, c.2956 C>T§ | None | Pathogenic | ICUS: neutropenia | Dystrophic nails, neutropenia for 16 y | None | Treated with G-CSF |
| KCH-11 | 54/F | <10th | R986X, c.2956 C>T§ | Not tested | Pathogenic | Macrocytosis, hypocellular BM | Dystrophic nail | Pedigree (Figure 3) | No treatment |
| KCH-15 | 30/F | <1st | c.301+1G>A | None | LP | AA/PNH | None | None | Treated with IST, LTFU |
| NIH-4 | 31/F | Normal | M652T, c.1955 T>C | SLX4, T750M c.2249 C>T | LP | ICUS: neutropenia | Normal BM cellularity | None | No treatment |
| Biallelic pathogenic or likely pathogenic variants | |||||||||
| NIH-1 | 32/M | <1st | D719N, c.2155 G>A P871L, c.2612 C>T | None | LP | MAA | Liver cirrhosis, pulmonary fibrosis | Pedigree (Figure 3) | Responded to androgen (danazol) |
| LB | |||||||||
| NIH-2 | 6/F | <1st | G951, c.2851 G>A F1262L, c.3786 C>G | None | LP | SAA | Prolonged thrombocytopenia | Pedigree (Figure 3) | Awaiting HSCT |
| Pathogenic | |||||||||
| Variants of uncertain significance | |||||||||
| KCH-2 | 71/M | <10th | V178A, c.533 T>C | None | US | MDS (RAEB1) | Laryngeal squamous cell cancer, age of 60 y; small cell lung cancer, age of 66 y | FH of cancer | Treated with 5-azacitidine, progressed to AML, died |
| KCH-4 | 37/M | <1st | A549T, c.1645 G>A | None | US | HypoMDS | Reticulate skin pigmentation, skin warts, liver fibrosis, portal hypertension, esophageal varices | FH of cancer | No treatment |
| KCH-5 | 33/F | <10th | Q397E, c.1189 C>G | None | US | ICUS | None | None | Evolved to hypoMDS |
| KCH-9 | 19/F | <1st | D220N, c.658 G>A | TERT, A1062T c.3184 G>A | US | MAA | Short stature, reticulate skin pigmentation, dystrophic nails, Lichen planus, epiphora | Pedigree (Figure 3) | No treatment |
| KCH-12 | 33/M | <10th | A990V, c.2969 C>T | None | US | BMFS, ICUS | Learning difficulties, epilepsy, urogenital anomalies, hyperostosis cranium, occult spina bifida | None | G-CSF, died lymphoma |
| KCH-13 | 73/M | <1st | P992L, c.2975 C>T | None | US | CMML1 | None | FH of cancer | No treatment |
| KCH-14 | 53/F | <1st | Q397E, c.1189 C>G | None | US | Thrombocytopenia/MAA | Short stature | FH of cancer, brother has short TL | Partial response to IST, relapsed |
| KCH-16 | 29/F | <1st | P824S, c.2470 C>T | None | US | MAA | Presented in pregnancy | None | No treatment |
| KCH-17 | 38/M | <1st | V402A, c.1205 T>C | None | US | HypoMDS | None | None | No treatment |
| KCH-19 | 63/M | <1st | D942N, c.2824 G>A | None | US | AML | None | None | Chemotherapy, MUD HSCT, died GVHD |
| NIH-3 | 17/M | Normal | P884L, c.2651 C>T | None | US | SAA | None | FH of cancer | Treated with IST/EPAG and evolved to −7/MDS |
| NIH-5 | 63/F | Normal | P82L, c.245 C>T | None | US | MAA | Mitral valve prolapse | Pedigree (Figure 3) | Progressed to SAA on EPAG and evolved to MDS/AML; died following HSCT of relapsed AML |
| NIH-7 | 32/F | <1st | A902G, c.2705 C>G | TERC, r.287 C>G§ | US | MAA | Frequent miscarriages, early graying of hair | Maternal early graying of hair, MDS in maternal uncle, BMF in paternal grandmother | No treatment |
| Likely benign variants | |||||||||
| KCH-6 | 52/M | <1st | M320T, c.959 T>C | TERT, A279T c.835 G>A | LB | HypoMDS | Celiac disease, hepatosplenomegaly, abnormal lung function | None | MUD HSCT; complete response |
| KCH-7 | 38/F | <10th | P867L, c.2600 C>T | None | LB | Macrocytosis | Short stature, normal BM cellularity | None | No treatment |
| KCH-18 | 73/M | Normal | M320T, c.959 T>C | None | LB | MDS (RAEB2) | None | None | Best supportive care; died |
| NIH-6 | 23/F | Normal | P867L, c.2672 C>T | TERT, R537C c.1609 C>T | LB | MAA | Eczema | Father and brother with early graying of hair, mother with macrocytic anemia | No treatment |
| NIH-8 | 47/M | Normal | P996H, c.2987 C>A | None | LB | hypoMDS | None | Sister with SLE, paternal grandfather with polycythemia vera | Responded to EPAG |
| Patient ID . | Age/sex . | TL* . | RTEL1 variants . | Other germline variants† . | RTEL1 ACGM‡ . | Hematologic diagnosis . | Somatic anomalies and other clinical features . | Family history . | Outcome . |
|---|---|---|---|---|---|---|---|---|---|
| Heterozygous pathogenic or likely pathogenic variants | |||||||||
| KCH-1 | 36/M | <1st | R974X, c.2920 C>T§ | TERT, R756C c.2266 C>T | Pathogenic | Familial hypoMDS | Abnormal lung function: TLCOc 72% | Brother has hypoMDS | Responded to cyclosporine |
| KCH-3 | 25/M | <1st | R974X, c.2920 C>T§ | None | Pathogenic | HypoMDS | Suspected to have inherited disease | FH of cancer | No treatment |
| KCH-8 | 29/F | <1st | c.301+1G>A | None | LP | ICUS: neutropenia | Bicuspid aortic valve, high arched palate | Pedigree (Figure 3) | Treated with G-CSF |
| KCH-10 | 31/F | <1st | R986X, c.2956 C>T§ | None | Pathogenic | ICUS: neutropenia | Dystrophic nails, neutropenia for 16 y | None | Treated with G-CSF |
| KCH-11 | 54/F | <10th | R986X, c.2956 C>T§ | Not tested | Pathogenic | Macrocytosis, hypocellular BM | Dystrophic nail | Pedigree (Figure 3) | No treatment |
| KCH-15 | 30/F | <1st | c.301+1G>A | None | LP | AA/PNH | None | None | Treated with IST, LTFU |
| NIH-4 | 31/F | Normal | M652T, c.1955 T>C | SLX4, T750M c.2249 C>T | LP | ICUS: neutropenia | Normal BM cellularity | None | No treatment |
| Biallelic pathogenic or likely pathogenic variants | |||||||||
| NIH-1 | 32/M | <1st | D719N, c.2155 G>A P871L, c.2612 C>T | None | LP | MAA | Liver cirrhosis, pulmonary fibrosis | Pedigree (Figure 3) | Responded to androgen (danazol) |
| LB | |||||||||
| NIH-2 | 6/F | <1st | G951, c.2851 G>A F1262L, c.3786 C>G | None | LP | SAA | Prolonged thrombocytopenia | Pedigree (Figure 3) | Awaiting HSCT |
| Pathogenic | |||||||||
| Variants of uncertain significance | |||||||||
| KCH-2 | 71/M | <10th | V178A, c.533 T>C | None | US | MDS (RAEB1) | Laryngeal squamous cell cancer, age of 60 y; small cell lung cancer, age of 66 y | FH of cancer | Treated with 5-azacitidine, progressed to AML, died |
| KCH-4 | 37/M | <1st | A549T, c.1645 G>A | None | US | HypoMDS | Reticulate skin pigmentation, skin warts, liver fibrosis, portal hypertension, esophageal varices | FH of cancer | No treatment |
| KCH-5 | 33/F | <10th | Q397E, c.1189 C>G | None | US | ICUS | None | None | Evolved to hypoMDS |
| KCH-9 | 19/F | <1st | D220N, c.658 G>A | TERT, A1062T c.3184 G>A | US | MAA | Short stature, reticulate skin pigmentation, dystrophic nails, Lichen planus, epiphora | Pedigree (Figure 3) | No treatment |
| KCH-12 | 33/M | <10th | A990V, c.2969 C>T | None | US | BMFS, ICUS | Learning difficulties, epilepsy, urogenital anomalies, hyperostosis cranium, occult spina bifida | None | G-CSF, died lymphoma |
| KCH-13 | 73/M | <1st | P992L, c.2975 C>T | None | US | CMML1 | None | FH of cancer | No treatment |
| KCH-14 | 53/F | <1st | Q397E, c.1189 C>G | None | US | Thrombocytopenia/MAA | Short stature | FH of cancer, brother has short TL | Partial response to IST, relapsed |
| KCH-16 | 29/F | <1st | P824S, c.2470 C>T | None | US | MAA | Presented in pregnancy | None | No treatment |
| KCH-17 | 38/M | <1st | V402A, c.1205 T>C | None | US | HypoMDS | None | None | No treatment |
| KCH-19 | 63/M | <1st | D942N, c.2824 G>A | None | US | AML | None | None | Chemotherapy, MUD HSCT, died GVHD |
| NIH-3 | 17/M | Normal | P884L, c.2651 C>T | None | US | SAA | None | FH of cancer | Treated with IST/EPAG and evolved to −7/MDS |
| NIH-5 | 63/F | Normal | P82L, c.245 C>T | None | US | MAA | Mitral valve prolapse | Pedigree (Figure 3) | Progressed to SAA on EPAG and evolved to MDS/AML; died following HSCT of relapsed AML |
| NIH-7 | 32/F | <1st | A902G, c.2705 C>G | TERC, r.287 C>G§ | US | MAA | Frequent miscarriages, early graying of hair | Maternal early graying of hair, MDS in maternal uncle, BMF in paternal grandmother | No treatment |
| Likely benign variants | |||||||||
| KCH-6 | 52/M | <1st | M320T, c.959 T>C | TERT, A279T c.835 G>A | LB | HypoMDS | Celiac disease, hepatosplenomegaly, abnormal lung function | None | MUD HSCT; complete response |
| KCH-7 | 38/F | <10th | P867L, c.2600 C>T | None | LB | Macrocytosis | Short stature, normal BM cellularity | None | No treatment |
| KCH-18 | 73/M | Normal | M320T, c.959 T>C | None | LB | MDS (RAEB2) | None | None | Best supportive care; died |
| NIH-6 | 23/F | Normal | P867L, c.2672 C>T | TERT, R537C c.1609 C>T | LB | MAA | Eczema | Father and brother with early graying of hair, mother with macrocytic anemia | No treatment |
| NIH-8 | 47/M | Normal | P996H, c.2987 C>A | None | LB | hypoMDS | None | Sister with SLE, paternal grandfather with polycythemia vera | Responded 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.