UKGTN Testing Criteria

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Brett Caldwell
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1 UKGTN Testing Criteria Test name: Inherited Bone Marrow Failure Syndromes 44 Gene Panel Approved name disorder/(s): See Appendix 1 Approved name (s): See Appendix 1 (s): (s): Patient name: Patient postcode: Date birth: NHS : Name referrer: Title/Position: Lab ID: Referrals will only be accepted from one the following: Referrer Consultant Clinical Geneticist Consultant Haematologist Consultant in Bone Marrow Transplantation Tick if this refers to you. Minimum criteria required for testing to be appropriate as stated in the Gene Dossier: Criteria Tick if this patient meets criteria One the following: Idiopathic monocytopenia Idiopathic bicytopenia Idiopathic pancytopenia Additional Information: For panel tests: At risk family members where familial mutation is known do not require a full panel test but should be fered analysis the known mutation. A prorma is required to be completed that is available from the laboratory. Contact genetics@nbt.nhs.uk. If the sample does not fulfil the clinical criteria or you are not one the specified types referrer and you still feel that testing should be performed please contact the laboratory to discuss testing the sample. A

2 Appendix 1 Genes in panel test and associated s. Rows where s are currently being fully analysed in the context a single separate UKGTN test are highlighted yellow. Inherited Bone Marrow Failure Syndromes 44 Gene Panel TERC TERT TINF RTEL standard Dominant, 1; DKCA1 Dominant, 2; DKCA2 Dominant, 3; DKCA3 Dominant, 4, Included; DKCA4 AD AD AD AD Vulliamy, T. et al The RNA component telomerase is mutated in autosomal dominant dyskeratosis congenita. Nature 413: , Armanios, M. et al. Haploinsufficiency telomerase reverse transcriptase leads to anticipation in autosomal dominant dyskeratosis congenita. Proc. Nat. Acad. Sci. 102: , Walne, A. J. et al. TINF2 mutations result in very short telomeres: analysis a large cohort patients with dyskeratosis congenita and related bone marrow failure syndromes. Blood 112: , Ballew, B. J. et al.germline mutations regulator telomere elongation helicase 1, RTEL1, in dyskeratosis 97.3%

3 NOP NHP WRAP RTEL DKC CTC standard Recessive, 1; DKCB1 Recessive, 2; DKCB2 Recessive, 3; DKCB3 Recessive, 5; DKCB5 Congenita, X Linked; DKCX Cerebroretinal AR AR AR AR XL AR congenita. Hum. Genet. 132: , Walne, A. J. et al Genetic heterogeneity in autosomal recessive dyskeratosis congenita with one subtype due to mutations in the telomeraseassociated protein NOP10. Hum. Molec. Genet. 16: , Vulliamy, T. et al. Mutations in the telomerase component NHP2 cause the premature ageing syndrome dyskeratosis congenita. Proc. Nat. Acad. Sci. 105: , 2008 Zhong, F. et al. Disruption telomerase trafficking by TCAB1 mutation causes dyskeratosis congenita. Genes Dev. 25: 11 16, 2011 Walne, A. J. et al. Constitutional mutations in RTEL1 cause severe dyskeratosis congenita. Am. J. Hum. Genet. 92: , Heiss, N. S. et al. X linked dyskeratosis congenita is caused by mutations in a highly conserved gene with putative nucleolar functions. Nature Genet. 19: 32 38, 1998 Walne A et al Mutations in the telomere capping complex in 100%

4 RPS RPS RPS RPL35A RPL RPL standard microangiopathy with calcifications and cysts/ctc1 related Congenita Anemia; DBA1 Anemia 3; DBA3 Anemia 4; DBA4 Anemia 5; DBA5 Anemia 6; DBA6 Anemia 7; DBA7 AD AD AD AD AD AD bone marrow failure and related syndromes. Haematologica 2013 Mar;98(3):334- Gazda, H. T. et al. Ribosomal protein S24 gene is mutated in anemia. Am. J. Hum. Genet. 79: , Gazda, H. T. et al Ribosomal protein S24 gene is mutated in anemia. Am. J. Hum. Genet. 79: , 2006 Cmejla, R. et al. Ribosomal protein S17 gene (RPS17) is mutated in anemia. Hum. Mutat. 28: , Arrar, J. E., et al Abnormalities the large ribosomal subunit protein, Rpl35a, in Diamond Blackfan anemia. Blood 112: , Gazda, H. T. et al. Ribosomal protein L5 and L11 mutations are associated with cleft palate and abnormal thumbs in anemia patients. Am. J. Hum. Genet. 83: , Gazda, H. T. et al. Ribosomal protein L5 and L11 mutations are associated with cleft palate

5 RPS standard Anemia 8; DBA8 AD and abnormal thumbs in anemia patients. Am. J. Hum. Genet. 83: , Gazda, H. T. et al. Ribosomal protein L5 and L11 mutations are associated with cleft palate and abnormal thumbs in anemia patients. Am. J. Hum. Genet. 83: , RPS RPS GATA Anemia 9; DBA9 Anemia 10; DBA10 Anemia, X linked, with/without neutropenia and/or platelet abnormalities AD AD XL Doherty, L. et al. Ribosomal protein genes RPS10 and RPS26 are commonly mutated in anemia. Am. J. Hum. Genet. 86: , Note: Erratum: Am. J. Hum. Genet 86: , 2010 Doherty, L. et al. Ribosomal protein genes RPS10 and RPS26 are commonly mutated in anemia. Am. J. Hum. Genet. 86: , Note: Erratum: Am. J. Hum. Genet 86: , 2010 Sankaran VG. Exome sequencing identifies GATA1 mutations resulting in anemia. J Clin Invest Jul 2;122(7): Aplastic Anaemia SBDS Shwachman Diamond AR Kuijpers, T. W. et al.

6 Neutropenia SRP TERT TERC standard Syndrome; SDS Bone Marrow Failure, Familial Telomere Related Pulmonary Fibrosis And/Or Bone Marrow Failure 1 Telomere Related Pulmonary Fibrosis And/Or Bone Marrow Failure 2 AD AD AD TINF Revesz Syndrome AD ELANE Congenital, 1, AR Hematologic abnormalities in Shwachman Diamond syndrome: lack genotypephenotype relationship. Blood 106: , Kirwan, M. et al. Exome sequencing identifies autosomal dominant SRP72 mutations associated with familial aplasia and myelodysplasia. Am. J. Hum. Genet. 90: , Yamaguchi, H. et al. Mutations in TERT, for telomerase reverse transcriptase, in aplastic anemia. New Eng. J. Med. 352: , 2005 Vulliamy, T. et al. Association between aplastic anaemia and mutations in telomerase RNA. Lat 359: , 2002 Savage, S. A. et al. TINF2, a component the shelterin telomere protection complex, is mutated in dyskeratosis congenita. Am. J. Hum. Genet. 82: , 2008 Dale, D. C. et al. Mutations in encoding neutrophil 99.9% 97.3% 98.9%

7 GFI HAX G6PC WAS GFI standard Autosomal Dominant; SCN1 Congenital, 2, Autosomal Dominant; SCN2 Congenital, 3, Autosomal Recessive; SCN3 Congenital, 4, Autosomal Recessive; SCN4 Congenital, X Linked; SCNX Neutropenia, Nonimmune Chronic Idiopathic, Of Adults AD AR AR XL AD ELANE Cyclic Neutropenia AD elastase in congenital and cyclic neutropenia. Blood 96: , Person, R. E. et al. Mutations in proto oncogene GFI1 cause human neutropenia and target ELA2. Nature Genet. 34: , 2003 Klein, C. et al. HAX1 deficiency causes autosomal recessive severe congenital neutropenia (Kostmann disease). Nature Genet. 39: 86 92, 2007 Boztug, K. et al. A syndrome with congenital neutropenia and mutations in G6PC3. New Eng. J. Med. 360: 32 43, Note: Erratum: New Eng. J. Med. 364: 1682 only, 2011 Ancliff, P. J. et al Two novel activating mutations in the Wiskott Aldrich syndrome protein result in congenital neutropenia. Blood 108: , 2006 Person, R. E. et al Mutations in proto oncogene GFI1 cause human neutropenia and target ELA2. Nature Genet. 34: , 2003 Horwitz, M. et al Mutations in ELA2, encoding neutrophil elastase, define a 21 day 95.5% 95.5% 98.9%

8 GATA2 deficiencies GATA GATA standard Dendritic Cell, Monocyte, B Lymphocyte, And Natural Killer Lymphocyte Deficiency Lymphedema, Primary, With Myelodysplasia AD AD biological clock in cyclic haematopoiesis. Nature Genet. 23: , Hsu, A. P. et al. Mutations in GATA2 are associated with the autosomal dominant and sporadic monocytopenia and mycobacterial infection (MonoMAC) syndrome. Blood 118: , Ostergaard, P. et al. Mutations in GATA2 cause primary lymphedema associated with a predisposition to acute myeloid leukemia (Emberger syndrome). Nature Genet. 43: , 2011 GATA Thrombocytopenia MPL WAS Myelodysplastic Syndrome; MDS Amegakaryocytic Thrombocytopenia, Congenital; CAMT Thrombocytopenia 1; THC1 AD AR XL Hahn, C. N. et al Heritable GATA2 mutations associated with familial myelodysplastic syndrome and acute myeloid leukemia. Nature Genet. 43: , 2011 Ballmaier, M. et al. c mpl mutations are the cause congenital amegakaryocytic thrombocytopenia. Blood 97: , Villa, A. et al X linked thrombocytopenia and

9 WAS RUNX standard Wiskott Aldrich Syndrome, WAS Platelet Disorder, Familial, With Associated Myeloid Malignancy XL AD Wiskott Aldrich syndrome are allelic diseases with mutations in the WASP gene. Nature Genet. 9: , Derry, J. M. J. et al Isolation a novel gene mutated in Wiskott Aldrich syndrome. Cell 78: , Note: Erratum: Cell 79: following 922, Michaud, J. et al. In vitro analyses known and novel RUNX1/AML1 mutations in dominant familial platelet disorder with predisposition to acute myelogenous leukemia: implications for mechanisms pathogenesis. Blood 99: , %

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The University of Chicago Genetic Services Laboratories The University of Chicago tic Services Laboratories 5841 S. Maryland Ave., Rm. G701, MC 0077, Chicago, Illinois 60637 ucgslabs@genetics.uchicago.edu dnatesting.uchicago.edu CLIA #: 14D0917593 CAP #: 18827-49