Nordic Guidelines for Germline Predisposition to Myeloid Neoplasms in Adults: Recommendations for Genetic Diagnosis, Clinical Management and Follow-up

Baliakas, Panagiotis; Tesi, Bianca; Wartiovaara‐Kautto, Ulla; Stray-Pedersen, Asbjørg; Friis, Lone Smidstrup; Dybedal, Ingunn; Hovland, Randi; Jahnukainen, Kirsi; Raaschou‐Jensen, Klas; Ljungman, Per; Rustad, Cecilie F.; Lautrup, Charlotte Kvist; Kilpivaara, Outi; Kittang, Astrid Olsnes; Grønbæk, Kirsten; Cammenga, Jörg; Hellström‐Lindberg, Eva; Andersen, Mette Klarskov

doi:10.1097/hs9.0000000000000321

Cited by 57 publications

(41 citation statements)

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“…Based on the findings from our study and the high morbidity and mortality rate reported by Donadieu et al, it is clear that these patients need to be monitored closely. Ideally, allo-HSCT should be performed before they develop malignancies (both solid tumors and hematological malignancies) [37] or severe/recurrent infections causing organ failure. In our opinion, a history of disseminated viral infection, aggressive HPV infection (particular with dysplasia), or myeloid clonal disease is clear indication to consider allo-HSCT [14].…”

Section: Discussionmentioning

confidence: 99%

A Nationwide Study of GATA2 Deficiency in Norway—the Majority of Patients Have Undergone Allo-HSCT

et al. 2021

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Purpose GATA2 deficiency is a rare primary immunodeficiency that has become increasingly recognized due to improved molecular diagnostics and clinical awareness. The only cure for GATA2 deficiency is allogeneic hematopoietic stem cell transplantation (allo-HSCT). The inconsistency of genotype–phenotype correlations makes the decision regarding “who and when” to transplant challenging. Despite considerable morbidity and mortality, the reported proportion of patients with GATA2 deficiency that has undergone allo-HSCT is low (~ 35%). The purpose of this study was to explore if detailed clinical, genetic, and bone marrow characteristics could predict end-point outcome, i.e., death and allo-HSCT. Methods All medical genetics departments in Norway were contacted to identify GATA2 deficient individuals. Clinical information, genetic variants, treatment, and outcome were subsequently retrieved from the patients’ medical records. Results Between 2013 and 2020, we identified 10 index cases or probands, four additional symptomatic patients, and no asymptomatic patients with germline GATA2 variants. These patients had a diverse clinical phenotype dominated by cytopenia (13/14), myeloid neoplasia (10/14), warts (8/14), and hearing loss (7/14). No valid genotype–phenotype correlations were found in our data set, and the phenotypes varied also within families. We found that 11/14 patients (79%), with known GATA2 deficiency, had already undergone allo-HSCT. In addition, one patient is awaiting allo-HSCT. The indications to perform allo-HSCT were myeloid neoplasia, disseminated viral infection, severe obliterating bronchiolitis, and/or HPV-associated in situ carcinoma. Two patients died, 8 months and 7 years after allo-HSCT, respectively. Conclusion Our main conclusion is that the majority of patients with symptomatic GATA2 deficiency will need allo-HSCT, and a close surveillance of these patients is important to find the “optimal window” for allo-HSCT. We advocate a more offensive approach to allo-HSCT than previously described.

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Section: Discussionmentioning

confidence: 99%

A Nationwide Study of GATA2 Deficiency in Norway—the Majority of Patients Have Undergone Allo-HSCT

et al. 2021

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“…The Nordic guidelines established by the Nordic MDS group initially focused on adults with germline predisposition to myeloid neoplasms and are intended for use in clinical practice [27]. They provide most detailed recommendations, based on the recent literature and clinical experience of the group, for the identification of individuals with genetic predisposition for hematological malignancies.…”

Section: Consensus Criteria For the Identification Of Patients With Genetic Predisposition For Hematologic Malignanciesmentioning

confidence: 99%

“…The Nordic guidelines contain very concise and clear recommendations for diagnostic workup, genetic diagnosis, clinical management and follow-up. Most importantly, they see a close collaboration between hematologists and clinical geneticists as mandatory [27]. Genetic counseling should be offered to all patients investigated for potential germline conditions, even if no pathogenic variant is detected.…”

Section: Consensus Criteria For the Identification Of Patients With Genetic Predisposition For Hematologic Malignanciesmentioning

confidence: 99%

“…The screening program is recommended only for patients with (likely) pathogenic variants, but not for variants of unknown significance and should also be offered to family members at risk [27].…”

Section: Recommendations For Screening Of Patients With Genetic Predisposition For Hematologic Malignanciesmentioning

confidence: 99%

“…Only in case of worsening CBC, BM aspirate/biopsy with cytogenetics and a myeloid genetic panel should be performed. An innovative recommendation is to do an annual blood testing for somatic pathogenic variants to follow clonal evolution [27]. Clonal hematopoiesis may be used to determine the time point for early intervention.…”

Section: Recommendations For Screening Of Patients With Genetic Predisposition For Hematologic Malignanciesmentioning

confidence: 99%

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Review of guidelines for the identification and clinical care of patients with genetic predisposition for hematological malignancies

2021

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Since WHO has recognized myeloid neoplasms with germline predisposition as a new entity in 2016, it has become increasingly clear that diagnosing familial leukemia has critical implications for both the patient and his/her family, and that interdisciplinary teams of hematologists and clinical geneticists should provide care for this specific patient group. Here, we summarize consensus criteria for the identification and screening of patients with genetic predisposition for hematologic malignancies, as provided by different working groups, e.g. by the Nordic MDS group and the AACR. In addition to typical clinical features, results from targeted deep sequencing may point to a genetic predisposition. We review strategies to distinguish somatic and germline variants and discuss recommendations for genetic analyses aiming to identify the underlying genetic variant that should follow established quality criteria to detect both SNVs and CNVs and to determine the pathogenicity of genetic variants. To enhance the knowledge about hematologic neoplasms with germline predisposition we recommend archiving clinical and genetic data and archiving them in international registries.

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The clinical phenotype of germline RUNX1 mutations in relation to the accompanying somatic variants and RUNX1 isoform expression

Granados

Barbosa

Baliakas

et al. 2023

Genes Chromosomes & Cancer

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Germline RUNX1 mutations lead to familial platelet disorder with associated myeloid malignancy (FPDMM), characterized by thrombocytopenia, abnormal bleeding, and an elevated risk of developing myelodysplastic neoplasia (MDS) and acute myeloid leukemia (AML) at young age. However, it is not known why or how germline carriers of RUNX1 mutations have a particular propensity to develop myeloid hematologic malignancies, but the acquisition and composition of somatic mutations are believed to initiate and determine disease progression. We present a novel family pedigree that shares a common germline RUNX1R204* variant and exhibits a spectrum of somatic mutations and related myeloid malignancies (MM). RUNX1 mutations are associated with inferior clinical outcome; however, the proband of this family developed MDS with ring sideroblasts (MDS‐RS), classified as a low‐risk MDS subgroup. His relatively indolent clinical course is likely due to a specific somatic mutation in the SF3B1 gene. While the three main RUNX1 isoforms have been ascribed various roles in normal hematopoiesis, they are now being increasingly recognized as involved in myeloid disease. We investigated the RUNX1 transcript isoform patterns in the proband and his sister, who carries the same germline RUNX1R204* variant, and has FPDMM but no MM. We demonstrate a RUNX1a increase in MDS‐RS, as previously reported in MM. Interestingly, we identify a striking unbalance of RUNX1b and ‐c in FPDMM. In conclusion, this report reinforces the relevance of somatic variants on the clinical phenotypic heterogeneity in families with germline RUNX1 deficiency and investigates a potential new role for RUNX1 isoform disequilibrium as a mechanism for development of MM.

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Nordic Guidelines for Germline Predisposition to Myeloid Neoplasms in Adults: Recommendations for Genetic Diagnosis, Clinical Management and Follow-up

Cited by 57 publications

References 60 publications

A Nationwide Study of GATA2 Deficiency in Norway—the Majority of Patients Have Undergone Allo-HSCT

A Nationwide Study of GATA2 Deficiency in Norway—the Majority of Patients Have Undergone Allo-HSCT

Review of guidelines for the identification and clinical care of patients with genetic predisposition for hematological malignancies

The clinical phenotype of germline RUNX1 mutations in relation to the accompanying somatic variants and RUNX1 isoform expression

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