Hematologic, pulmonary, and other characteristics of confirmed carriers of P or LP telomere gene variants in 16 families
| Pedigree ID . | Proband/relative . | Sex . | Gene . | Variant cDNA . | Variant protein . | Variant class . | Hematologic phenotype . | Age at diagnosis of hematologic disease, y . | Pulmonary phenotype . | Age at diagnosis of pulmonary disease, y . | Comorbidities . | Autoimmune features . | PB lymphocyte telomere length (flowFISH, percentile) . | Variant previously reported (PMID if yes) . |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 557 II.1 | Proband | M | PARN | c.24del | p.F8Lfs*12 | P | Polycythemia | 52 | ILD/UIP | 51 | AbTPO↑ | <1st | 29463756 | |
| 1080 III.1 | Proband | M | PARN | c.709C>T | p.R237* | P | Macrocytosis | 47 | ILD/UIP | 52 | GERD | 10th | 26810774, 28099038 | |
| 1080 II.1 | Aunt | F | Macrocytosis | ILD | 77 | 10th-50th | ||||||||
| 1080 II.2 | Aunt | F | ILD | 74 | 10th-50th | |||||||||
| 1080 II.3 | Aunt | F | ILD | 62 | GERD | 10th-50th | ||||||||
| 1080 II.4 | Aunt | F | 1st-10th | |||||||||||
| 841 II.1 | Proband | M | PARN | c.1006-2A>G | p.? | LP | BM dyserythropoiesis | 54 | ILD/UIP | 49 | 10th | No | ||
| 832 III.1 | Proband | M | PARN | Deletion exon 1-21 | NA | P | ILD/UIP and constrictive bronchiolitis | 61 | 50th | No | ||||
| 832 III.3 | Brother | M | ILD/UIP | 67 | ND | |||||||||
| 832 III.4 | Brother | M | ILD | 63 | 1st-10th | |||||||||
| 832 III.7 | Sister | F | ND | |||||||||||
| 832 III.9 | Cousin | F | ND | |||||||||||
| 832 III.11 | Cousin | F | ND | |||||||||||
| 832 III.12 | Cousin | F | ND | |||||||||||
| 832 III.13 | Cousin | F | ILD/UIP | 63 | Osteoporosis, elevated LFT results | 10th-50th | ||||||||
| 832 IV.6 | Niece | F | 10th-50th | |||||||||||
| 1210 II.1 | Proband | M | PARN | Deletion exon 12 | NA | LP | Intermittent thrombocytopenia | 56 | ILD (unclassifiable) | 56 | GERD, small hiatal hernia, generalized anxiety disorder/ depression upon ILD diagnosis | ANA 1:320 (speckled and nucleolar), ACE↑, CCP↑ | <1st | No |
| 909 II.1 | Proband | M | RTEL1 | c.1135+1G>A | p.? | P | Gastric DLBCL, AML | 48 | early graying | <1st | No | |||
| 684 II.1 | Proband | M | TERC | n.114_115del | NA | LP | Chronic pancytopenia/AA with macrocytosis | 18 | ND | 27192671 | ||||
| 218 III.1 | Proband | M | TERC | n.114_115del | NA | LP | Neutropenia | Mildly reduced diffusion capacity | 31 | 1st | 27192671 | |||
| 218 II.1 | Mother | F | Chronic pancytopenia/AA | 40 | ILD | 60 | ND | |||||||
| 875 III.1 | Proband | M | TERC | n.357_365del | NA | LP | Pancytopenia, MDS (MDS-U) | 40, 53 | 20th | No | ||||
| 775 III.1 | Proband | M | TERC | Whole-gene deletion | NA | LP | Chronic neutropenia, macrocytosis, intermittent thrombocytopenia, hypocellular bone marrow, CD3/CD4 lymphocytopenia, low IgM | 14 | Pancreatic insufficiency (sweat chloride normal), fine reticular skin hypopigmentation | ANA 1:320 (speckled) | <1st | No | ||
| 865 II.1 | Proband | F | TERT | c.230T>C | p.L77P | LP | ILD/CHP | 73 | SCC (skin), skin hypopigmentation, osteoporosis | ILD/CHP, psoriasis | <1st | No | ||
| 865 II.2 | Brother | M | ILD/CHP | 74 | ILD/CHP | ND | ||||||||
| 865 II.3 | Sister | F | Asthma | ND | ||||||||||
| 865 III.1 | Son | M | ILD/CHP | 53 | ILD/CHP | ND | ||||||||
| 913 II.4 | Proband | M | TERT | c.347C>T | p.T116I | LP | ILD/IPAF | 55 | SCC tongue, osteoporosis with multiple compression fractures, GERD | ILD/IPAF, ANA 1:320 (speckled), Raynaud syndrome | <1st | No | ||
| 913 III.5 | Daughter | F | Raynaud syndrome | <1st | ||||||||||
| 913 III.4 | Daughter | F | <1st | |||||||||||
| 913 II.2 | Sister | F | Osteoporosis | ND | ||||||||||
| 913 II.1 | Sister | F | Macrocytosis | 61 | Osteoporosis | 1st-10th | ||||||||
| 913 III.1 | Nephew | M | asthma | <1st | ||||||||||
| 913 III.3 | Niece | F | <1st | |||||||||||
| 246 II.1 | Proband | M | TERT | c.1891C>T | p.R631W | P | AML with MDS features | 75 | ND | 18460650, 26859482 | ||||
| 088 II.4 | Proband | F | TERT | c.1990G>C | p.V664L | LP | MDS (complex karyotype) | 56 | ND | 29463756 | ||||
| 088 II.1 | Brother | M | Pancytopenia with macrocytosis | 1st-10th | ||||||||||
| 088 II.2 | Sister | F | MDS (RARS) | 62 | Skin hypopigmentation, osteoporosis | Pernicious anemia | 1st-10th | |||||||
| 088 III.2 | Niece | F | <1st | |||||||||||
| 669 III.1 | Proband | M | TERT | c.2011C>G | p.R671G | LP | Macrocytic anemia, thrombocytopenia (CCUS with acquired U2AF1 variant) | ILD/UIP | 51 | ANA 1:160 (hom/speckled), Aldolase↑ | <1st | No | ||
| 669 III.2 | Brother | M | Thrombocytopenia | 48 | Liver fibrosis | Near 1st | ||||||||
| 1020 II.1 | Proband | F | TERT | c.2812C>T | p.R938W | LP | Macrocytic anemia | ILD/UIP | 48 | Early graying | <1st | 28099038 |
| Pedigree ID . | Proband/relative . | Sex . | Gene . | Variant cDNA . | Variant protein . | Variant class . | Hematologic phenotype . | Age at diagnosis of hematologic disease, y . | Pulmonary phenotype . | Age at diagnosis of pulmonary disease, y . | Comorbidities . | Autoimmune features . | PB lymphocyte telomere length (flowFISH, percentile) . | Variant previously reported (PMID if yes) . |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 557 II.1 | Proband | M | PARN | c.24del | p.F8Lfs*12 | P | Polycythemia | 52 | ILD/UIP | 51 | AbTPO↑ | <1st | 29463756 | |
| 1080 III.1 | Proband | M | PARN | c.709C>T | p.R237* | P | Macrocytosis | 47 | ILD/UIP | 52 | GERD | 10th | 26810774, 28099038 | |
| 1080 II.1 | Aunt | F | Macrocytosis | ILD | 77 | 10th-50th | ||||||||
| 1080 II.2 | Aunt | F | ILD | 74 | 10th-50th | |||||||||
| 1080 II.3 | Aunt | F | ILD | 62 | GERD | 10th-50th | ||||||||
| 1080 II.4 | Aunt | F | 1st-10th | |||||||||||
| 841 II.1 | Proband | M | PARN | c.1006-2A>G | p.? | LP | BM dyserythropoiesis | 54 | ILD/UIP | 49 | 10th | No | ||
| 832 III.1 | Proband | M | PARN | Deletion exon 1-21 | NA | P | ILD/UIP and constrictive bronchiolitis | 61 | 50th | No | ||||
| 832 III.3 | Brother | M | ILD/UIP | 67 | ND | |||||||||
| 832 III.4 | Brother | M | ILD | 63 | 1st-10th | |||||||||
| 832 III.7 | Sister | F | ND | |||||||||||
| 832 III.9 | Cousin | F | ND | |||||||||||
| 832 III.11 | Cousin | F | ND | |||||||||||
| 832 III.12 | Cousin | F | ND | |||||||||||
| 832 III.13 | Cousin | F | ILD/UIP | 63 | Osteoporosis, elevated LFT results | 10th-50th | ||||||||
| 832 IV.6 | Niece | F | 10th-50th | |||||||||||
| 1210 II.1 | Proband | M | PARN | Deletion exon 12 | NA | LP | Intermittent thrombocytopenia | 56 | ILD (unclassifiable) | 56 | GERD, small hiatal hernia, generalized anxiety disorder/ depression upon ILD diagnosis | ANA 1:320 (speckled and nucleolar), ACE↑, CCP↑ | <1st | No |
| 909 II.1 | Proband | M | RTEL1 | c.1135+1G>A | p.? | P | Gastric DLBCL, AML | 48 | early graying | <1st | No | |||
| 684 II.1 | Proband | M | TERC | n.114_115del | NA | LP | Chronic pancytopenia/AA with macrocytosis | 18 | ND | 27192671 | ||||
| 218 III.1 | Proband | M | TERC | n.114_115del | NA | LP | Neutropenia | Mildly reduced diffusion capacity | 31 | 1st | 27192671 | |||
| 218 II.1 | Mother | F | Chronic pancytopenia/AA | 40 | ILD | 60 | ND | |||||||
| 875 III.1 | Proband | M | TERC | n.357_365del | NA | LP | Pancytopenia, MDS (MDS-U) | 40, 53 | 20th | No | ||||
| 775 III.1 | Proband | M | TERC | Whole-gene deletion | NA | LP | Chronic neutropenia, macrocytosis, intermittent thrombocytopenia, hypocellular bone marrow, CD3/CD4 lymphocytopenia, low IgM | 14 | Pancreatic insufficiency (sweat chloride normal), fine reticular skin hypopigmentation | ANA 1:320 (speckled) | <1st | No | ||
| 865 II.1 | Proband | F | TERT | c.230T>C | p.L77P | LP | ILD/CHP | 73 | SCC (skin), skin hypopigmentation, osteoporosis | ILD/CHP, psoriasis | <1st | No | ||
| 865 II.2 | Brother | M | ILD/CHP | 74 | ILD/CHP | ND | ||||||||
| 865 II.3 | Sister | F | Asthma | ND | ||||||||||
| 865 III.1 | Son | M | ILD/CHP | 53 | ILD/CHP | ND | ||||||||
| 913 II.4 | Proband | M | TERT | c.347C>T | p.T116I | LP | ILD/IPAF | 55 | SCC tongue, osteoporosis with multiple compression fractures, GERD | ILD/IPAF, ANA 1:320 (speckled), Raynaud syndrome | <1st | No | ||
| 913 III.5 | Daughter | F | Raynaud syndrome | <1st | ||||||||||
| 913 III.4 | Daughter | F | <1st | |||||||||||
| 913 II.2 | Sister | F | Osteoporosis | ND | ||||||||||
| 913 II.1 | Sister | F | Macrocytosis | 61 | Osteoporosis | 1st-10th | ||||||||
| 913 III.1 | Nephew | M | asthma | <1st | ||||||||||
| 913 III.3 | Niece | F | <1st | |||||||||||
| 246 II.1 | Proband | M | TERT | c.1891C>T | p.R631W | P | AML with MDS features | 75 | ND | 18460650, 26859482 | ||||
| 088 II.4 | Proband | F | TERT | c.1990G>C | p.V664L | LP | MDS (complex karyotype) | 56 | ND | 29463756 | ||||
| 088 II.1 | Brother | M | Pancytopenia with macrocytosis | 1st-10th | ||||||||||
| 088 II.2 | Sister | F | MDS (RARS) | 62 | Skin hypopigmentation, osteoporosis | Pernicious anemia | 1st-10th | |||||||
| 088 III.2 | Niece | F | <1st | |||||||||||
| 669 III.1 | Proband | M | TERT | c.2011C>G | p.R671G | LP | Macrocytic anemia, thrombocytopenia (CCUS with acquired U2AF1 variant) | ILD/UIP | 51 | ANA 1:160 (hom/speckled), Aldolase↑ | <1st | No | ||
| 669 III.2 | Brother | M | Thrombocytopenia | 48 | Liver fibrosis | Near 1st | ||||||||
| 1020 II.1 | Proband | F | TERT | c.2812C>T | p.R938W | LP | Macrocytic anemia | ILD/UIP | 48 | Early graying | <1st | 28099038 |
All variants have been detected in a heterozygous state and were described according to the recommendations of the Human Genome Variation Society using the following transcripts: TERC NR_001566.1, TERT NM_198253.2, RTEL1 NM_001283009.1, and PARN NM_002582.3. Confirmed variant carriers from each individual family are organized in a single gray or white band with row names indicating individual and relationship.
ACE, angiotensin-converting enzyme; ANA, antinuclear antibody; BM, bone marrow; CCP, cyclic citrullinated peptide; CCUS, clonal cytopenia of undetermined significance; cDNA, complementary DNA; CHP, chronic hypersensitivity pneumonitis; DLBCL, diffuse large B-cell lymphoma; GERD, gastroesophageal reflux disease; hom, homogenous; IgM, immunoglobulin M; IPAF, interstitial pneumonia with autoimmune features; LFT, liver function test; MDS-U, MDS, unclassifiable; NA, not applicable; ND, not done; PB, peripheral blood; PMID, PubMed identifier; RARS, refractory anemia with ring sideroblasts; SCC, squamous cell carcinoma; UIP, usual interstitial pneumonia.