Inherited Bone Marrow Failure Panel

Bone marrow failure (BMF) can be acquired or inherited and is associated with hematologic abnormalities such as single or multi-lineage cytopenias and increased risk for hematologic malignancies. Inherited bone marrow failure (IBMF) is different from acquired bone marrow failure in that patients with IBMF harbor pathogenic germline variants that can be inherited by future generations. It is important to distinguish inherited from acquired bone marrow failure for proper clinical management of patients and their families. Genetic testing for inherited bone marrow failure syndromes (IBMFS) can help identify possible causes of disease that inform decisions regarding appropriate therapies, potential donors for bone marrow transplant, and potential risk for comorbidities (Furutani and Shimamura. 2017. PubMed ID: 28297620). Genetic testing may also reveal at-risk family members who may benefit from genetic testing and specific surveillance strategies. A recent study identified pathogenic germline variants in 18% of adult patients with hematologic malignancies (DiNardo et al. 2016. PubMed ID: 27210295) while another study found pathogenic variants in 29% of adult patients with Hereditary Myelodysplastic Syndrome / Acute Myeloid Leukemia (Churpek et al. 2015. PubMed ID: 26492932). These studies suggest that pathogenic germline variants may account for a larger fraction of hematologic malignancies than was previously thought.

IBMFS comprise a heterogeneous group of disorders characterized by hematological abnormalities which may or may not be accompanied by other clinical manifestations including physical abnormalities, developmental delay, and solid tumor formation. There is considerable phenotypic overlap among the IBMFS, and determining a proper diagnosis is complicated by the fact that many patients do not have a strong family history of disease nor present classical stigmata or distinguishing physical conditions related to IBMFS. For example, in one study, 8 out of 71 (~11.3%) patients with a clinical diagnosis of idiopathic bone marrow failure or myelodysplastic syndrome were found to harbor pathogenic germline variants in IBMF-related genes (Zhang et al. 2015. PubMed ID: 25239263). However, none of the 8 patients had typical clinical symptoms or laboratory findings consistent with IBMF syndromes, and only 4 patients had a family history of disease (Zhang et al. 2015. PubMed ID: 25239263). In addition, out of the 85 genes sequenced for the 71 patients in Zhang et al., pathogenic variants were found in only 4 genes. In another study, 72 genes were sequenced among a cohort of bone marrow failure patients. In this study, causal variants were found in 59% of patients (in 24 different genes) with known IBMFS such as Fanconi anemia, whereas causal variants were found in 18% of patients (in 13 different genes) with unclassified IBMFS (Ghemlas et al. 2015. PubMed ID: 26136524). In yet another study, a causal or likely causal variant was identified in a 48% of BMF patients in a total of 28 genes (Bluteau et al. 2018. PubMed ID: 29146883). These data suggest that simultaneous genetic testing for a large subset of IBMF-related genes may provide the most efficient approach for establishing an accurate and timely diagnosis.

This panel includes genes that are known to be associated with bone marrow failure disorders and increased risk for hematologic malignancies. IBMFS are inherited in either an autosomal dominant (AD), autosomal recessive (AR), or X-linked (XL) manner. This test may help in the differential diagnosis and rule out particular syndromes through simultaneous analysis of many genes associated with inherited bone marrow failure.

Some of the more frequently occurring and well known IBMFS involve genes whose products are associated with DNA repair, telomere maintenance, and ribosomal biogenesis. Therefore, this panel test includes genes associated with Fanconi anemia (Rosenberg et al. 2003. PubMed ID: 12393424), Shwachman Diamond syndrome (Dall’Oca et al. 2012. PubMed ID: 22201042), Diamond Blackfan anemia (Gazda and Sieff. 2006. PubMed ID: 16942586), and dyskeratosis congenita (Kirwan and Dokal. 2008. PubMed ID: 18005359). Highly penetrant germline variants have been identified that can explain up to 95% of Fanconi anemia cases, 95% of Shwachman-Diamond syndrome cases, 50% of Diamond Blackfan anemia cases, and 70% of dyskeratosis congenita cases (Khincha and Savage. 2013. PubMed ID: 24246701).

In addition to these disorders, pathogenic variants in many other genes associated with a wide range of disorders have also been reported in patients with IBMF. This test involves sequence and copy number variant analysis of genes that represent some of the more frequent and well-documented causes of inherited bone marrow failure.

See individual gene summaries for more information about molecular biology of gene products and spectra of pathogenic variants.

The sensitivity of this test varies, though causal or likely causal variants have been identified in up to 48% of patients with suspected IBMF in studies that included analysis of a large number of IBMF-related genes (Bluteau et al. 2018. PubMed ID: 29146883). The sensitivity is reported to increase, up to 59%, when a patient is diagnosed with a known IBMFS (Ghemlas et al. 2015. PubMed ID: 26136524).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel typically provides 98.8% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

DNA analysis of the PMS2 gene is complicated due to the presence of several pseudogenes. One particular pseudogene, PMS2CL, has high sequence similarity to PMS2 exons 11 to 15 (Blount et al. 2018. PubMed ID: 29286535). Next-generation sequencing (NGS) based copy number variant (CNV) analysis can detect deletions and duplications involving exons 1 to 10 of PMS2 but has less sensitivity for exons 11 through 15. Multiplex ligation-dependent probe amplification (MLPA) can detect deletions and duplications involving PMS2 exons 1 to 15. Of note, PMS2 MLPA is not typically included in this test but can be ordered separately using test code 6062, if desired. 

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).