Saturday, September 23, 2023
| Variable | |
|---|---|
| No. of patients | 402 |
| Age, y (median, range) | 56 (18–86) |
| Sex (female/male) | 203/199 |
| Hemoglobin, g/dL (median, range) | 11.8 (3.9–17.4) |
| MCV, fL (median, range) | 95 (60–124) |
| WBC, ×109/L (median, range) | 3.5 (0.5–28.51) |
| ANC, ×109/L (median, range) | 1.63 (0.09–9.77) |
| PLT, ×109/L (median, range) | 129 (1–666) |
| Diagnosis based on the standard work-up | |
| Idiopathic cytopenia of undetermined significance | 162 (40%) |
| Clonal cytopenia of undetermined significance | 26 (6%) |
| Myeloid neoplasm | 73 (43%) |
| Acute myeloid leukaemia | 11 (6%) |
| MDS | 148 (86%) |
| MDS single-lineage dysplasia | 19 (13%) |
| MDS multilineage dysplasia | 60 (41%) |
| MDS with ring sideroblasts | 8 (5%) |
| MDS excess blasts | 51 (34%) |
| MDS del(5q) | 8 (6%) |
| MDS, unclassified | 2 (1%) |
| Myelodysplastic/myeloproliferative neoplasm | 14 (8%) |
| AA | 41 (10%) |
| Nonsevere | 27 (66%) |
| Severe | 14 (34%) |
| Bone marrow cellularity, % (median, range) | 25 (5–50) |
| ≤25% | 206 (51%) |
| Reduced for age | 196 (49%) |
Table 1: Clinical and hematologic features of individuals included in the study
ANC, absolute neutrophil count; MCV, mean corpuscular volume; MDS del(5q), myelodysplastic syndrome with isolated deletion of chromosome 5q; PLT, platelet count; WBC, white blood cell count.
| Patient ID | Age/sex | Germ line gene mutation | VAF myeloid | VAF Germ line | Congenital S/D | Somatic mutation | Cytogenetics (% abnormal metaphases) | Hb g/dl | ANC, ×109/L | Plt, ×109/L | Diagnosis | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Mutated gene | VAF | |||||||||||
| PV1185 | 51/F |
CSF3R c.1474+1G>C CSF3R p.(W566*) |
0.40 0.40 |
0.48 0.45 |
SCN | WT | 46XX | 13.2 | 0.5 | 275 | ICUS | |
| PV1395 | 82/M | DDX41 p.(M1?) | 0.46 | 0.48 | DDX41-associated predisposition | DDX41 | 0.11 | 45X;-Y (50) | 13 | 0.9 | 193 | MDS-MLD |
| PV1583 | 56/F | DDX41 p.(M1?) | 0.48 | 0.50 | DDX41-associated predisposition | SF3B1 | 0.02 | 46XX | 10.4 | 0.4 | 90 | MDS-EB-2 |
| PV1336 | 59/M | DDX41 p.(Q48*) | 0.48 | 0.48 | DDX41-associated predisposition | WT | 46XY | 12.2 | 2.9 | 165 | MDS-EB-2 | |
| PV1475 | 66/M | DDX41 p.(K102fs) | 0.45 | 0.48 | DDX41-associated predisposition | WT | failed | NA | MDS-EB-2 | |||
| PV10015 | 62/M | DDX41 p.(K102fs) | 0.48 | 0.45 | DDX41-associated predisposition | WT | 46XY; del(7) add(4) (18) | 8.3 | 1.47 | 24 | AML | |
| PV1178 | 57/M | DDX41 p.(I207T) | 0.49 | 0.40 | DDX41-associated predisposition | DDX41 | 0.01 | 46XY | 10.1 | 0.5 | 47 | MDS-EB-2 |
| PV1581 | 64/M | DDX41 p.(I207T) | 0.46 | 0.48 | DDX41-associated predisposition | WT | 46XY | 11.4 | 0.8 | 48 | MDS-EB-2 | |
| PV693 | 49/M | DDX41 p.(G218D) | 0.49 | 0.50 | DDX41-associated predisposition |
ASXL1
STAG2 |
0.29 0.35 |
46XY | 14.4 | 1.76 | 80 | MDS-EB-2 |
| PV1591 | 66/M | DDX41 p.(G218D) | 0.48 | 0.49 | DDX41-associated predisposition | WT | 46XY | 11.8 | 1.67 | 181 | MDS-EB-2 | |
| PV2607 | 65/M | DDX41 p.(P258L) | 0.49 | 0.46 | DDX41-associated predisposition | WT | 46XY | 12.5 | 2.44 | 60 | ICUS | |
| PV583 | 73/M | DDX41 p.(Y259H) | 0.46 | 0.48 | DDX41-associated predisposition | DDX41 | 0.11 | 46XY | 11.6 | 1.5 | 101 | MDS-MLD |
| PV554 | 60/F | DDX41 p.(R267W) | 0.44 | 0.50 | DDX41-associated predisposition |
ASXL1
ATRX BCOR |
0.38 0.14 0.12 |
46XX | 11.1 | 1.65 | 40 | CCUS |
| PV1546 | 35/M | ELANE p.(R220Q) | 0.50 | 0.52 | SCN | WT | 46XY | 14 | 0.8 | 141 | MDS-MLD | |
| PV2613 | 54/F |
FANCA c.79+1G>C FANCA p.(P1324L) |
0.50 0.49 |
0.50 0.44 |
FA | WT | 46XX; trp(q21;q32) add(19)(p13) (100) | 10.6 | 0.8 | 33 | MDS-MLD | |
| PV2443 | 37/F | FANCA p.(V372fs)* | 0.99 | 0.97 | FA | WT | complex karyotype (100) | 12.5 | 0.7 | 106 | MDS-MLD | |
| PV1047 | 45/M | FANCA p.(N1140fs) | 1.00 | 0.98 | FA |
ASXL1
EZH2 STAG2 TET2 |
0.45 0.94 0.50 0.22 |
46XY/47XY; del(5q) del(17p) +mar (80) | 12 | 2.3 | 145 | MDS-EB-1 |
| PV10061 | 41/F | FANCG p.(E395fs) | 1.00 | 0.98 | FA | WT | 46XX | 10.6 | 1.4 | 110 | ICUS | |
| PV2292 | 32/M | GATA1 c.-19-2A>G* | 0.97 | 0.98 | DBA | WT | 46XY | 11.6 | 0.5 | 108 | ICUS | |
| PV2663 | 29/F | GATA2 p.(R330*) | 0.50 | 0.46 | GATA2-deficiency syndrome | WT | 46XX | 9.5 | 1.2 | 148 | ICUS | |
| PV2274 | 23/F | GATA2 c.1018–1G>A | 0.56 | 0.54 | GATA2-deficiency syndrome | NPM1 | NA | 46XX | 10.7 | 31 | 215 | AML |
| PV1264 | 24/F | GATA2 p.(R398W) | 0.52 | 0.42 | GATA2-deficiency syndrome | STAG2 | 0.04 | 46XX | 8.1 | 0.8 | 58 | MDS-MLD |
| PV2661 | 45/M | NF1 c.3113+2T>A | 0.47 | 0.44 | NF |
RAF1
TET2 |
0.25 0.22 |
45X;-Y (60) | 8.4 | 2.2 | 184 | CMML-0 |
| PV2662 | 44/F | PTPN11 p.(T468M) | 0.51 | 0.51 | NS | WT | 46XX | 8.2 | 1.5 | 19 | ICUS | |
| PV2664 | 38/M | RPS26 p.(M1?) | 0.51 | 0.53 | DBA | WT | 46XY | 12.7 | 0.25 | 152 | ICUS | |
| PV1774 | 52/F | RUNX1 p.(L56fs)* | 0.50 | NA | RUNX1-related FPD | WT | 46XX | 5.9 | 2.0 | 111 | MDS/MPN-U | |
| PV2117 | 24/F |
SBDS p.(K62*)* SBDS c.258+2T>C* |
0.48 0.54 |
0.40 0.52 |
SDS | WT | 46XX | 10.4 | 0.4 | 90 | ICUS | |
Table 2. Characteristics of patients with germ line variants classified as P/LP, per the ACMG/AMP criteria, and causative for a congenital syndrome/disorder
ANC, absolute neutrophil count; CMML, chronic myelomonocytic leukemia; DBA, Diamond-Blackfan anemia; F, female; FA, Fanconi anemia; FPD, familial platelet disorder; Hb, hemoglobin concentration; M, male; MDS-EB, MDS with excess blasts; MDS-MLD, MDS with multilineage dysplasia; MDS/MPN-U, MDS/myeloproliferative neoplasm unclassifiable; NA, not available; NF, neurofibromatosis; NS, Noonan syndrome; Plt, platelet count; SCN, severe congenital neutropenia; S/D, syndrome/disorder; SDS, Shwachman-Diamond syndrome; VAF, variant allele frequency; WT, wild-type.
*FANCA p.(V372fs) variant was detected in an unaffected male (son), with VAF 0.43. GATA1 c.-19-2A>G variant was detected in an affected sibling, with VAF 0.50. RUNX1 p.(L56fs) variant was detected in an affected sibling, with VAF 0.54. SBDS p.(K62*) and c.258+2T>C variants were detected in an affected sibling, with VAFs 0.48 and 0.40, respectively.
| Patient ID | Age/sex | Germ line gene mutation | VAF myeloid | VAF germ line | Congenital S/D | Somatic mutation | Cytogenetics (% abnormal metaphases) | Hb g/dl | ANC, ×109/L | Plt, ×109/L | Diagnosis | Extrahematologic phenotype | Family history of cancer hem/solid | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Mutated gene | VAF | |||||||||||||
| PV1410 | 70/M | CSF3R* p.(P146fs) | 0.43 | 0.46 | SCN |
JAK2
U2AF1 ZRSR2 |
0.10 0.12 0.15 |
Failed | 11.6 | 1.10 | 290 | MDS/MPN | + | −/− |
| PV1515 | 45/F | FANCD1 (BRCA2)* p.(Y2624C) | 0.44 | 0.48 | FA/HBOC | WT | Failed | 13.8 | 1.35 | 129 | ICUS | − | −/− | |
| PV1949 | 25/M | FANCD1 (BRCA2)* p.(Y3226fs) | 0.46 | 0.52 | FA/HBOC | WT | 46XY | 15.6 | 2.7 | 131 | ICUS | + | −/− | |
| PV2480 | 25/M | DNAJC21 p.(Ter577fs) | 0.53 | 0.50 | SDS | WT | 46XY | 13.2 | 0.57 | 151 | ICUS | + | −/− | |
| PV30044 | 50/M | FANCD2 p.(P679fs) | 0.48 | 0.45 | FA | DNMT3A | 0.10 | 46XY | 6 | 1.12 | 44 | AML | − | +/− |
| PV1174 | 38/F | SBDS c.258+2T>C† | 0.40 | 0.48 | SDS | WT | 46XX | 14.6 | 1.8 | 144 | ICUS | − | −/- | |
| PV1338 | 49/M | SBDS c.258+2T>C† | 0.40 | 0.48 | SDS |
ASXL1
NRAS WT1 WT1 |
0.43 0.04 0.36 0.03 |
46XY | 10.6 | 0.81 | 66 | AML | + | −/- |
| PV2281 | 70/F | SBDS c.258+2T>C† | 0.41 | 0.40 | SDS | TET2 | 0.38 | 46XX; del(5q) (60) | 11.6 | 1.24 | 173 | MDS del(5q) | + | −/− |
| PV2346 | 47/M | SBDS c.258+2T>C† | 0.41 | 0.41 | SDS |
PHF6
SRSF2 |
0.93 0.47 |
46XY | 12.5 | 6.4 | 35 | CCUS | − | −/− |
| PV2360 | 47/M | SBDS c.258+2T>C† | 0.40 | 0.40 | SDS | WT | 46XY | 12.8 | 2.5 | 209 | ICUS | − | −/+ | |
Table 3. Characteristics of patients carrying P/LP heterozygous germ line variants in genes involved in autosomal recessive disorders
ANC, absolute neutrophil count; F, female; FA/HBOC, Fanconi anemia/hereditary breast and ovarian cancer syndrome; Hb, hemoglobin concentration; Hem, hematopoietic; M, male; MDS/MPN, MDS/myeloproliferative neoplasm; MDS del(5q), myelodysplastic syndrome with deletion of chromosome 5q; Plt, platelet count; SCN, severe congenital neutropenia; S/D, syndrome/disorder; SDS, Shwachman-Diamond syndrome; WT, wild-type; VAF, variant allele frequency.
*Heterozygous CSF3R and FANCD1 (BRCA2) variants were described, associated with predisposition to hematologic malignancies.34–36
†Manual revision of the BAM files on the SBDS gene and its pseudogene SBDSP1 confirmed the absence of the variant p.(K62*) in patients heterozygous for c.258+2T>C.
| Patient ID | Age/sex | Germ line mutated gene | Congenital syndrome/disorder | Diagnosis | Extrahematologic phenotype | Family history | |
|---|---|---|---|---|---|---|---|
| Hematologic/solid cancer | Other | ||||||
| PV1185 | 51/F |
CSF3R
CSF3R |
SCN | ICUS | Connective tissue disease treated with methotrexate | — | — |
| PV1395 | 82/M | DDX41 | DDX41-associated predisposition | MDS-MLD | Hyperthyroidism treated with radiometabolic therapy | — | — |
| PV1583 | 56/F | DDX41 | DDX41-associated predisposition | MDS-EB-2 | — | — | — |
| PV1336 | 59/M | DDX41 | DDX41-associated predisposition | MDS-EB-2 | — | — | — |
| PV1475 | 66/M | DDX41 | DDX41-associated predisposition | MDS-EB-2 | — | — | — |
| PV10015 | 62/M | DDX41 | DDX41-associated predisposition | AML | Colon cancer treated with chemotherapy | Mother with colon and uterine cancers | — |
| PV1178 | 57/M | DDX41 | DDX41-associated predisposition | MDS-EB-2 | — | — | — |
| PV1581 | 64/M | DDX41 | DDX41-associated predisposition | MDS-EB-2 | — | — | — |
| PV693 | 49/M | DDX41 | DDX41-associated predisposition | MDS-EB-2 | — | — | — |
| PV1591 | 66/M | DDX41 | DDX41-associated predisposition | MDS-EB-2 | Cardiomyopathy | — | — |
| PV2607 | 65/M | DDX41 | DDX41-associated predisposition | ICUS | Chronic gastritis HP+; APCA-positive | — | — |
| PV583 | 73/M | DDX41 | DDX41-associated predisposition | MDS-MLD | — | — | — |
| PV554 | 60/M | DDX41 | DDX41-associated predisposition | CCUS | — | — | — |
| PV1546 | 35/M | ELANE | SCN | MDS-MLD | Mild splenomegaly | Father with MDS died after bone marrow transplant | Brother with isolated neutropenia |
| PV2613 | 54/F |
FANCA
FANCA |
FA | MDS-MLD | Short stature, triangular facies, small head café au lait spots, hypertrichosis, learning disabilities; spinocellular cell and genital carcinoma | Brother with BMF died at age 10 | Father with low platelet counts died of intracranial bleeding |
| PV2443 | 37/F | FANCA* | FA | MDS-MLD | Short stature; intrauterine fetal death (seventh month); hepatic steatosis | — | — |
| PV1047 | 45/M | FANCA | FA | MDS-EB-1 | — | — | — |
| PV10061 | 41/F | FANCG | FA | ICUS | Short stature intellectual disability, congenital right hearing loss, horseshoe kidney; polyabortivity; squamous cell carcinoma | One brother with ALL and 1 brother with esophagus cancer died at age 33; mother with breast cancer died at age 56 | — |
| PV2292 | 32/M | GATA1* | DBA | ICUS | — | Sister with primary myelofibrosis | — |
| PV2663 | 29/F | GATA2 | GATA2-deficiency syndrome | ICUS | Hashimoto thyroiditis and papillary carcinoma; chronic gastritis; obesity; early menarche | Paternal aunt with breast cancer and paternal grandfather with esophagus cancer; maternal grandmother with pancreatic cancer | — |
| PV2274 | 23/F | GATA2 | GATA2-deficiency syndrome | AML | Long-lasting peripheral blood cytopenia; recurrent respiratory infections | — | — |
| PV1264 | 24/F | GATA2 | GATA2-deficiency syndrome | MDS-MLD | — | Grandfather with multiple myeloma | — |
| PV2661 | 45/M | NF1 | NF | CMML-0 | Moderate-to-severe cognitive deficit, aortic stenosis and hypertension, short stature; GIST in imatinib therapy | — | — |
| PV2662 | 44/F | PTPN11 | NS | ICUS | Short stature, amenorrhea since age 25, hepatic fibrosis, portal hypertension and esophageal varices | — | — |
| PV2664 | 38/M | RPS26 | DBA | ICUS | Steroid diabetes | Paternal grandmother died of lung cancer | — |
| PV1774 | 52/F | RUNX1* | RUNX1-related FPD | MDS/MPN-U | Essential tremor since age 29; low count platelets since 1985 | Brother with CMML; cousin died of leukemia | Father died of lung fibrosis |
| PV2117 | 24/F |
SBDS* SBDS* |
SDS | ICUS | Short stature, intellectual disability/low IQ; pancreatic insufficiency; knee chondropathy | — | Brother with isolated neutropenia |
Table 4. Clinical phenotype and family history of patients with P/LP germ line, per ACMG/AMP criteria, causative of a congenital syndrome/disorder
ALL, acute lymphoblastic leukemia; APCAs, antiparietal cell antibodies; CMML, chronic myelomonocytic leukemia; DBA, Diamond-Blackfan anemia; F, female; FA, Fanconi anemia; FPD, familial platelet disorder; GIST, gastrointestinal stromal tumor; ID, identification number; M, male; MDS-EB, MDS with excess blasts; MDS-MLD, myelodysplastic syndrome with multilineage dysplasia; MDS/MPN-U, MDS/myeloproliferative neoplasm unclassifiable; NF, neurofibromatosis; NS, Noonan syndrome; SDS, Shwachman-Diamond syndrome; SCN, severe congenital neutropenia.
*The same FANCA variant was detected in heterozygosity in the son who was not affected. The same GATA1 variant was detected in a sister with primary myelofibrosis. The same RUNX1 variant was detected in the brother affected with CMML. Both SBDS variants were detected in the brother with isolated neutropenia.
Physicians - maximum of 1.00 AMA PRA Category 1 Credit(s)™
ABIM Diplomates - maximum of 1.00 ABIM MOC points
This activity is intended for hematologists, oncologists, internists, geneticists, and other clinicians caring for adults with cytopenias and hypoplastic bone marrow who may have germline genetic predisposition to myeloid neoplasms.
The goal of this activity is for members of the healthcare team to be better able to describe prevalence and phenotypic expressivity of germline variants predisposing to myeloid neoplasms among adults with cytopenia and hypoplastic bone marrow, based on a large cohort study using germline and somatic targeted sequencing.
Upon completion of this activity, participants will:
Medscape, LLC requires every individual in a position to control educational content to disclose all financial relationships with ineligible companies that have occurred within the past 24 months. Ineligible companies are organizations whose primary business is producing, marketing, selling, re-selling, or distributing healthcare products used by or on patients.
All relevant financial relationships for anyone with the ability to control the content of this educational activity are listed below and have been mitigated. Others involved in the planning of this activity have no relevant financial relationships.
Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to 1.0 MOC points in the American Board of Internal Medicine’s (ABIM) Maintenance of Certification (MOC) program. Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider’s responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC credit.
For questions regarding the content of this activity, contact the accredited provider for this CME/CE activity noted above. For technical assistance, contact [email protected]
There are no fees for participating in or receiving credit for this online educational activity. For information on applicability
and acceptance of continuing education credit for this activity, please consult your professional licensing board.
This activity is designed to be completed within the time designated on the title page; physicians should claim only those
credits that reflect the time actually spent in the activity. To successfully earn credit, participants must complete the
activity online during the valid credit period that is noted on the title page. To receive AMA PRA Category 1 Credit™, you must receive a minimum score of 70% on the post-test.
Follow these steps to earn CME/CE credit*:
You may now view or print the certificate from your CME/CE Tracker. You may print the certificate, but you cannot alter it.
Credits will be tallied in your CME/CE Tracker and archived for 6 years; at any point within this time period, you can print
out the tally as well as the certificates from the CME/CE Tracker.
*The credit that you receive is based on your user profile.
CME / ABIM MOC Released: 8/17/2023
Valid for credit through: 8/17/2024, 11:59 PM EST
processing....
Systematic studies of germ line genetic predisposition to myeloid neoplasms in adult patients are still limited. In this work, we performed germ line and somatic targeted sequencing in a cohort of adult patients with hypoplastic bone marrow (BM) to study germ line predisposition variants and their clinical correlates. The study population included 402 consecutive adult patients investigated for unexplained cytopenia and reduced age-adjusted BM cellularity. Germ line mutation analysis was performed using a panel of 60 genes, and variants were interpreted per the American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines; somatic mutation analysis was performed using a panel of 54 genes. Of the 402 patients, 27 (6.7%) carried germ line variants that caused a predisposition syndrome/disorder. The most frequent disorders were DDX41-associated predisposition, Fanconi anemia, GATA2-deficiency syndrome, severe congenital neutropenia, RASopathy, and Diamond-Blackfan anemia. Eighteen of 27 patients (67%) with causative germ line genotype were diagnosed with myeloid neoplasm, and the remaining with cytopenia of undetermined significance. Patients with a predisposition syndrome/disorder were younger than the remaining patients and had a higher risk of severe or multiple cytopenias and advanced myeloid malignancy. In patients with myeloid neoplasm, causative germ line mutations were associated with increased risk of progression into acute myeloid leukemia. Family or personal history of cancer did not show significant association with a predisposition syndrome/disorder. The findings of this study unveil the spectrum, clinical expressivity, and prevalence of germ line predisposition mutations in an unselected cohort of adult patients with cytopenia and hypoplastic BM.
Genetic germ line variants are increasingly recognized as predisposing factors to myeloid neoplasms and aplastic anemia (AA), and a category of myeloid neoplasms with germ line predisposition was included in the 2017 World Health Organization classification of hematopoietic tumors that comprises cases of myelodysplastic syndromes (MDSs), myelodysplastic/myeloproliferative neoplasms, and acute myeloid leukemia (AML) that occur with the background of a germ line mutation.[1,2] According to this classification and recent proposals for revision, the underlying genetic defects or syndromes are classified based on the absence or presence of a preexisting clinical phenotype, reflecting variable penetrance and clinical expressivity of these conditions.[1,3,4]
The available studies on the frequency of germ line predisposition in patients with myeloid malignancies or bone marrow failure (BMF) mainly focused on cohorts of young adults who were selected based on clinical suspicion or family history.[5,6] Although germ line testing is increasingly performed in the work-up of patients with suspected myeloid neoplasm and expert guidance has been offered,[2,7–10] systematic studies of the frequency of germ line predisposition in adult patients with MDS or AA are limited, and reliable clinical indicators driving appropriate genetic testing are lacking.[11–14] Although the age at diagnosis is an important criterion to identify individuals at risk,[15] recent data consistently indicate that selected conditions, such as DDX41-associated susceptibility to myeloid neoplasms, may result in phenotypic expression in older individuals.[16–21]
A hypoplastic bone marrow is a common feature of adult patients with late onset, inherited BMF syndromes.[15] Bone marrow hypocellularity also characterizes acquired hematologic disorders, including AA and hypoplastic MDS, a condition with variable clinical features and outcome,[22] which has recently been recognized as a distinct disease subtype.[4] Bone marrow hypocellularity may lead to difficulties in the differential diagnosis, and, accordingly, it has also been reported in cytopenias of undetermined significance.[22]
In this work, we performed germ line and somatic targeted sequencing in a large, well-annotated cohort of adult patients with cytopenia and hypoplastic bone marrow to define prevalence and phenotypic expressivity of germ line variants predisposing to myeloid neoplasms.
