1. Bone marrow failure

Bone marrow failure

October 18, 2018

Disease summary:

Bone Marrow Failure is a clinically and genetically heterogeneous collection of diseases affecting hematopoiesis, resulting in reduced or abnormal production of one or more of the three blood cell types (red blood cell, white blood cell and platelets). Symptoms and onset vary greatly depending on the gene mutated and the nature of the mutation, but most cases have severe clinical implications from infancy or early childhood.

The main inherited bone marrow failure syndromes are Fanconi anemia (FA), Dyskeratosis congenita, Diamond Blackfan anemia and Shwachman Diamond syndrome. Many bone marrow failure disorders are additionally associated with an increased risk of cancer such as leukaemia and solid tumors1. Bone marrow failure can affect other systems of the body and patients may also display skeletal and organ abnormalities and disorders of the cardiovascular and central nervous system.

Other bone marrow failure disorders with multiple possible genetic origins include severe congenital neutropenia (SCN), thrombocytopenia and autoimmune lymphoproliferative syndrome. SCN is characterized by profound neutropenia diagnosed early in life and complicated by recurrent severe and life-threatening bacterial infections2. Thrombocytopenia usually presents in infancy or early childhood, most commonly with intensive and frequent mucosal bleeding, intermittent petechiae and purpura, and recurrent bacterial and viral infections.3


  • Autosomal dominant
  • Autosomal recessive
  • X-linked

FA: 1/100,000; carrier frequency is 1/100 in Ashkenazi Jewish, Spanish Gypsy, and black South African4

Dyskeratosis congenita: 1 in 1,000,0005

SCN: 2-3/1,000,000

Diamond Blackfan anemia: 1:100,000 and 1: 200,000

Thrombocytopenia: 4.6-5.3/100,000 in Sweden 9,5/100,00 in US, 1.6/1,00,00 worldwide

  • Pallor, lethargy
  • Recurrent infections (neutropenia)
  • Excessive bleeding or bruising (thrombocytopenia)
  • Abnormal skin pigmentation
  • Enlarged spleen, also other organs
  • Skeletal abnormalities
  • Growth retardation
  • Malignancies 
  • Low count or abnormality of one or more type of blood cell or platelet in peripheral blood
  • Abnormal Bone marrow aspirate)
  • Disease-specific cytological testing e.g. the chromosome breakage assay for FA6,7
  • Detection of a pathogenic variant in candidate gene/s
  • Hematopoietic stem cell transfer8,9
  • Blood transfusion
  • Corticosteroid treatment (Diamond Blackfan anemia)10
  • Hematopoietic growth factors e.g. recombinant human granulocyte colony-stimulating factor (SCN) 2,11
  • Acquired anemia12
  • Autoimmune disease12
  • Leukemia and Melyodysplasic syndromes12

To confirm bone marrow failure, CENTOGENE offers the following tests:

  • Bone marrow failure NGS panel or NGS panel plus
  • Bone marrow failure NGS panel or NGS panel plus + CNV which includes sequencing of the genes and additionally detection of large deletions and duplications from the NGS data
  • Bone marrow failure NGS panel genomic
  • Bone marrow failure deletion/duplication testing using MLPA/qPCR

Step 1: Bone Marrow Failure NGS Panel Plus 

Step 2: Bone Marrow Failure  NGS Panel Plus + CNV which includes full gene sequencing and additionally detection of large deletions and duplications from the NGS data.   

  • Individuals with any of the symptoms of Bone Marrow Failure, regardless of family history, especially infants.
  • Individuals with a positive family history of Bone Marrow Failure


Confirmation of a clinical diagnosis through genetic testing of Bone Marrow Failure can allow for genetic counseling and may direct medical management, particularly in infants and young children.

Table 1. Overview of the genes in CENTOGENE´s Bone Marrow Failure panel:

Gene OMIM (Gene) Associated diseases (OMIM) Inheritance CentoMD® exclusive variant numbers (++)
ABCB7 300135 Anemia, sideroblastic, with ataxia XL R 1
AK2 103020 Reticular dysgenesis AR 0
ALAS2 301300 Anemia, sideroblastic, 1; Protoporphyria, erythropoietic, X-linked XL, XL R 1
ANKRD26 610855 Thrombocytopenia 2 AD 4
BRCA2 600185 Breast cancer, male, susceptibility to; Medulloblastoma; Prostate cancer; Wilms tumor; Fanconi anemia, complementation group D1; Breast-ovarian cancer, familial, 2; Glioblastoma 3; Pancreatic cancer 2 AD, AR, Somatic mutation 227
BRIP1 605882 Breast cancer, early-onset; Fanconi anemia, complementation group J AD 15
CASP10 601762 Autoimmune lymphoproliferative syndrome, type II; Lymphoma, non-Hodgkin, somatic; Gastric cancer, somatic AD 2
CBL 165360 ?Juvenile myelomonocytic leukemia; Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia AD, Somatic mutation 10
CDAN1 607465 Dyserythropoietic anemia, congenital, type Ia AR 13
CSF3R 138971 Neutropenia, severe congenital, 7, autosomal recessive AR 1
CXCR4 162643 WHIM syndrome AD 2
DKC1 300126 Dyskeratosis congenita, X-linked XL R 2
ELANE 130130 Neutropenia, cyclic; Neutropenia, severe congenital 1, autosomal dominant AD 4
ERCC4 133520 Xeroderma pigmentosum, group F; Xeroderma pigmentosum, type F/Cockayne syndrome; ?XFE progeroid syndrome; Fanconi anemia, complementation group Q AR 0
FANCA 607139 Fanconi anemia, complementation group A AR 62
FANCB 300515 Fanconi anemia, complementation group B 6
FANCC 613899 Fanconi anemia, complementation group C AR 10
FANCD2 613984 Fanconi anemia, complementation group D2 AR 22
FANCE 613976 Fanconi anemia, complementation group E AR 8
FANCF 613897 Fanconi anemia, complementation group F 4
FANCG 602956 Fanconi anemia, complementation group G 13
FANCI 611360 Fanconi anemia, complementation group I AR 34
FANCL 608111 Fanconi anemia, complementation group L AR 15
FANCM 609644 16
G6PC3 611045 Dursun syndrome; Neutropenia, severe congenital 4, autosomal recessive AR 1
GATA1 305371 Leukemia, megakaryoblastic, with or without Down syndrome, somatic; Thrombocytopenia, X-linked, with or without dyserythropoietic anemia; Anemia, X-linked, with/without neutropenia and/or platelet abnormalities; Thrombocytopenia with beta-thalassemia, X-linked XL R 4
GFI1 600871 ?Neutropenia, nonimmune chronic idiopathic, of adults; ?Neutropenia, severe congenital 2, autosomal dominant AD 0
HAX1 605998 Neutropenia, severe congenital 3, autosomal recessive AR 1
HOXA11 142958 Radioulnar synostosis with amegakaryocytic thrombocytopenia 1 AD 2
JAGN1 616012 Neutropenia, severe congenital, 6, autosomal recessive AR 2
KLF1 600599 Blood group--Lutheran inhibitor; [Hereditary persistence of fetal hemoglobin]; Dyserythropoietic anemia, congenital, type IV AD 2
LYST 606897 Chediak-Higashi syndrome AR 30
MASTL 608221 4
MPL 159530 Myelofibrosis with myeloid metaplasia, somatic; Thrombocythemia 2; Thrombocytopenia, congenital amegakaryocytic AD, AR, Somatic mutation 6
MYH9 160775 Fechtner syndrome; Epstein syndrome; May-Hegglin anomaly; Macrothrombocytopenia and progressive sensorineural deafness; Deafness, autosomal dominant 17; Sebastian syndrome AD 9
NBN 602667 Nijmegen breakage syndrome; Aplastic anemia; Leukemia, acute lymphoblastic AR 11
NHP2 606470 Dyskeratosis congenita, autosomal recessive 2 AR 0
NOP10 606471 Dyskeratosis congenita, autosomal recessive 1 AR 0
PALB2 610355 Breast cancer, susceptibility to; Fanconi anemia, complementation group N; Pancreatic cancer, susceptibility to, 3 AD 11
PARN 604212 Dyskeratosis congenita, autosomal recessive 6; Pulmonary fibrosis and/or bone marrow failure, telomere-related, 4 AD, AR 2
PRF1 170280 Hemophagocytic lymphohistiocytosis, familial, 2; Lymphoma, non-Hodgkin; Aplastic anemia AR 18
PUS1 608109 Myopathy, lactic acidosis, and sideroblastic anemia 1 AR 10
RAC2 602049 Neutrophil immunodeficiency syndrome 0
RAD51C 602774 Fanconi anemia, complementation group O; Breast-ovarian cancer, familial, susceptibility to, 3 AR 3
RPL11 604175 Diamond-Blackfan anemia 7 AD 8
RPL15 604174 ?Diamond-Blackfan anemia 12 AD 4
RPL26 603704 ?Diamond-Blackfan anemia 11 AD 0
RPL27 607526 ?Diamond-Blackfan anemia 16 AD 0
RPL35A 180468 Diamond-Blackfan anemia 5 AD 4
RPL5 603634 Diamond-Blackfan anemia 6 AD 12
RPS10 603632 Diamond-Blackfan anemia 9 AD 1
RPS17 180472 Diamond-Blackfan anemia 4 AD 4
RPS19 603474 Diamond-Blackfan anemia 1 AD 8
RPS24 602412 Diamond-blackfan anemia 3 AD 8
RPS26 603701 Diamond-Blackfan anemia 10 AD 8
RPS27 603702 ?Diamond-Blackfan anemia 17 AD 0
RPS28 603685 Diamond Blackfan anemia 15 with mandibulofacial dysostosis AD 0
RPS29 603633 Diamond-Blackfan anemia 13 AD 1
RPS7 603658 Diamond-Blackfan anemia 8 AD 6
RTEL1 608833 Dyskeratosis congenita, autosomal dominant 4; Dyskeratosis congenita, autosomal recessive 5; Pulmonary fibrosis and/or bone marrow failure, telomere-related, 3 AD, AR 6
SBDS 607444 Shwachman-Diamond syndrome; Aplastic anemia, susceptibility to AR 11
SEC23B 610512 Dyserythropoietic anemia, congenital, type II; Cowden syndrome 7 AD, AR 10
SLC19A2 603941 Thiamine-responsive megaloblastic anemia syndrome AR 1
SLC25A38 610819 Anemia, sideroblastic, 2, pyridoxine-refractory AR 1
SLC46A1 611672 Folate malabsorption, hereditary AR 1
SLX4 613278 Fanconi anemia, complementation group P AR 11
SRP72 602122 Bone marrow failure syndrome 1 AD 0
STX11 605014 Hemophagocytic lymphohistiocytosis, familial, 4 AR 2
STXBP2 601717 Hemophagocytic lymphohistiocytosis, familial, 5 10
TCN2 613441 Transcobalamin II deficiency AR 6
TERC 602322 Dyskeratosis congenita, autosomal dominant 1; Aplastic anemia; Pulmonary fibrosis, idiopathic, susceptibility to AD 1
TERT 187270 Leukemia, acute myeloid; Dyskeratosis congenita, autosomal dominant 2; Dyskeratosis congenita, autosomal recessive 4; Pulmonary fibrosis and/or bone marrow failure, telomere-related, 1; Melanoma, cutaneous malignant, 9 AD, AR 4
TINF2 604319 Revesz syndrome; Dyskeratosis congenita, autosomal dominant 3 AD 1
UBE2T 610538 Fanconi anemia, complementation group T AR 0
VPS45 610035 Neutropenia, severe congenital, 5, autosomal recessive AR 1
WAS 300392 Neutropenia, severe congenital, X-linked; Wiskott-Aldrich syndrome; Thrombocytopenia, X-linked; Thrombocytopenia, X-linked, intermittent XL R 3
WRAP53 612661 Dyskeratosis congenita, autosomal recessive 3 AR 0
XRCC2 600375 ?Fanconi anemia, complementation group U AR 7

Abbreviations: AD autosomal dominant; AR autosomal recessive; XL X-linked