Fanconi Anemia Panel

  • bpg-method PLUS
  • bpg-method SEQ
  • bpg-method DEL/DUP

Test code: HE0301

The Blueprint Genetics Fanconi Anemia Panel is a 22 gene test for genetic diagnostics of patients with clinical suspicion of Fanconi anemia or Nijmegen breakage syndrome.

Fanconi anemia (FA) is primarily an autosomal recessive genetic disorder although X-linked inheritance is observed in 2% of FA cases caused by FANCB mutations. Eighty to 90 percent of the cases of FA are due to mutations in FANCA, FANCC and FANCG. This panel is included in the Anemia Panel, Bone Marrow Failure Syndrome Panel and Comprehensive Hematology Panel.

About Fanconi Anemia

FA is a rare, inherited blood disorder that leads to bone marrow failure. The genetic defect in FA affects a cluster of proteins responsible for DNA repair. It is clinically defined by pancytopenia in the first decade of life and increased risk of cancer, most often acute myeloid leukemia. Over half of the FA patients have congenital defects such as short stature, abnormalities of the skin, cardiac, kidney and limb malformations especially radius aplasia are frequent. Mild microcephaly usually without intellectual disability is observed in 10%-25% of cases. Endocrine problems are common as well. Affected adults are also at high risk for non-hematologic malignancies. Allogeneic stem cell transplantation is the only treatment allowing long-term outcome. Fanconi anemia occurs in 1 in 160,000 individuals worldwide. It is more common among people of Ashkenazi Jewish descent, the Roma population of Spain, and black South Africans. Syndromes establishing differential diagnostic challenges include Seckel syndrome, Bloom syndrome and more common Nijmegen breakage syndrome (1:100,000 live births).

Availability

Results in 3-4 weeks. We do not offer a maternal cell contamination (MCC) test at the moment. We offer prenatal testing only for cases where the maternal cell contamination studies (MCC) are done by a local genetic laboratory. Read more: http://blueprintgenetics.com/faqs/#prenatal

Genes in the Fanconi Anemia Panel and their clinical significance
Gene Associated phenotypes Inheritance ClinVar HGMD
ATM Breast cancer, Ataxia-Telangiectasia AD/AR 455 853
ATR Cutaneous telangiectasia and cancer syndrome, Seckel syndrome AD/AR 6 13
BLM Bloom syndrome AR 53 92
BRCA2 Fanconi anemia, Medulloblastoma, Glioma susceptibility, Pancreatic cancer, Wilms tumor, Breast-ovarian cancer, familial AD/AR 2514 1791
BRIP1 Fanconi anemia, Breast cancer AD/AR 87 87
CXCR4 Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome AD 4 14
ERCC4 Fanconi anemia, Xeroderma pigmentosum AR 11 37
FANCA Fanconi anemia AR 33 474
FANCB Fanconi anemia XL 7 14
FANCC Fanconi anemia AR 34 34
FANCD2* Fanconi anemia AR 10 49
FANCE Fanconi anemia AR 3 9
FANCF Fanconia anemia AR 6 8
FANCG Fanconi anemia AR 11 73
FANCI Fanconi anemia AR 8 27
FANCL Fanconi anemia AR 6 15
FANCM Fanconi anemia AR 1 13
NBN Breast cancer, Nijmegen breakage syndrome AD/AR 57 62
PALB2 Fanconi anemia, Pancreatic cancer, Breast cancer AD/AR 237 223
RAD51C Fanconi anemia, Breast-ovarian cancer, familial AD/AR 49 86
SLX4 Fanconi anemia AR 8 31
XRCC2 Hereditary breast cancer AD/AR 3 13

*Some regions of the gene are duplicated in the genome leading to limited sensitivity within the regions. Thus, low-quality variants are filtered out from the duplicated regions and only high-quality variants confirmed by other methods are reported out. Read more.

Gene, refers to HGNC approved gene symbol; Inheritance to inheritance patterns such as autosomal dominant (AD), autosomal recessive (AR) and X-linked (XL); ClinVar, refers to a number of variants in the gene classified as pathogenic or likely pathogenic in ClinVar (http://www.ncbi.nlm.nih.gov/clinvar/); HGMD, refers to a number of variants with possible disease association in the gene listed in Human Gene Mutation Database (HGMD, http://www.hgmd.cf.ac.uk/ac/). The list of associated (gene specific) phenotypes are generated from CDG (http://research.nhgri.nih.gov/CGD/) or Orphanet (http://www.orpha.net/) databases.

Gene Genomic location HG19 HGVS RefSeq RS-number Comment Reference
ATM Chr11:108098321 c.-30-1G>T NM_000051.3 rs869312754
ATM Chr11:108141209 c.2839-579_2839-576delAAGT NM_000051.3
ATM Chr11:108179837 c.5763-1050A>G NM_000051.3 rs774925473
FANCC Chr9:98011653 c.-78-2A>G NM_000136.2 rs587779898

Blueprint Genetics offers a comprehensive Fanconi Anemia Panel that covers classical genes associated with Bloom syndrome, Fanconi anemia and Nijmegen breakage syndrome. The genes are carefully selected based on the existing scientific evidence, our experience and most current mutation databases. Candidate genes are excluded from this first-line diagnostic test. The test does not recognise balanced translocations or complex inversions, and it may not detect low-level mosaicism. The test should not be used for analysis of sequence repeats or for diagnosis of disorders caused by mutations in the mitochondrial DNA.

Analytical validation is a continuous process at Blueprint Genetics. Our mission is to improve the quality of the sequencing process and each modification is followed by our standardized validation process. Average sensitivity and specificity in Blueprint NGS Panels is 99.3% and 99.9% for detecting SNPs. Sensitivity to for indels vary depending on the size of the alteration: 1-10bps (96.0%), 11-20 bps (88.4%) and 21-30 bps (66.7%). The longest detected indel was 46 bps by sequence analysis. Detection limit for Del/Dup (CNV) analysis varies through the genome depending on exon size, sequencing coverage and sequence content. The sensitivity is 71.5% for single exon deletions and duplications and 99% for three exons’ deletions and duplications. We have validated the assays for different starting materials including EDTA-blood, isolated DNA (no FFPE) and saliva that all provide high-quality results. The diagnostic yield varies substantially depending on the used assay, referring healthcare professional, hospital and country. Blueprint Genetics’ Plus Analysis (Seq+Del/Dup) maximizes the chance to find molecular genetic diagnosis for your patient although Sequence Analysis or Del/Dup Analysis may be cost-effective first line test if your patient’s phenotype is suggestive for a specific mutation profile.

The sequencing data generated in our laboratory is analyzed with our proprietary data analysis and annotation pipeline, integrating state-of-the art algorithms and industry-standard software solutions. Incorporation of rigorous quality control steps throughout the workflow of the pipeline ensures the consistency, validity and accuracy of results. The highest relevance in the reported variants is achieved through elimination of false positive findings based on variability data for thousands of publicly available human reference sequences and validation against our in-house curated mutation database as well as the most current and relevant human mutation databases. Reference databases currently used are the 1000 Genomes Project (http://www.1000genomes.org), the NHLBI GO Exome Sequencing Project (ESP; http://evs.gs.washington.edu/EVS), the Exome Aggregation Consortium (ExAC; http://exac.broadinstitute.org), ClinVar database of genotype-phenotype associations (http://www.ncbi.nlm.nih.gov/clinvar) and the Human Gene Mutation Database (http://www.hgmd.cf.ac.uk). The consequence of variants in coding and splice regions are estimated using the following in silico variant prediction tools: SIFT (http://sift.jcvi.org), Polyphen (http://genetics.bwh.harvard.edu/pph2/), and Mutation Taster (http://www.mutationtaster.org).

Through our online ordering and statement reporting system, Nucleus, the customer can access specific details of the analysis of the patient. This includes coverage and quality specifications and other relevant information on the analysis. This represents our mission to build fully transparent diagnostics where the customer gains easy access to crucial details of the analysis process.

In addition to our cutting-edge patented sequencing technology and proprietary bioinformatics pipeline, we also provide the customers with the best-informed clinical report on the market. Clinical interpretation requires fundamental clinical and genetic understanding. At Blueprint 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 statement. Our goal is to provide clinically meaningful statements that are understandable for all medical professionals, even without training in genetics.

Variants reported in the statement are always classified using the Blueprint Genetics Variant Classification Scheme modified from the ACMG guidelines (Richards et al. 2015), which has been developed by evaluating existing literature, databases and with thousands of clinical cases analyzed in our laboratory. Variant classification forms the corner stone of clinical interpretation and following patient management decisions. Our statement also includes allele frequencies in reference populations and in silico predictions. We also provide PubMed IDs to the articles or submission numbers to public databases that have been used in the interpretation of the detected variants. In our conclusion, we summarize all the existing information and provide our rationale for the classification of the variant.

A final component of the analysis is the Sanger confirmation of the variants classified as likely pathogenic or pathogenic. This does not only bring confidence to the results obtained by our NGS solution but establishes the mutation specific test for family members. 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. Furthermore, in the case VUS we do not recommend use of genetic information in patient management or genetic counseling. For some cases Blueprint Genetics offers a special free of charge service to investigate the role of identified VUS.

We constantly follow genetic literature adapting new relevant information and findings to our diagnostics. Relevant novel discoveries can be rapidly translated and adopted into our diagnostics without delay. These processes ensure that our diagnostic panels and clinical statements remain the most up-to-date on the market.

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ICD & CPT codes

CPT codes

SEQ 81479
DEL/DUP 81479


ICD codes

Commonly used ICD-10 codes when ordering the Fanconi Anemia Panel

ICD-10 Disease
D61.0 Fanconi anemia

Accepted sample types

  • EDTA blood, min. 1 ml
  • Purified DNA, min. 5μg
  • 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.

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