Collect

Blood sample in an EDTA (purple-top) tube.

Storage/Transport Temperature

Room Temp

Performed

Monday through Friday 9:00am - 4:00pm

Volume Required

3-5 ml

Minimum Required

1.5 ml

Phlebotomy Draw

Yes

Performed

Monday through Friday 9:00am - 4:00pm

Methodology

One hundred and twelve genes known to be associated with predisposition to BMF, MDS/leukemia are analyzed using Next Generation Sequence (NGS) technology. All coding exons of the 112 genes and 20 base pairs of 5' and 3' flanking intronic sequences are analyzed. All known intronic mutations of these genes are also evaluated. Pathogenic/likely pathogenic variants detected by NGS are confirmed by Sanger sequencing.
The panel also evaluates gross copy number variations of these genes by analyzing NGS data. Pathogenic/likely pathogenic CNVs detected by NGS are confirmed by MLPA and/or ddPCR. Certain genes or exons may not be evaluated for gross copy number variations, such as genes with no known gross deletion/duplication mutations, or genes or exons with pseudogenes or highly homologous sequences in the genome.

Reported

28 days

Synonyms

  • BMLRE

LIS Mnemonic

BMLRE

Performed By

Division of Genomic Diagnostics

Available STAT

No

Clinical Features

The Comprehensive BMF/MDS/Leukemia Predisposition Panel - Reflex is a next generation sequencing panel designed to reflex from the smaller bone marrow failure and MDS/leukemia associated panels offered by CHOP Genomic Diagnostic Laboratory that yielded negative or inconclusive results. This comprehensive panel can identify underlying genetic variants associated with inherited myelodysplastic syndromes (MDS) and leukemia, and bone marrow failure. Inherited predisposition to hematological malignancies [acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and bone marrow myelodysplastic syndrome (MDS)] may be isolated or in association with syndromic features. MDS and AML may present as part of known bone marrow failure syndromes (eg. dyskeratosis congenita, severe congenital neutropenia, Fanconi anemia).
Bone marrow failure (BMF) disorders are characterized by inadequate production of one or more blood cell lineages by bone marrow, and results from either acquired immunologic, infectious or toxic insults, or from inherited mutations in genes (at least 90 at present time) associated with bone marrow failure.  Identification of an underlying genetic cause is critical in establishing an inherited versus acquired etiology for bone marrow failure, which in turn has profound impacts on patient management and genetic counseling for families of affected patients. 
Other hereditary cancer predisposition syndromes associated with hematologic malignancies include Li-Fraumeni syndrome, ataxia telangiectasia, Bloom syndrome, neurofibromatosis type 1, Noonan syndrome, or mismatch-repair deficiency syndrome. Myelodysplastic syndrome and secondary leukemia are rare in children and young adults. The occurrence of these disorders in these age groups is increasingly associated with inherited pathogenic variants in genes associated with familial cancer predisposition.
Such predisposition syndromes may also be associated with sensitivity to cytotoxic anti-cancer therapy, and thus identification of underlying genetic predisposition may not only impact family screening, but also may directly impact therapeutic approaches.

Detection Rate

The diagnostic yield for comprehensive NGS panels is not yet well-established, and depends on the panel's gene content and the patient's clinical features. However, based on a recent study, pathogenic variants in inherited bone marrow failure/myelodysplastic syndrome genes were found in 5.1% (5/98) of aplastic anemia patients and 13.6% (15/110) of myelodysplastic syndrome patients by massively parallel sequencing. In addition, 18.1% of patients with unclassified inherited bone marrow failure syndromes were found to carry germline pathogenic variants in CXCR4, GATA2, G6PC3, MAST, MYH9, RPL5, RTEL1, TERT, TERC, TINF2, or WAS genes [PMID: 27418648]. Another recent study identified GATA2 pathogenic germline variants in 7% of children and adolescents with de novo MDS [PMID: 26702063].
Estimated detection rates may differ depending whether the proband meets the clinical diagnostic criteria for specific cancer predisposition syndromes mentioned above.  Estimated detection rates for certain syndromes are as follows:

Ataxia-telangiectasia: ~90-97% [PMID: 17910737, 20301790]
Barth syndrome: >90%  [PMID: 24237972]
Bloom syndrome: ~87-93% [PMID: 17407155]
Cartilage-hair hypoplasia: >95% [PMID: 17189938]
Chediak-Higashi syndrome: ~90% [PMID: 24237972]
Cohen syndrome: ~100% [PMID: 24237972]
Congenital amegakaryocytic thrombocytopenia (CAMT): ~95% of patients have biallelic pathogenic variants in MPL [PMID: 23351987]
Congenital Neutropenia: ~38-80% associated with ELANE pathogenic variants [PMID: 20301705]
Diamond-Blackfan anemia: ~55% [PMID: 19327583]
Dyskeratosis congenita: ~50% [PMID: 21659346]
Fanconi Anemia: ~90% [PMID: 23613520]
Nijmegen breakage syndrome: >95% [PMID: 20301355]
Shwachman Diamond syndrome: ~80% of individuals who meet diagnostic criteria [PMID: 19327581]
Wiskott-Aldrich syndrome: >95% [PMID: 20301357]

Molecular Testing Notes

Conditions associated with predisposition to BMF, MDS, and leukemia can be inherited in an autosomal dominant, autosomal recessive, or X-linked manner. The Comprehensive BMF/MDS/Leukemia Predisposition Panel includes the following 112 genes: AK2, ABCB7, ACD, ALAS2, ANKRD26, APC, ATM,  ATR, BLM, BRCA1, BRCA2, C15ORF41, CBL, CDAN1,  CDKN2A, CEBPA, CHEK2, CSF3R, CTC1,CXCR4, DDX11, DDX41, DKC1, ELANE, EPCAM, ERCC4, ESCO2, ETV6, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ, FANCL, FANCM, G6PC3, GATA1, GATA2, GFI1, GLRX5, HAX1, KIF23, KLF1, KRAS, LAMTOR2, LIG4, LYST, MLH1, MPL, MSH2, MSH6, NBN, NF1, NF2, NHEJ1, NHP2, NOP10, PALB2, PARN, PAX5, PMS2, PTPN11, RAB27A, RAC2, RAD51, RAD51C, RAF1, RBM8A, RECQL, RMRP, RPL11, RPL15, RPL19, RPL26, RPL27, RPL35A, RPL5, RPS10, RPS17, RPS19, RPS24, RPS26, RPS27, RPS29, RPS7, RTEL1, RUNX1, SBDS, SH2B3, SEC23B, SLC25A38, SLC37A4, SLX4, SOS1, SRP72, TAZ, TERC, TERT, TINF2, TP53, USB1, VPS13B, VPS45, WAS, WIPF1, WRAP53, SAMD9, and SAMDL9

CPT Codes

81201, 81209, 81163, 81218, 81242, 81292, 81295, 81298, 81317, 81402, 81403, 81404, 81405 x 3, 81406 x 7, 81408 x 3, 81479, 81307

 
Collection

Collect

Blood sample in an EDTA (purple-top) tube.

Storage/Transport Temperature

Room Temp

Performed

Monday through Friday 9:00am - 4:00pm

Volume Required

3-5 ml

Minimum Required

1.5 ml

Phlebotomy Draw

Yes
Ordering

Performed

Monday through Friday 9:00am - 4:00pm

Methodology

One hundred and twelve genes known to be associated with predisposition to BMF, MDS/leukemia are analyzed using Next Generation Sequence (NGS) technology. All coding exons of the 112 genes and 20 base pairs of 5' and 3' flanking intronic sequences are analyzed. All known intronic mutations of these genes are also evaluated. Pathogenic/likely pathogenic variants detected by NGS are confirmed by Sanger sequencing.
The panel also evaluates gross copy number variations of these genes by analyzing NGS data. Pathogenic/likely pathogenic CNVs detected by NGS are confirmed by MLPA and/or ddPCR. Certain genes or exons may not be evaluated for gross copy number variations, such as genes with no known gross deletion/duplication mutations, or genes or exons with pseudogenes or highly homologous sequences in the genome.

Reported

28 days

Synonyms

  • BMLRE

LIS Mnemonic

BMLRE

Performed By

Division of Genomic Diagnostics

Available STAT

No

Clinical Features

The Comprehensive BMF/MDS/Leukemia Predisposition Panel - Reflex is a next generation sequencing panel designed to reflex from the smaller bone marrow failure and MDS/leukemia associated panels offered by CHOP Genomic Diagnostic Laboratory that yielded negative or inconclusive results. This comprehensive panel can identify underlying genetic variants associated with inherited myelodysplastic syndromes (MDS) and leukemia, and bone marrow failure. Inherited predisposition to hematological malignancies [acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and bone marrow myelodysplastic syndrome (MDS)] may be isolated or in association with syndromic features. MDS and AML may present as part of known bone marrow failure syndromes (eg. dyskeratosis congenita, severe congenital neutropenia, Fanconi anemia).
Bone marrow failure (BMF) disorders are characterized by inadequate production of one or more blood cell lineages by bone marrow, and results from either acquired immunologic, infectious or toxic insults, or from inherited mutations in genes (at least 90 at present time) associated with bone marrow failure.  Identification of an underlying genetic cause is critical in establishing an inherited versus acquired etiology for bone marrow failure, which in turn has profound impacts on patient management and genetic counseling for families of affected patients. 
Other hereditary cancer predisposition syndromes associated with hematologic malignancies include Li-Fraumeni syndrome, ataxia telangiectasia, Bloom syndrome, neurofibromatosis type 1, Noonan syndrome, or mismatch-repair deficiency syndrome. Myelodysplastic syndrome and secondary leukemia are rare in children and young adults. The occurrence of these disorders in these age groups is increasingly associated with inherited pathogenic variants in genes associated with familial cancer predisposition.
Such predisposition syndromes may also be associated with sensitivity to cytotoxic anti-cancer therapy, and thus identification of underlying genetic predisposition may not only impact family screening, but also may directly impact therapeutic approaches.

Detection Rate

The diagnostic yield for comprehensive NGS panels is not yet well-established, and depends on the panel's gene content and the patient's clinical features. However, based on a recent study, pathogenic variants in inherited bone marrow failure/myelodysplastic syndrome genes were found in 5.1% (5/98) of aplastic anemia patients and 13.6% (15/110) of myelodysplastic syndrome patients by massively parallel sequencing. In addition, 18.1% of patients with unclassified inherited bone marrow failure syndromes were found to carry germline pathogenic variants in CXCR4, GATA2, G6PC3, MAST, MYH9, RPL5, RTEL1, TERT, TERC, TINF2, or WAS genes [PMID: 27418648]. Another recent study identified GATA2 pathogenic germline variants in 7% of children and adolescents with de novo MDS [PMID: 26702063].
Estimated detection rates may differ depending whether the proband meets the clinical diagnostic criteria for specific cancer predisposition syndromes mentioned above.  Estimated detection rates for certain syndromes are as follows:

Ataxia-telangiectasia: ~90-97% [PMID: 17910737, 20301790]
Barth syndrome: >90%  [PMID: 24237972]
Bloom syndrome: ~87-93% [PMID: 17407155]
Cartilage-hair hypoplasia: >95% [PMID: 17189938]
Chediak-Higashi syndrome: ~90% [PMID: 24237972]
Cohen syndrome: ~100% [PMID: 24237972]
Congenital amegakaryocytic thrombocytopenia (CAMT): ~95% of patients have biallelic pathogenic variants in MPL [PMID: 23351987]
Congenital Neutropenia: ~38-80% associated with ELANE pathogenic variants [PMID: 20301705]
Diamond-Blackfan anemia: ~55% [PMID: 19327583]
Dyskeratosis congenita: ~50% [PMID: 21659346]
Fanconi Anemia: ~90% [PMID: 23613520]
Nijmegen breakage syndrome: >95% [PMID: 20301355]
Shwachman Diamond syndrome: ~80% of individuals who meet diagnostic criteria [PMID: 19327581]
Wiskott-Aldrich syndrome: >95% [PMID: 20301357]

Molecular Testing Notes

Conditions associated with predisposition to BMF, MDS, and leukemia can be inherited in an autosomal dominant, autosomal recessive, or X-linked manner. The Comprehensive BMF/MDS/Leukemia Predisposition Panel includes the following 112 genes: AK2, ABCB7, ACD, ALAS2, ANKRD26, APC, ATM,  ATR, BLM, BRCA1, BRCA2, C15ORF41, CBL, CDAN1,  CDKN2A, CEBPA, CHEK2, CSF3R, CTC1,CXCR4, DDX11, DDX41, DKC1, ELANE, EPCAM, ERCC4, ESCO2, ETV6, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ, FANCL, FANCM, G6PC3, GATA1, GATA2, GFI1, GLRX5, HAX1, KIF23, KLF1, KRAS, LAMTOR2, LIG4, LYST, MLH1, MPL, MSH2, MSH6, NBN, NF1, NF2, NHEJ1, NHP2, NOP10, PALB2, PARN, PAX5, PMS2, PTPN11, RAB27A, RAC2, RAD51, RAD51C, RAF1, RBM8A, RECQL, RMRP, RPL11, RPL15, RPL19, RPL26, RPL27, RPL35A, RPL5, RPS10, RPS17, RPS19, RPS24, RPS26, RPS27, RPS29, RPS7, RTEL1, RUNX1, SBDS, SH2B3, SEC23B, SLC25A38, SLC37A4, SLX4, SOS1, SRP72, TAZ, TERC, TERT, TINF2, TP53, USB1, VPS13B, VPS45, WAS, WIPF1, WRAP53, SAMD9, and SAMDL9
Result Interpretation
Administrative

CPT Codes

81201, 81209, 81163, 81218, 81242, 81292, 81295, 81298, 81317, 81402, 81403, 81404, 81405 x 3, 81406 x 7, 81408 x 3, 81479, 81307