Bone Marrow Failure Syndrome Panel

128 gene panel that includes assessment of non-coding variants

Ideal for patients with a clinical suspicion of inherited bone marrow failure syndromes. The genes on this panel are included in the Comprehensive Hematology Panel.

Analysis methods Availability Number of genes Test code CPT codes
4 weeks 32 GHC0103 SEQ 81216
SEQ 81406
SEQ 81408
DEL/DUP 81479


Sample requirements:

  • EDTA blood, min. 1 ml
  • Purified DNA, min. 3μg
  • Saliva (Oragene DNA OG-500 kit)

Label the sample tube with your patient’s name, date of birth and the date of sample collection. Note that we do not accept DNA samples isolated from formalin-fixed paraffin-embedded (FFPE) tissue.


Inherited bone marrow failure syndromes (IBMFS) are a diverse set of genetic disorders characterized by the inability of the bone marrow to produce sufficient circulating blood cells. Bone marrow failure can affect all blood cell lineages causing clinical symptoms similar to aplastic anemia, or be restricted to one or two blood cell lineages. The clinical presentation may include thrombocytopenia or neutropenia. Hematological manifestations may be accompanied by physical features such as short stature and abnormal skin pigmentation in Fanconi anemia and dystrophic nails, lacy reticular pigmentation and oral leukoplakia in dyskeratosis congenita. Patients with IBMFS have an increased risk of developing cancer—either hematological or solid tumors. Early and correct disease recognition is important for management and surveillance of the diseases. Currently, accurate genetic diagnosis is essential to confirm the clinical diagnosis. The most common phenotypes that are covered by the panel are Fanconi anemia, Diamond-Blackfan anemia, dyskeratosis congenita, Shwachman-Diamond syndrome and WAS-related disorders.

Panel Content

Genes in the Bone Marrow Failure Syndrome Panel and their clinical significance

Gene Associated phenotypes Inheritance ClinVar HGMD
ACDDyskeratosis congenita, autosomal dominant 6, Dyskeratosis congenita, autosomal recessive 7AD/AR28
ACTBBaraitser-Winter syndromeAD4654
AK2Reticular dysgenesisAR1417
AP3B1Hermansky-Pudlak syndromeAR1431
ATMBreast cancer, Ataxia-TelangiectasiaAD/AR8601026
ATRCutaneous telangiectasia and cancer syndrome, Seckel syndromeAD/AR818
BLMBloom syndromeAR91107
BLOC1S3Hermansky-Pudlak syndromeAR22
BLOC1S6Hermansky-Pudlak syndromeAR11
BRAFLEOPARD syndrome, Noonan syndrome, Cardiofaciocutaneous syndromeAD13565
BRCA1Pancreatic cancer, Breast-ovarian cancer, familialAD25602361
BRCA2Fanconi anemia, Medulloblastoma, Glioma susceptibility, Pancreatic cancer, Wilms tumor, Breast-ovarian cancer, familialAD/AR29592364
BRIP1Fanconi anemia, Breast cancerAD/AR182166
CBLNoonan syndrome-like disorder with or without juvenile myelomonocytic leukemiaAD2338
CDKN2AMelanoma, familial, Melanoma-pancreatic cancer syndromeAD81230
CEBPAAcute myeloid leukemia, familialAD1510
CLPB3-methylglutaconic aciduria with cataracts, neurologic involvement, and neutropenia (MEGCANN)AR2525
CSF2RASurfactant metabolism dysfunction, pulmonaryXL217
CSF3RNeutrophilia, hereditaryAD1010
CTC1Cerebroretinal microangiopathy with calcifications and cystsAR1630
CTSCPeriodontitis, juvenile, Haim-Munk syndrome, Papillon-Lefevre syndromeAR1692
CXCR4Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndromeAD515
DDX41Familial myeloproliferative/lymphoproliferative neoplasms, multiple types, susceptibility toAD814
DKC1Hoyeraal-Hreidarsson syndrome, Dyskeratosis congenitaXL4771
DNAJC21Bone marrow failure syndrome 3AR58
DTNBP1Hermansky-Pudlak syndromeAR22
EPCAMDiarrhea 5, with tufting enteropathy, congenital, Colorectal cancer, hereditary nonpolyposisAD/AR2675
ERCC4Fanconi anemia, Xeroderma pigmentosum, XFE progeroid syndromeAR1159
ERCC6L2Bone marrow failure syndrome 2AR42
ETV6Thrombocytopenia 5AD1033
FADDInfections, recurrent, with encephalopathy, hepatic dysfunction, and cardiovascular malformationsAR21
FANCAFanconi anemiaAR76541
FANCBFanconi anemiaXL1020
FANCCFanconi anemiaAR7058
FANCD2Fanconi anemiaAR1457
FANCEFanconi anemiaAR516
FANCFFanconia anemiaAR716
FANCGFanconi anemiaAR1389
FANCIFanconi anemiaAR1243
FANCLFanconi anemiaAR722
FANCMFanconi anemiaAR249
FASAutoimmune lymphoproliferative syndromeAD/AR28131
FASLGAutoimmune lymphoproliferative syndrome, type IBAD39
G6PC3Neutropenia, severe congenital, Dursun syndromeAR1237
GATA1Anemia, without thrombocytopenia, Thrombocytopenia with beta-thalessemia,, Dyserythropoietic anemia with thrombocytopeniaXL1915
GATA2Myelodysplastic syndrome, Chronic neutropenia associated with monocytopenia, evolving to myelodysplasia and acute myeloid leukemia, Acute myeloid leukemia, Emberger syndrome, ImmunodeficiencyAD26105
GFI1Neutropenia, severe congenital, 2 autosomal dominant, Neutropenia, nonimmune chronic idiopathic, of adultsAD25
HAX1Neutropenia, severe congenitalAR919
HPS1Hermansky-Pudlak syndromeAR2845
HPS3Hermansky-Pudlak syndromeAR815
HPS4Hermansky-Pudlak syndromeAR1618
HPS5Hermansky-Pudlak syndromeAR2027
HPS6Hermansky-Pudlak syndromeAR1326
HRASCostello syndrome, Congenital myopathy with excess of muscle spindlesAD4129
IKZF1Immunodeficiency, common variable, 13AD712
ITKLymphoproliferative syndromeAR410
JAGN1Neutropenia, severe congenitalAR88
KRASNoonan syndrome, Cardiofaciocutaneous syndromeAD6134
LAMTOR2Immunodeficiency due to defect in MAPBP-interacting proteinAR11
LYSTChediak-Higashi syndromeAR4687
MAGT1Immunodeficiency, with magnesium defect, Epstein-Barr virus infection and neoplasia, Mental retardation, X-linked 95XL514
MAP2K1Cardiofaciocutaneous syndromeAD4521
MAP2K2Cardiofaciocutaneous syndromeAD2135
MKL1Primary immunodeficiencyAR3
MLH1Muir-Torre syndrome, Endometrial cancer, Mismatch repair cancer syndrome, Colorectal cancer, hereditary nonpolyposisAD/AR8291174
MPLThrombocythemia, Amegakaryocytic thrombocytopeniaAD/AR2250
MSH2Muir-Torre syndrome, Endometrial cancer, Colorectal cancer, hereditary nonpolyposis,, Mismatch repair cancer syndromeAD/AR8741224
MSH6Endometrial cancer, Mismatch repair cancer syndrome, Colorectal cancer, hereditary nonpolyposisAD/AR580569
MYO5AGriscelli syndromeAR56
NBNBreast cancer, Nijmegen breakage syndromeAD/AR14187
NF1Watson syndrome, Neurofibromatosis, Neurofibromatosis-Noonan syndromeAD8102703
NHP2Dyskeratosis congenitaAR33
NOP10Dyskeratosis congenitaAR11
NRASNoonan syndromeAD3114
PALB2Fanconi anemia, Pancreatic cancer, Breast cancerAD/AR422358
PAX5Pre-B cell acute lymphoblastic leukemiaAD5
PGM3Immunodeficiency 23AR1314
PMS2Mismatch repair cancer syndrome, Colorectal cancer, hereditary nonpolyposisAD/AR259324
PRF1Lymphoma, non-Hodgkin, Aplastic anemia, adult-onset, Hemophagocytic lymphohistiocytosisAR22172
PTPN11Noonan syndrome, MetachondromatosisAD128139
RAB27AGriscelli syndrome, Elejalde syndromeAR1753
RAC2Neutrophil immunodeficiency syndromeAD23
RAD51CFanconi anemia, Breast-ovarian cancer, familialAD/AR92112
RBM8AThrombocytopenia - absent radiusAD/AR410
RECQL4Baller-Gerold syndrome, RAPADILINO syndrome, Rothmund-Thomson syndromeAR53100
RIT1Noonan syndromeAD2025
RPL5Diamond-Blackfan anemiaAD1472
RPL11Diamond-Blackfan anemiaAD941
RPL15Diamond-Blackfan anemiaAD22
RPL35ADiamond-Blackfan anemiaAD514
RPS7Diamond-Blackfan anemiaAD29
RPS10Diamond-Blackfan anemiaAD35
RPS19Diamond-Blackfan anemiaAD22168
RPS24Diamond-Blackfan anemiaAD59
RPS26Diamond-Blackfan anemiaAD1030
RPS29Diamond-Blackfan anemiaAD43
RTEL1Pulmonary fibrosis and/or bone marrow failure, Dyskeratosis congenitaAD/AR3345
RUNX1Platelet disorder, familial, with associated myeloid malignancyAD2592
SAMD9Mirage syndrome, Tumoral calcinosis, normophosphatemicAR717
SAMD9LAtaxia-pancytopenia syndromeAD44
SBDSAplastic anemia, Shwachman-Diamond syndrome, Severe spondylometaphyseal dysplasiaAD/AR2190
SH2D1ALymphoproliferative syndromeXL15126
SLC37A4Glycogen storage diseaseAR29109
SLX4Fanconi anemiaAR1454
SMARCD2Specific granule defiency 2AR31
SOS1Noonan syndromeAD4567
SRP72Bone marrow failure syndrome 1AD22
STX11Hemophagocytic lymphohistiocytosis, familialAR618
STXBP2Hemophagocytic lymphohistiocytosis, familialAR969
TERCAplastic anemia, Pulmonary fibrosis and/or bone marrow failure, telomere-related, Dyskeratosis congenitaAD3867
TERTAplastic anemia, Pulmonary fibrosis and/or bone marrow failure, telomere-related, Dyskeratosis congenitaAD/AR43152
THPOThrombocythemia 1AD59
TINF2Revesz syndrome, Dyskeratosis congenitaAD2337
TP53Colorectal cancer, Li-Fraumeni syndrome, Ependymoma, intracranial, Choroid plexus papilloma, Breast cancer, familial, Adrenocortical carcinoma, Osteogenic sarcoma, Hepatoblastoma, Non-Hodgkin lymphomaAD372481
UNC13DHemophagocytic lymphohistiocytosis, familialAR15156
USB1Poikiloderma with neutropeniaAR2322
VPS13BCohen syndromeAR248199
VPS45Neutropenia, severe congenital, 5, autosomal recessiveAR34
WASNeutropenia, severe congenital, Thrombocytopenia, Wiskott-Aldrich syndromeXL53435
WIPF1Wiskott-Aldrich syndrome 2AR22
WRAP53Dyskeratosis congenitaAR75
XIAPLymphoproliferative syndromeXL983
XRCC2Hereditary breast cancerAD/AR1020

Non-coding variants covered by the panel

Gene Genomic location HG19 HGVS RefSeq RS-number

Panel Update

Genes added

  • ACD
  • ANKRD26
  • BRAF
  • BRCA1
  • CBL
  • CLPB
  • CSF3R
  • DDX41
  • DNAJC21
  • ERCC6L2
  • ETV6
  • FADD
  • GFI1
  • GINS1
  • IKZF1
  • MAP2K1
  • MAP2K2
  • MKL1
  • PAX5
  • PGM3
  • RAC2
  • RBM8A
  • RIT1
  • SAMD9
  • SAMD9L
  • SLC37A4
  • SOS1
  • SRP72
  • THPO
  • VPS13B
  • VPS45
  • WDR1
  • WIPF1

Genes removed

  • RPS17
  • TCIRG1

Test strength and Limitations

The strengths of this test include:

  • CAP and ISO-15189 accreditations covering all operations at GHC Genetics including all Whole Exome Sequencing, NGS panels and confirmatory testing
  • CLIA-certified personnel performing clinical testing in a CLIA-certified laboratory
  • Powerful sequencing technologies, advanced target enrichment methods and precision bioinformatics pipelines ensure superior analytical performance
  • Careful construction of clinically effective and scientifically justified gene panels
  • Our Nucleus online portal providing transparent and easy access to quality and performance data at the patient level
  • Our publically available analytic validation demonstrating complete details of test performance
  • ~1,500 non-coding disease causing variants in GHC WES assay (please see below ‘Non-coding disease causing variants covered by this panel’)
  • Our rigorous variant classification based on modified ACMG variant classification scheme
  • Our systematic clinical interpretation workflow using proprietary software enabling accurate and traceable processing of NGS data
  • Our comprehensive clinical statements

Test limitations The following exons are not included in the panel as they are not sufficiently covered with high quality sequence reads: *PPA2* (11, 12). Genes with partial, or whole gene, segmental duplications in the human genome are marked with an asterisk if they overlap with the UCSC pseudogene regions. The technology may have limited sensitivity to detect variants in genes marked with these symbols (please see the Panel content table above).

This test does not detect the following:
  • Complex inversions
  • Gene conversions
  • Balanced translocations
  • Mitochondrial DNA variants
  • Repeat expansion disorders unless specifically mentioned
  • Non-coding variants deeper than ±20 base pairs from exon-intron boundary unless otherwise indicated (please see above Panel Content / non-coding variants covered by the panel).

This test may not reliably detect the following:
  • Low level mosaicism
  • Stretches of mononucleotide repeats
  • Indels larger than 50bp
  • Single exon deletions or duplications
  • Variants within pseudogene regions/duplicated segments

The sensitivity of this test may be reduced if DNA is extracted by a laboratory other than GHC Genetics.

For additional information, please refer to the Test performance section and see our Analytic Validation.

Test Performance

The GHC Genetics panel covers classical genes associated with Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia (CPVT), cardiac arrest underlying cardiac condition, cardiac arrest cause unspecified, syncope and collapse, abnormal ECG, Long QT syndrome, arrhythmogenic right ventricular cardiomyopathy (ARVC) and Short QT syndrome. The genes on the panel have been carefully selected based on scientific literature, mutation databases and our experience.

Our panels are sliced from our high-quality whole exome sequencing data. Please see our sequencing and detection performance table for different types of alterations at the whole exome level (Table).

Assays have been validated for different starting materials including EDTA-blood, isolated DNA (no FFPE), saliva and dry blood spots (filter card) and all provide high-quality results. The diagnostic yield varies substantially depending on the assay used, referring healthcare professional, hospital and country. GHC Genetics’ Plus Analysis (Seq+Del/Dup) maximizes the chance to find a molecular genetic diagnosis for your patient although Sequence Analysis or Del/Dup Analysis may be a cost-effective first line test if your patient’s phenotype is suggestive of a specific mutation type.

Performance of GHC Genetics Whole Exome Sequencing (WES) assay.
All individual panels are sliced from WES data.

Sensitivity % (TP/(TP+FN) Specificity %
Single nucleotide variants 99.65% (412,456/413,893) >99.99%
Insertions, deletions and indels by sequence analysis
1-10 bps 96.94% (17,070/17,608) >99.99%
11-50 bps 99.07% (957/966) >99.99%
Copy number variants (exon level dels/dups)
Clinical samples (small CNVs, n=52)
1 exon level deletion 92.3% (24/26) NA
2 exons level deletion/duplication 100.0% (11/11) NA
3-7 exons level deletion/duplication 93.3% (14/15) NA
Microdeletion/-duplication sdrs (large CNVs, n=37))
Size range (0.1-47 Mb) 100% (37/37)
Simulated CNV detection
2 exons level deletion/duplication 90.98% (7,357/8,086) 99.96%
5 exons level deletion/duplication 98.63% (7,975/8,086) 99.98%
The performance presented above reached by WES with the following coverage metrics
Mean sequencing depth at exome level 174x
Nucleotides with >20x sequencing coverage (%) 99.4%

Our mission is to improve the quality of the sequencing process and each modification is followed by our standardized validation process. Detection of Del/Dup of several genes is by MLPA analysis (MS Holland). All genes are performed by CNV analysis through the genome depending on exon size, sequencing coverage and sequence content. We have validated the assays for different starting materials including isolated DNA from EDTA blood that provide high-quality results.

Bioinformatics & clinical interpretation

The sequencing data generated in our laboratory is analysed by our bioinformatic pipeline, integrating state-of-the art algorithms and industry-standard software solutions. We use also JSI medical systems software for sequencing data analysis. JSI medical systems is a certified system offering sophisticated bioinformatic software solutions covering a wide field of sequencing techniques.

Incorporation of rigorous quality control steps throughout the workflow of the pipeline ensures the consistency, validity and accuracy of results.

Every pathogenic or probably pathogenic variant is confirmed by the Sanger sequencing method. Sanger sequencing is also used occasionally with other variants reported in the statement. In the case of variant of uncertain significance (VUS) we do not recommend risk stratification based on the genetic finding. The analysis of detected variants was performed on the basis of the reference database of polymorphisms and international mutation databases: UMD, LOVD and ClinVar.

The consequence of variants in coding and splice regions are estimated using Alamut software. The Alamut database contains more than 28000 coding genes, non-protein coding genes and pseudogenes. This database (shared with the high throughput annotation engine for NGS data, Alamut Batch) is frequently updated. Information comes from different public databases such as NCBI, EBI, and UCSC, as well as other sources including gnomAD, ESP, Cosmic, ClinVar, or HGMD and CentoMD (for those a separate subscription from Qiagen/Biobase and Centogene respectively is required). Alamut Visual finds information about nucleotide conservation data through many vertebrates’ species, with the phastCons and phyloP scores, amino acid conservation data through orthologue alignments and information on protein domains.

Moreover, we integrate several missense variant pathogenicity prediction tools and algorithms such as SIFT, PolyPhen, AlignGVGD or MutationTaster. It also offers a window dedicated to the in silico study of variants’ effect on RNA splicing, allowing the assessment of their potential impact on splice junctions and visualization of cryptic or de novo splice sites. Impact on splicing regulation is also assessed.

Clinical interpretation

At GHC Genetics our geneticists and clinicians, who together evaluate the results from the sequence analysis pipeline in the context of phenotype information provided in the requisition form, prepare the clinical report. We recommend an interpretation of the findings of this molecular genetic analysis, including subsequent oncological consultation for the patient in the context of genetic counselling for the patient.

We strive to continuously monitor current genetic literature identifying new relevant information and findings and adapting them to our diagnostics. This enables relevant novel discoveries to be rapidly translated and adopted into our ongoing diagnostics development without delay. The undertaking of such comprehensive due diligence ensures that our diagnostic panels and clinical statements are the most up-to-date on the market.

Variant classification is the corner stone of clinical interpretation and resulting patient management decisions. Minor modifications were made to increase reproducibility of the variant classification and improve the clinical validity of the report. Our experience with tens of thousands of clinical cases analysed at our laboratories enables us to further develop the industry standard.

The final step in the analysis of sequence variants is confirmation of variants classified as pathogenic or likely pathogenic using bi-directional Sanger sequencing. Variant(s) fulfilling all of the following criteria are not Sanger confirmed: 1) the variant quality score is above the internal threshold for a true positive call, 2) an unambiguous IGV in-line with the variant call and 3) previous Sanger confirmation of the same variant three times at GHC Genetics. Reported variants of uncertain significance (VUS) are confirmed with bi-directional Sanger sequencing only if the quality score is below our internally defined quality score for true positive call. Reported copy number variations with a size >10 exons are confirmed by orthogonal methods such as qPCR if the specific CNV has been seen less than three times at GHC Genetics.

Our clinical statement includes tables for sequencing and copy number variants that include basic variant information (genomic coordinates, HGVS nomenclature, zygosity, allele frequencies, in silico predictions, OMIM phenotypes and classification of the variant). In addition, the statement includes detailed descriptions of the variant, gene and phenotype(s) including the role of the specific gene in human disease, the mutation profile, information about the gene’s variation in population cohorts and detailed information about related phenotypes. We also provide links to the references used, and mutation databases to help our customers further evaluate the reported findings if desired. The conclusion summarizes all of the existing information and provides our rationale for the classification of the variant.

Identification of pathogenic or likely pathogenic variants in dominant disorders or their combinations in different alleles in recessive disorders are considered molecular confirmation of the clinical diagnosis. In these cases, family member testing can be used for risk stratification within the family. In the case of variants of uncertain significance (VUS), we do not recommend family member risk stratification based on the VUS result. Furthermore, in the case of VUS, we do not recommend the use of genetic information in patient management or genetic counselling.

Our Clinical interpretation team analyses millions of variants from thousands of individuals with rare diseases. Thus, our database, and our understanding of variants and related phenotypes, is growing by leaps and bounds. Our laboratories are therefore well positioned to re-classify previously reported variants as new information becomes available. If a variant previously reported by GHC Genetics is re-classified, our laboratories will issue a follow-up statement to the original ordering health care provider at no additional cost.