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
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 11727 602322 TERT 11730 187270 TINF2 11824 604319 RTEL1 15888 608833 standard Dominant, 1; DKCA1 Dominant, 2; DKCA2 Dominant, 3; DKCA3 Dominant, 4, Included; DKCA4 AD 127550 AD 613989 AD 613990 AD 615190 Vulliamy, T. et al The RNA component telomerase is mutated in autosomal dominant dyskeratosis congenita. Nature 413: 432 435, 2001. Armanios, M. et al. Haploinsufficiency telomerase reverse transcriptase leads to anticipation in autosomal dominant dyskeratosis congenita. Proc. Nat. Acad. Sci. 102: 15960 15964, 2005. 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: 3594 3600, 2008. Ballew, B. J. et al.germline mutations regulator telomere elongation helicase 1, RTEL1, in dyskeratosis 97.3%
NOP10 14378 606471 NHP2 14377 606470 WRAP53 25522 612661 RTEL1 15888 608833 DKC1 2890 300126 CTC1 26169 613129 standard Recessive, 1; DKCB1 Recessive, 2; DKCB2 Recessive, 3; DKCB3 Recessive, 5; DKCB5 Congenita, X Linked; DKCX Cerebroretinal AR 224230 AR 613987 AR 613988 AR 615190 XL 305000 AR 612199 congenita. Hum. Genet. 132: 473 480, 2013. 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: 1619 1629, 2007. Vulliamy, T. et al. Mutations in the telomerase component NHP2 cause the premature ageing syndrome dyskeratosis congenita. Proc. Nat. Acad. Sci. 105: 8073 8078, 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: 448 453, 2013. 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%
RPS19 10402 603474 RPS24 10411 602412 RPS17 10397 180472 RPL35A 10345 180468 RPL5 10360 603634 RPL11 10301 604175 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 105650 AD 610629 AD 612527 AD 612528 AD 612561 AD 612562 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: 1110 1118, 2006. Gazda, H. T. et al Ribosomal protein S24 gene is mutated in anemia. Am. J. Hum. Genet. 79: 1110 1118, 2006 Cmejla, R. et al. Ribosomal protein S17 gene (RPS17) is mutated in anemia. Hum. Mutat. 28: 1178 1182, 2007. Arrar, J. E., et al Abnormalities the large ribosomal subunit protein, Rpl35a, in Diamond Blackfan anemia. Blood 112: 1582 1592, 2008. 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: 769 780, 2008. Gazda, H. T. et al. Ribosomal protein L5 and L11 mutations are associated with cleft palate
RPS7 10440 603658 standard Anemia 8; DBA8 AD 612563 and abnormal thumbs in anemia patients. Am. J. Hum. Genet. 83: 769 780, 2008. 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: 769 780, 2008. RPS10 10383 603632 RPS26 10414 603701 GATA1 4170 305371 Anemia 9; DBA9 Anemia 10; DBA10 Anemia, X linked, with/without neutropenia and/or platelet abnormalities AD 613308 AD 613309 XL 300835 Doherty, L. et al. Ribosomal protein genes RPS10 and RPS26 are commonly mutated in anemia. Am. J. Hum. Genet. 86: 222 228, 2010. Note: Erratum: Am. J. Hum. Genet 86: 655 656, 2010 Doherty, L. et al. Ribosomal protein genes RPS10 and RPS26 are commonly mutated in anemia. Am. J. Hum. Genet. 86: 222 228, 2010. Note: Erratum: Am. J. Hum. Genet 86: 655 656, 2010 Sankaran VG. Exome sequencing identifies GATA1 mutations resulting in anemia. J Clin Invest. 2012 Jul 2;122(7):2439 43. Aplastic Anaemia SBDS 19440 607444 Shwachman Diamond AR 260400 Kuijpers, T. W. et al.
Neutropenia SRP72 11303 602122 TERT 11730 187270 TERC 11727 602322 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 614675 AD 614742 AD 614743 TINF2 11824 604319 Revesz Syndrome AD 268130 ELANE 3309 130130 Congenital, 1, AR 202700 Hematologic abnormalities in Shwachman Diamond syndrome: lack genotypephenotype relationship. Blood 106: 356 361, 2005. Kirwan, M. et al. Exome sequencing identifies autosomal dominant SRP72 mutations associated with familial aplasia and myelodysplasia. Am. J. Hum. Genet. 90: 888 892, 2012. Yamaguchi, H. et al. Mutations in TERT, for telomerase reverse transcriptase, in aplastic anemia. New Eng. J. Med. 352: 1413 1424, 2005 Vulliamy, T. et al. Association between aplastic anaemia and mutations in telomerase RNA. Lat 359: 2168 2170, 2002 Savage, S. A. et al. TINF2, a component the shelterin telomere protection complex, is mutated in dyskeratosis congenita. Am. J. Hum. Genet. 82: 501 509, 2008 Dale, D. C. et al. Mutations in encoding neutrophil 99.9% 97.3% 98.9%
GFI1 4237 600871 HAX1 16915 605998 G6PC3 24861 611045 WAS 12731 300392 GFI1 4237 600871 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 613107 AR 610738 AR 612541 XL 300299 AD 607847 ELANE 3309 130130 Cyclic Neutropenia AD 162800 elastase in congenital and cyclic neutropenia. Blood 96: 2317 2322, 2000. Person, R. E. et al. Mutations in proto oncogene GFI1 cause human neutropenia and target ELA2. Nature Genet. 34: 308 312, 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, 2009. 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: 2182 2189, 2006 Person, R. E. et al Mutations in proto oncogene GFI1 cause human neutropenia and target ELA2. Nature Genet. 34: 308 312, 2003 Horwitz, M. et al Mutations in ELA2, encoding neutrophil elastase, define a 21 day 95.5% 95.5% 98.9%
GATA2 deficiencies GATA2 4171 137295 GATA2 4171 137295 standard Dendritic Cell, Monocyte, B Lymphocyte, And Natural Killer Lymphocyte Deficiency Lymphedema, Primary, With Myelodysplasia AD 614172 AD 614038 biological clock in cyclic haematopoiesis. Nature Genet. 23: 433 436, 1999. Hsu, A. P. et al. Mutations in GATA2 are associated with the autosomal dominant and sporadic monocytopenia and mycobacterial infection (MonoMAC) syndrome. Blood 118: 2653 2655, 2011. Ostergaard, P. et al. Mutations in GATA2 cause primary lymphedema associated with a predisposition to acute myeloid leukemia (Emberger syndrome). Nature Genet. 43: 929 931, 2011 GATA2 4171 137295 Thrombocytopenia MPL 7217 159530 WAS 12731 300392 Myelodysplastic Syndrome; MDS Amegakaryocytic Thrombocytopenia, Congenital; CAMT Thrombocytopenia 1; THC1 AD 614286 AR 604498 XL 313900 Hahn, C. N. et al Heritable GATA2 mutations associated with familial myelodysplastic syndrome and acute myeloid leukemia. Nature Genet. 43: 1012 1017, 2011 Ballmaier, M. et al. c mpl mutations are the cause congenital amegakaryocytic thrombocytopenia. Blood 97: 139 146, 2001. Villa, A. et al X linked thrombocytopenia and
WAS 12731 300392 RUNX1 10471 151385 standard Wiskott Aldrich Syndrome, WAS Platelet Disorder, Familial, With Associated Myeloid Malignancy XL 301000 AD 601399 Wiskott Aldrich syndrome are allelic diseases with mutations in the WASP gene. Nature Genet. 9: 414 417, 1995. Derry, J. M. J. et al Isolation a novel gene mutated in Wiskott Aldrich syndrome. Cell 78: 635 644, 1994. Note: Erratum: Cell 79: following 922, 1994. 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: 1364 1372, 2002 100%