Plicy Guidelines: Genetic Testing fr Carrier Screening and Reprductive Planning Cntents Overview... 1 Cverage guidelines... 2 General cverage guidelines... 2 Rutine carrier screening... 2 Carrier screening based n family histry... 2 Partner testing f knwn carrier r affected individuals... 3 Test-specific examples... 3 Carrier screening fr cystic fibrsis (CF)... 3 Carrier screening fr Ashkenazi Jewish diseases... 4 Carrier screening fr hemglbinpathies... 5 Fragile X carrier testing... 5 Exclusins... 6 Multiplex Carrier Screening... 6 Overview Carrier screening is perfrmed t identify genetic risks that culd impact reprductive decisin-making fr parents r prspective parents. Carriers are generally nt affected but have an increased risk t have a child with a genetic cnditin. Carrier screening may be available fr autsmal recessive cnditins, X-linked cnditins, and certain chrmsme abnrmalities. Ideally, carrier screening is perfrmed prir t pregnancy s that a full range f reprductive ptins are available t an at-risk cuple. Hwever, in practice, it is ften perfrmed early in pregnancy when prenatal care is established. This plicy des nt include prenatal r preimplantatin genetic testing. Refer t plicies n Genetic Testing fr Prenatal Screening and Diagnstic Testing and Preimplantatin Genetic Diagnsis fr thse purpses. In additin, testing that may identify carriers wh have clinical signs and symptms (e.g., cystic fibrsis testing fr men with cngenital absence f the vas deferens, fragile X genetic testing fr wmen with premature varian failure) is addressed as Diagnstic Genetic Testing f a Symptmatic Patient Fr Cnditins Other Than Cancer. Cpyright 2010-2011. DNA Direct, Inc. All Rights Reserved.
Plicy Guidelines: Genetic Testing fr Carrier Screening and Reprductive Planning Cverage guidelines General cverage guidelines Individuals may be cnsidered fr genetic testing fr carrier screening when ALL f the fllwing cnditins are met: Technical and clinical validity: The test must be accurate, sensitive and specific, based n sufficient, quality scientific evidence t supprt the claims f the test. Clinical utility: Healthcare prviders can use the test results t prvide significantly better medical care and/r assist individuals with reprductive planning. Reasnable use: The usefulness f the test is nt significantly ffset by negative factrs, such as expense, clinical risk, r scial r ethical challenges. Limits: Testing will nly be cnsidered fr the number f genes r tests necessary t establish carrier status. A tiered apprach t testing, with reflex t mre detailed testing and/r different genes, will be required when clinically pssible. Carrier testing will be allwed nce per lifetime. Exceptins may be cnsidered if technical advances in testing demnstrate significant advantages that wuld supprt a medical need t retest. Carrier testing is indicated nly in adults. Carrier screening in minr children is nt indicated, except in the case f a pregnancy f the minr child. Rutine carrier screening Individuals may be cnsidered fr rutine carrier screening when testing is supprted by evidence-based guidelines frm gvernmental rganizatins and/r well-recgnized prfessinal scieties in the United States. Test-specific plicy examples are available belw fr: Cystic fibrsis Hemglbinpathies (alpha- and beta-thalassemia, sickle cell anemia) Ashkenazi Jewish diseases Carrier screening based n family histry Individuals may be cnsidered fr carrier screening based n a family histry f a genetic cnditin when ALL f the fllwing cnditins are met in additin t the general criteria abve: The diagnsis f a genetic cnditin in a family member is knwn. The parent(s) r prspective parent(s) are at-risk t be carriers f that cnditin based n the pattern f inheritance. The genetic cnditin is assciated with ptentially severe disability r has a lethal natural histry. A test-specific plicy example is available belw fr fragile X syndrme. Cpyright 2010-2011. DNA Direct, Inc. All Rights Reserved.
Plicy Guidelines: Genetic Testing fr Carrier Screening and Reprductive Planning Partner testing f knwn carrier r affected individuals Individuals may be cnsidered fr carrier screening if their partners are knwn carrier r affected individuals when all f the fllwing cnditins are met in additin t the general criteria abve: The diagnsis f a genetic cnditin r carrier status in the partner is knwn. The genetic cnditin is assciated with ptentially severe disability r has a lethal natural histry. Test-specific examples Carrier screening fr cystic fibrsis (CF) The American Cllege f Medical Genetics (ACMG) and the American Cllege f Obstetrics and Gyneclgy (ACOG) have current practice guidelines regarding the use f CF carrier screening. 1-4 The ACMG guideline identifies 23 cmmn pan-ethnic mutatins that define the minimum standard fr a mutatin panel. 4 Many labratries ffer standard mutatin panels (including all 23 cre mutatins), expanded mutatin panels, and gene sequencing. The apprpriate use f these technlgies depends n the indicatin fr testing. Testing may be cnsidered when ANY f the fllwing are met: The standard CF mutatin panel is cnsidered fr any individual planning a pregnancy r currently pregnant; OR Adults with a family histry f CF: If the familial mutatin(s) are knwn and included in the standard mutatin panel, then that test nly is needed; OR If the familial mutatin(s) are nt knwn r are nt included in the standard mutatin panel, then an expanded mutatin panel can be cnsidered; OR Individuals whse partners are knwn carriers f r affected with CF r cngenital absence f the vas deferens (CAVD/CBAVD) are cnsidered fr testing with an expanded mutatin panel r sequencing. In ur pinin, a standard mutatin panel shuld include all 23 f the ACMG/ACOG recmmended mutatins and n mre than 27 additinal mutatins, fr a ttal f 50 r fewer mutatins n the panel. These additinal mutatins may imprve the detectin rate fr specific ethnic grups. Panels that include >50 mutatins shuld be cnsidered expanded mutatin panels and have mre restricted use. They typically d nt substantially increase the detectin rate References: 1. American Cllege f Obstetricians and Gyneclgists, American Cllege f Medical Genetics. Precnceptin and Prenatal Carrier Screening fr Cystic Fibrsis: Clinical and labratry guidelines. Washingtn, DC: ACOG, ACMG; 2001;1-32. 2. Cmmittee n Genetics, American Cllege f Obstetricians and Gyneclgists. ACOG Cmmittee Opinin. Number 325, December 2005. Update n carrier screening fr cystic fibrsis. Obstet Gynecl. 2005;106(6):1465-8. Cpyright 2010-2011. DNA Direct, Inc. All Rights Reserved.
Plicy Guidelines: Genetic Testing fr Carrier Screening and Reprductive Planning 3. Grdy WW, Cutting GR, Klinger KW, et al.; Subcmmittee n Cystic Fibrsis Screening, Accreditatin f Genetic Services Cmmittee, ACMG. American Cllege f Medical Genetics. Labratry standards and guidelines fr ppulatin-based cystic fibrsis carrier screening. Genet Med. 2001;3(2):149-54. PDF available at: http://www.acmg.net/am/template.cfm?sectin=plicy_statements&template=/cm/htmldisplay.cfm&cntentid=4157 4. Watsn MS, Cutting GR, Desnick RJ, et al. Cystic fibrsis ppulatin carrier screening: 2004 revisin f American Cllege f Medical Genetics mutatin panel. Genet Med. 2004;6(5):387-91. PDF available at: http://www.acmg.net/staticcntent/staticpages/cf_mutatin.pdf. Carrier screening fr Ashkenazi Jewish diseases Carrier screening is widely available fr at least 11 genetic disrders that are mre cmmn and/r have superir mutatin detectin rates in the Ashkenazi Jewish ppulatin. The American Cllege f Obstetrics and Gyneclgy (ACOG) 1 and the American Cllege f Medical Genetics (ACMG) 2 recmmend carrier screening fr a grup f disrders when at least ne member f a cuple is Ashkenazi Jewish and that cuple is pregnant r planning pregnancy. Bth rganizatins agree that testing shuld be ffered fr cystic fibrsis, Canavan disease, familial dysautnmia, and Tay-Sachs disease. ACMG als recmmends rutine testing fr Fancni anemia, Niemann-Pick disease, Blm syndrme, muclipidsis IV, and Gaucher disease. 2 Maple syrup urine disease and glycgen strage disease 1a carrier screening fr cmmn Ashkenazi Jewish mutatins is nw clinically available, but nt addressed in current carrier screening guidelines. These tw tests meet the criteria fr additinal carrier screening set in the 2008 ACMG guidelines. 2 Testing may be cnsidered fr carrier screening fr all r any desired subset f the Ashkenazi Jewish genetic diseases when BOTH f the fllwing are met: The individual is planning a pregnancy r currently pregnant; AND At least ne partner f a cuple is Ashkenazi Jewish NOTE: Detectin rates fr testing are higher in peple with Ashkenazi Jewish ancestry. If nly ne partner f a cuple is Ashkenazi Jewish, testing shuld start in that persn when pssible. Testing may be cnsidered fr carrier screening f a single Ashkenazi Jewish disease if EITHER f the fllwing are met: The individual has a family histry f ne f these cnditins; OR The individual s partner is a knwn carrier r affected with any f these cnditins References: 1. Cmmittee n Genetics, American Cllege f Obstetricians and Gyneclgists. ACOG Cmmittee Opinin, Number 442, Octber 2009. Precnceptin and prenatal carrier screening fr genetic diseases in individuals f Eastern Eurpean Jewish descent. Obstet Gynecl. 2009;114(4):950-3. 2. Grss SJ, Pletcher BA, Mnaghan KG; ACMG Prfessinal Practice and Guidelines Cmmittee. Carrier screening in individuals f Ashkenazi Jewish descent. Genet Med. 2008;10(1):54-6. Cpyright 2010-2011. DNA Direct, Inc. All Rights Reserved.
Plicy Guidelines: Genetic Testing fr Carrier Screening and Reprductive Planning Carrier screening fr hemglbinpathies Hemglbinpathies include genetic changes in the alpha- and beta-glbin genes, which cause alphathalassemia, beta-thalassemia, sickle cell anemia, and ther less cmmn bld disrders. The American Cllege f Obstetricians and Gyneclgists (ACOG) states that carrier screening fr hemglbinpathies is apprpriate fr peple with African, Mediterranean, and/r Sutheast Asian ancestry wh are pregnant r planning a pregnancy. 1 Hwever, they nte that carrier frequencies may be higher in sme ther ethnic ppulatins as well. 1 Hemglbinpathy screening by red bld cell indices (cmplete bld cunt) and quantitative hemglbin analysis may be cnsidered when ANY f the fllwing are met: The individual is planning a pregnancy r currently pregnant AND at least ne member f the cuple is in an at-risk ppulatin. (This includes but may nt be limited t peple f African, Sutheast Asian, and/r Mediterranean ancestry.); OR The individual has a family histry f a hemglbinpathy; OR The individual s partner is a knwn carrier r affected with a hemglbinpathy. The individual is participating in cllege athletics, military training, r ther strenuus activity in which a carrier may becme symptmatic. Mlecular genetic testing may be cnsidered when ANY f the fllwing are met: The individual is knwn r suspected t be a carrier f a hemglbinpathy based n the results f red bld cell indices and hemglbin analysis, and/r ethnic backgrund and family histry AND mutatin cnfirmatin is needed t verify carrier status, r fr cnsideratin f preimplantatin r prenatal diagnsis; OR The individual has a family histry f a hemglbinpathy and the familial mutatins are knwn Reference: ACOG Practice Bulletin, Number 78, January 2007. Hemglbinpathies in pregnancy. Obstet Gynecl. 2007;109(1):229-37. Fragile X carrier testing Fragile X syndrme is the mst cmmn inherited cause f mental retardatin. Guidelines frm the American Cllege f Obstetricians and Gyneclgy (ACOG) 1, the American Cllege f Medical Genetics (ACMG) 2, the American Sciety fr Reprductive Medicine (ASRM) 3, and the Natinal Sciety f Genetic Cunselrs (NSGC) 4 supprt fragile X carrier testing in adults with a family histry f mental retardatin r a knwn family histry f fragile X syndrme. Testing may be cnsidered when EITHER f the fllwing are met: The individual has a knwn family histry f fragile X syndrme; OR The individual has a family histry f mental retardatin f unknwn cause. Cpyright 2010-2011. DNA Direct, Inc. All Rights Reserved.
Plicy Guidelines: Genetic Testing fr Carrier Screening and Reprductive Planning References: 1. ACOG Cmmittee Opinin, Number 338, June 2006. Screening fr fragile X syndrme. Obstet Gynecl. 2006;107:1483-5. 2. Sherman, S., Pletcher, BA, and Driscll, DA. ACMG Practice Guideline. Fragile X syndrme: Diagnstic and carrier testing. Genet Med. 2005;7(8):584-7. 3. American Sciety f Reprductive Medicine (February 2008). Indicatins fr Fragile X Mental Retardatin (FMR-1) Genetic Testing. White paper. 4. McCnkie-Rsell A, Finucane B, Crnister A, Abrams L, Bennett RL, Pettersen BJ. Genetic cunseling fr fragile X syndrme: updated recmmendatins f the Natinal Sciety f Genetic Cunselrs. J Genet Cunsel. 2005; 14(4):249-70. Exclusins Multiplex Carrier Screening Multiplex carrier screening tests are designed t identify carrier status r predict risk fr many genetic diseases (70 r mre) in a single test. Several multiplex carrier screening tests are available nw. Others are knwn t be in develpment and will cme t market in the next few years. Each test has a unique set f diseases included in nvel and prprietary genetic testing platfrms. Of the genetic cnditins included in the currently available multiplex carrier screening tests, 12 f them are recmmended fr at least sme peple based n ethnicity by either the American Cllege f Obstetrics and Gyneclgy (ACOG) and/r the American Cllege f Medical Genetics (ACMG). 3-8 Hwever, mutatin analysis is nt the preferred initial screening test fr sme. These tests d nt meet the criteria abve fr technical and clinical validity and clinical utility: The technlgies used by the multiplex carrier screening tests are nvel. Infrmatin abut the test's perfrmance, if available, is ften prvided cmpletely by the labratry marketing the test, which culd be subject t bias. Sme f the cmmnly included tests, such as beta-thalassemia and Tay-Sachs disease, have inexpensive and reliable screening tests available (CBC with RBC indices and hexsaminidase A enzyme activity, respectively) that are superir t genetic testing. Multiplex carrier screening tests typically include carrier screening fr many diseases that have nt been identified as apprpriate fr ppulatin-based carrier screening. They may als include disrders, such as hereditary hemchrmatsis and factr V Leiden, which affect primarily adults and are generally manageable. These kinds f cnditins d nt meet the requirements fr reprductive carrier screening prgrams. Cpyright 2010-2011. DNA Direct, Inc. All Rights Reserved.