Hereditary Myeloid Neoplasms Panel, Sequencing

Regions of low coverage and reported variants are confirmed by Sanger sequencing as necessary

Indication for Testing
  • Assesses for inherited/germline DNA variants associated with familial myeloid dysplasias and malignancies
  • NOT intended to detect somatic variants
  • Cultured skin fibroblasts are the preferred sample type to assess the germline status of patients suspected of a hereditary predisposition to myeloid neoplasms
  • ARUP will perform culturing services for skin samples at an additional charge
Indication for Testing
  • Recommended test for a known familial sequencing variant previously identified in a family member
  • A copy of the affected family member's test result documenting the familial variant is required

While the majority of myelodysplastic syndromes (MDSs), myeloid neoplasms, and malignancies occur sporadically due to somatic mutations, a portion are due to inherited or hereditary predispositions. Identification of an inherited predisposition can affect therapy options and surveillance strategies, as well as lead to testing of biological relatives, and inform stem cell transplant donor selection. Individuals with an inherited predisposition to myeloid neoplasms may present at a younger age, have more than one first-degree relative with MDS/acute myeloid leukemia (AML), and/or a family history of physical findings associated with a known cancer predisposition syndrome. The preferred specimen type to assess the germline status of patients suspected of, or at risk for, a hereditary predisposition to myeloid neoplasms is cultured skin fibroblasts in order to exclude somatic variants and to avoid false negatives due to peripheral blood somatic mosaicism. ARUP will perform culturing services for skin samples at an additional charge.

Disease Overview

Symptoms/Associated Disorders

  • Pathogenic germline variants in several genes have been associated with familial MDS and acute leukemias.
    • Inherited myeloid neoplasm predisposition genes included in this panel that often do NOT present with cytopenia, dysplasia, or other organ dysfunction prior to myeloid malignancy:
      • CEBPA
      • DDX41
    • Inherited myeloid neoplasm predisposition genes included in this panel that often DO present with preexisting cytopenia(s) or other organ dysfunction prior to myeloid malignancy:
      • ANKRD26
      • ETV6
      • GATA2
      • RUNX1
      • SAMD9
      • SAMD9L
      • SRP72
    • Inherited myeloid neoplasm predisposition genes that also predispose to other solid tumors/cancers or syndromic findings:
      • ATM
      • BLM
      • CBL
      • GATA1
      • KRAS
      • NBN
      • PTPN11
      • TP53
    • Inherited bone marrow failure genes:
      • ELANE
      • TERC
      • TERT
  • For a complete list of genes and associated disorders, please see the Genes Tested table.

Epidemiology

  • In the general population, MDS and AML occur in approximately 4.5 and 3.7 per 100,000 individuals, respectively. 
  • MDS is rare in children and young adults; approximately 50% of childhood MDS is associated with an inherited cause. 

Inheritance

Variable, see Genes Tested table

Test Description

See Genes Tested table for genes included in this panel.

Clinical Sensitivity

Variable, dependent on phenotype/condition

  • Pathogenic germline genetic variants have been identified in approximately 18% of families with hereditary MDS/acute leukemia or other hematologic malignancy.  

Contraindications for Ordering

  • Should not be ordered to detect somatic variants associated with malignancy because sensitivity for mosaic variants is low with methodology used for germline assays.
  • Individuals with hematological malignancy and/or a previous allogenic bone marrow transplant should not undergo molecular genetic testing on a peripheral blood specimen. Testing of cultured skin fibroblasts is required for accurate interpretation of test results.
  • When a relative has a previously identified germline pathogenic variant, see Familial Mutation, Targeted Sequencing.

Limitations

  • A negative result does not exclude a diagnosis of cancer nor a heritable form of myeloid neoplasm.
  • Diagnostic errors can occur due to rare sequence variations.
  • Interpretation of the test result may be impacted if the patient has had an allogeneic stem cell transplantation.
  • This assay is not intended to detect somatic variants associated with hematologic malignancy, although such variants may be detected.
  • This assay cannot definitively distinguish the germline or somatic origin of detected variants when the patient has a hematologic malignancy, and the assay was performed on blood or other tissue that may be contaminated by malignant cells. In such instances, confirmation of germline variant status by testing of cultured skin fibroblasts is strongly recommended.
  • The following will not be evaluated:
    • Variants outside the coding regions and intron-exon boundaries of targeted gene(s)
    • Regulatory region and deep intronic variants, unless specifically targeted for their clinical relevance
    • Large deletions/duplications in the targeted genes
    • Noncoding transcripts
    • The following exons are not sequenced due to technical limitations of the assay:
      • ANKRD26 (NM_014915) exon 19
      • PTPN11 (NM_002834) exon 9
      • SRP72 (NM_006947) exon 19
  • The following may not be detected:
    • Deletions/duplications/insertions of any size by massively parallel sequencing
    • Some variants due to technical limitations in the presence of pseudogenes, or repetitive or homologous regions
    • Low-level somatic variants, including those that have undergone somatic reversion

Analytical Sensitivity

Variant Class Analytical Sensitivity (PPA) Estimatea (%) Analytical Sensitivity (PPA) 95% Credibility Regiona (%)

SNVs

99.2

96.9-99.4

Deletions 1-10 bp

93.8

84.3-98.2

Deletions 11-44 bp

99.9

87.8-100

Insertions 1-10 bp

94.8

86.8-98.5

Insertions 11-23 bp

99.9

62.1-100

aGenes included on this test are a subset of a larger methods-based validation from which the PPA values are derived.

bp, base pairs; PPA, positive percent agreement; SNVs, single nucleotide variants

Genes Tested

Gene MIM Number Inherited Disorder, Hematological Disease Associations, Cancer Predispositions Inheritance

ANKRD26 

610855

ANKRD26-related thrombocytopenia

MDS

Leukemia

AD

ATM  

607585

Ataxia-telangiectasia

Leukemia

Lymphoma

AR

Breast cancer

Pancreatic cancer

AD

BLM 

604610

Bloom syndrome

Leukemia

Lymphoma

Increased frequency of sister-chromatid exchanges (SCEs)

AR

CBL

165360

Juvenile myelomonocytic leukemia (JMML)

Noonan syndrome-like disorder

AD

CEBPA 

116897

CEBPA-associated AML

AD

DDX41 

608170

Adult onset MDS/AML, with or without macrocytosis or other cytopenias

Chronic myeloid leukemia (CML)

Non-Hodgkin or Hodgkin lymphoma

AD

ELANE 

130130

ELANE-related neutropenia

Congenital or cyclic neutropenia

Severe or recurrent infections

AD

ETV6  

600618

MDS/AML

Thrombocytopenia

Red cell macrocytosis

AD

GATA1 

305371

GATA1-related x-linked cytopenia

Thrombocytopenia and/or platelet dysfunction

Anemia

Mild beta thalassemia

Neutropenia

Congenital erythropoietic porphyria (CEP)

X-LR

GATA2  

137295

MDS/AML

Cytopenias

Chronic myelomonocytic leukemia (CMML)

Frequent infections/immunodeficiency

Pulmonary alveolar proteinosis

Lymphedema

Sensorineural hearing loss

AD

KRAS  

190070

Noonan syndrome

Cardiofaciocutaneous (CFC) syndrome

Costello syndrome

JMML

AD

NBN  

602667

Nijmegen breakage syndrome (NBS)

Aplastic anemia

Acute lymphoblastic leukemia (ALL)

AR

Breast cancer

AD

PTPN11 

176876

Noonan syndrome

LEOPARD syndrome

JMML

Metachondromatosis

AD

RUNX1

151385

Familial platelet disorder with associated myeloid malignancy (FPDMM)

MDS/AML

Thrombocytopenia

AD

SAMD9

610456

MIRAGE Syndrome

MDS sometimes accompanied by loss of chromosome 7

AD

Normophosphatemic familial tumoral calcinosis (NFTC)

AR

SAMD9L  

611170

SAMD9L-related ataxia-pancytopenia syndrome (ATXPC)

MDS/leukemia associated with monosomy 7

Somatic revertant mosaicism associated with milder disease

Cerebellar ataxia

Immunodeficiency

AD

SRP72

602122

MDS

Aplastic anemia/bone marrow failure

Hearing loss

AD

TERC 

602322

Dyskeratosis congenita

Aplastic anemia/bone marrow failure

Shortened telomeres

Pulmonary fibrosis

Somatic revertant mosaicism reported

AD

TERT 

187270

Dyskeratosis congenita

MDS/AML

Aplastic anemia/bone marrow failure

Shortened telomeres

Cutaneous malignant melanoma

Pulmonary fibrosis

AD

Dyskeratosis congenita (severe)

AR

TP53  

191170

Li-Fraumeni syndrome (LFS)

Leukemia

Multiple solid tumors (sarcoma, breast, brain)

AD

AD, autosomal dominant; AR, autosomal recessive; X-LR, X-linked recessive

References

  1. GeneReviews - Bloom Syndrome

    Flanagan M, Cunniff CM. Bloom syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews, University of Washington; 1993-2020. [Last Update: Feb 2019; Accessed: May 2020]

    Online
  2. GeneReviews - Noonan syndrome

    Allanson JE, Roberts AE. Noonan syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al, editors. GeneReviews, University of Washington; 1993-2020. [Last revision: Aug 2019; Accessed: Aug 2020]

    Online