Misclassified cases of cluster A from the validation cohort (n = 12 of 127; 9%): 7% (6 of 81) of acquired and 20% (6 of 29) of inherited cases
| . | Label . | Prediction . | Sex . | Age . | Clinical diagnosis . | Pathogenic germ line variant (zygosity) . | TL (flow-FISH) . | Patient clinical features . |
|---|---|---|---|---|---|---|---|---|
| USP021 | Acquired | Inherited | M | 9 | DC | None∗ | <First | DC clinical triad. |
| USP035 | Acquired | Inherited | F | 18 | DC | None∗ | <First | DC clinical triad since childhood. Sister and cousin with Hodgkin lymphoma. |
| USP036 | Acquired | Inherited | M | 11 | MAA | None∗ | <10th | Chronic pancytopenia and family history of leukemia. |
| USP045 | Acquired | Inherited | F | 7 | MAA | None∗ | Normal | ALL and BMF with café-au-lait spots after chemotherapy. Despite suspicion of FA, DEB in peripheral blood was negative and no variant in FANC-related genes was identified. Patients' uncle also died from ALL. |
| USP051 | Acquired | Inherited | M | 3 | SAA | None∗ | <First | No family history or classical signs of IBMFS. |
| USP159 | Acquired | Inherited | F | 3 | DC | None | <First | DC clinical triad. |
| USP022 | Inherited | Acquired | M | 20 | MAA | TERT: c.2154C>A; p.D718E (het) | <First | No family history or signs of IBMFS. PNH clone of 6%. |
| USP023 | Inherited | Acquired | F | 8 | MAA | TERT: c.1072C>T; p.R358W (hom) | <10th | Consanguinity but no classical signs of inherited disease. |
| USP026 | Inherited | Acquired | F | 38 | MAA | TERT: c.193C>A; p.P65T (hom) | <10th | Pulmonary fibrosis. |
| USP030 | Inherited | Acquired | F | 18 | MAA | 1TINF2:c.844C>T; p.R282C (het) | <First | History of miscarriage. Son with DC and same pathogenic variant in TINF2. |
| USP065 | Inherited | Acquired | M | 24 | HypoMDS | RUNX1: c.497G>C; p.R166P (het) | Normal | Hypocellular bone marrow. Brother died of ALL. |
| USP152 | Inherited | Acquired | F | 1 | SAA | 2MECOM: c.2518delC; p.E841KfsTer3 (het) | Normal | No family history or classical signs of IBMFS. |
| . | Label . | Prediction . | Sex . | Age . | Clinical diagnosis . | Pathogenic germ line variant (zygosity) . | TL (flow-FISH) . | Patient clinical features . |
|---|---|---|---|---|---|---|---|---|
| USP021 | Acquired | Inherited | M | 9 | DC | None∗ | <First | DC clinical triad. |
| USP035 | Acquired | Inherited | F | 18 | DC | None∗ | <First | DC clinical triad since childhood. Sister and cousin with Hodgkin lymphoma. |
| USP036 | Acquired | Inherited | M | 11 | MAA | None∗ | <10th | Chronic pancytopenia and family history of leukemia. |
| USP045 | Acquired | Inherited | F | 7 | MAA | None∗ | Normal | ALL and BMF with café-au-lait spots after chemotherapy. Despite suspicion of FA, DEB in peripheral blood was negative and no variant in FANC-related genes was identified. Patients' uncle also died from ALL. |
| USP051 | Acquired | Inherited | M | 3 | SAA | None∗ | <First | No family history or classical signs of IBMFS. |
| USP159 | Acquired | Inherited | F | 3 | DC | None | <First | DC clinical triad. |
| USP022 | Inherited | Acquired | M | 20 | MAA | TERT: c.2154C>A; p.D718E (het) | <First | No family history or signs of IBMFS. PNH clone of 6%. |
| USP023 | Inherited | Acquired | F | 8 | MAA | TERT: c.1072C>T; p.R358W (hom) | <10th | Consanguinity but no classical signs of inherited disease. |
| USP026 | Inherited | Acquired | F | 38 | MAA | TERT: c.193C>A; p.P65T (hom) | <10th | Pulmonary fibrosis. |
| USP030 | Inherited | Acquired | F | 18 | MAA | 1TINF2:c.844C>T; p.R282C (het) | <First | History of miscarriage. Son with DC and same pathogenic variant in TINF2. |
| USP065 | Inherited | Acquired | M | 24 | HypoMDS | RUNX1: c.497G>C; p.R166P (het) | Normal | Hypocellular bone marrow. Brother died of ALL. |
| USP152 | Inherited | Acquired | F | 1 | SAA | 2MECOM: c.2518delC; p.E841KfsTer3 (het) | Normal | No family history or classical signs of IBMFS. |
ALL, acute lymphocytic leukemia; F, female; FISH, fluorescence in situ hybridization; het, heterozygous; hom, homozygous; HypoMDS, hypoplastic MDS; M, male; <First, TL below the first percentile of age-matched controls; <10th, TL below the tenth percentile of age-matched controls.
These patients were not screened for variants in MECOM, SAMD9, and SAMD9L because these genes were included in the panel after these samples were sequenced.1 Although the TINF2 R282C variant is commonly associated with DC of early onset, USP030 did not have the clinical triad or any classical sign of IBMFS other than a past history of multiple miscarriages. Telomere disease was later suspected after her son was diagnosed with DC at age of 2 years; he was later found to have the same TINF2 pathogenic variant.2 MECOM isoform (NM_004991.4).