Beyond the Brochure - CEConnection · for fetal diagnosis of trisomy 21 and other chromosomal conditions, while carrier screening was available for a handful of single gene disorders

Continuing EducationJ Perinat Neonat Nurs Volume 33 Number 1 12ndash25 Copyright Ccopy 2019 Wolters Kluwer Health Inc All rights reserved

DOI 101097JPN0000000000000374

Beyond the BrochureInnovations in Clinical Counseling Practices for Prenatal GeneticTesting Options

Dana Knutzen MS LGC Katie Stoll MS LGC

ABSTRACTRemarkable advancements related to preconception andprenatal genetic screening have emerged in recent yearsWhile technology and testing options are more numerousand complex fundamental genetic counseling issues re-main the same It is essential that with any prenatal genetictesting women have an opportunity to make informed andautonomous decisions that are consistent with their per-sonal needs and values Opportunities to discuss testingoptions including potential benefits and limitations areoften limited in obstetric visits due to time constraints orlack of sufficient provider education As genetic testing isnot considered a routine component of antepartum carereview of information regarding testing options is impera-tive so women can decide which if any testing to pursueDeveloping new strategies to address the growing com-plexity of prenatal testing while ensuring provider educationis accurate is crucial in imparting evidence-based care Thisarticle will arm providers with the knowledge needed toeducate women about currently available prenatal geneticscreening and diagnostic tests along with guidance on theessential elements and importance of genetic counselingKey Words decision making genetic counseling genetictesting informed consent

Author Affiliations Department of Obstetrics and GynecologyBaylor College of Medicine (Ms Knutzen) and Genetic SupportFoundation (Ms Stoll)

Disclosure The authors have disclosed that they have no significantrelationships with or financial interest in any commercial companiespertaining to this article

Each author has indicated that he or she has met the journalrsquos require-ments for Authorship

Corresponding Author Dana Knutzen MS LGC Department of Ob-stetrics and Gynecology Baylor College of Medicine The ChildrenrsquosHospital of San Antonio 315 N San Saba Ste 930 San Antonio TX78207 (danaknutzenbcmedu)

Submitted for publication July 29 2018 accepted for publicationSeptember 17 2018

While genetic testing has been available inprenatal care settings for nearly half a cen-tury the number and complexity of prena-

tal options have grown dramatically in recent years12

Initially procedures such as amniocentesis could allowfor fetal diagnosis of trisomy 21 and other chromosomalconditions while carrier screening was available for ahandful of single gene disorders (eg Tay-Sachs disease[TSD] sickle cell anemia and cystic fibrosis) Todayprenatal diagnosis is available for hundreds of geneticconditions with noninvasive prenatal screening meth-ods for chromosomal disorders becoming more sensi-tive and specific

Many women may have preconceived ideas aboutprenatal genetic testing influenced by friends and fam-ily the media or commercial laboratories3 Although ge-netic testing is generally available to pregnant womenunlike other prenatal laboratory tests these are not or-dered routinely Discussions regarding prenatal genetictesting options are typically conducted by a physicianmidwife or nurse-practitioner however appointmentsmay be short with multiple topics to discuss leaving lit-tle time to review prenatal screening options and testingnuances45 This scenario coupled with the expansionof available prenatal screening options may result ininadequate counseling by healthcare providers6 Thuswomen may agree to testing simply based on the factthat screening was offered without making an informeddecision

Pretest counseling is provided to women so that theyhave an opportunity to make informed decisions aboutwhat if any prenatal genetic testing to undergo afterweighing potential benefits drawbacks and limitationsof tests in the context of specific needs and valuesWomen may find prenatal testing information helpfulin preparation for an infant with a genetic conditionor special medical needs Others may elect to undergoprenatal testing because pregnancy termination is being

Copyright copy 2019 Wolters Kluwer Health Inc Unauthorized reproduction of this article is prohibited

12 wwwjpnnjournalcom JanuaryMarch 2019

considered for a genetic diagnosis In addition somewomen decline prenatal testing because results will notchange pregnancy management if a genetic conditionis identified thus screening may evoke unwanted anx-iety The purpose of this article was to incorporate anoverview of currently available prenatal genetic screen-ing and diagnostic tests with guidance on critical ele-ments of pre- and posttest genetic counseling

OVERVIEW OF GENETIC TESTINGTo help women navigate various prenatal genetic test-ing options within established appointment time lim-its clinicians are obligated to understand differencesamong available tests as well as risks and benefits be-fore counseling patients Generally prenatal genetictesting is divided into 2 categories screening tests anddiagnostic tests17 Diagnostic testing during pregnancyinvolves a procedure such as amniocentesis or chori-onic villus sampling (CVS) to allow for direct testingon fetal or placental cells2 These tests provide defini-tive information about a diagnosis of a chromosomal orsingle gene condition in the fetus In contrast screen-ing tests such as maternal serum and prenatal cell freeDNA testing can only determine if there is a higheror lower chance of a chromosomal or genetic condi-tion in the pregnancy but cannot provide a definitivediagnosis17 Imaging modalities such as ultrasound andfetal magnetic resonance imaging (MRI) can providediagnostic information regarding birth defects but likescreening tests cannot diagnose an underlying geneticetiology17 Finally carrier screening for recessive dis-orders can identify those couples at increased risk tohave a child with a genetic condition however a diag-nostic procedure and test are needed to identify thosefetuses that are affected8 Both screening and diagnos-tic tests are typically available to pregnant women butthe amount of information desired by women can varysignificantly

ANEUPLOIDY SCREENINGGiven that diagnostic invasive procedures carry a riskof miscarriage screening tests performed on mater-nal blood allow for a mechanism to identify womenwho have a higher probability of a pregnancy affectedwith aneuploidy (eg conditions caused by the pres-ence or absence of chromosomal material)7 There aregenerally 2 types of screening for aneuploidy maternalserum screening and cell free DNA screening (cfDNAscreening) Each type of aneuploidy screen has multi-ple versions offered by a number of laboratories witheach modality demonstrating different strengths andweaknesses7

Maternal serum screening

Maternal serum screening for fetal aneuploidy requiresmeasurement of specific analytes detected in preg-nancy The data obtained from these analyte measure-ments are then used to calculate a posttest probabilityfor aneuploidy based on specific analyte values mater-nal age and other factors7 For example lower than av-erage levels of maternal serum alpha-fetoprotein duringthe second trimester of pregnancy are associated witha higher probability of trisomy 21 (Down syndrome)9

Through discovery of new analytes and an associationto aneuploidy risk maternal serum screening has gonethrough many updates (eg triple quad first trimestersequential and integrated screening) and now includesevaluation of multiple maternal analytes in the first andsecond trimesters to screen for trisomy 21 trisomy 18and in some cases trisomy 13 and Smith-Lemli-Opitzsyndrome17 Analyte screening also screens for con-ditions other than aneuploidy including neural tubeand abdominal wall defects given the association ofthese conditions with elevated maternal serum alpha-fetoprotein17

Prenatal cell free DNA

Also referred to as noninvasive prenatal screening ornoninvasive prenatal testing this clinical test involvesmeasurement of cell-free fragments of DNA in mater-nal serum for trisomy 13 18 21 and sex chromosomevariations71011 During pregnancy shedding placentalcells which usually have the same genetic make-up asthe fetus enter the maternal bloodstream710 These pla-cental DNA fragments can be detected and measuredfrom about 10 weeksrsquo gestation through the remain-der of the pregnancy710 Next-generation sequencingallows for amplification of cell-free DNA with analysisto determine if genetic material is over- or underrep-resented relative to what would be expected and thuscan predict if there is a higher or lower chance for ane-uploidy in the pregnancy1011

The relative amount of placental cfDNA to mater-nal cfDNA is known as the fetal fraction710 In somecases the fetal fraction is insufficient for the test tobe performed resulting in a ldquono-callrdquo result7 Fetal frac-tion is inversely correlated to maternal body mass indexand obese women are more likely to have a ldquono-callrdquoresult12 In addition no call results have been associ-ated with a higher likelihood of fetal aneuploidy710

Thus it is recommended that women with a no-call re-sult be offered genetic counseling and consideration ofdiagnostic testing1013

The positive and negative predictive values for ane-uploidy most notably Down syndrome are higherwith cfDNA screening than seen with maternal serum


The Journal of Perinatal amp Neonatal Nursing wwwjpnnjournalcom 13

screening1415 The chance that a positive result is a truepositive and not a false positive and the likelihood anegative result is a true negative is based on factorsincluding maternal age other screening test results (egmaternal serum) and family history57 The sensitivityor detection rate often listed as 98ndash99 for Downsyndrome does not correlate with a 98ndash99 chancethat the fetus is affected in the event of a positive resultas noted in Box 1

This vital clarification is often misunderstood byboth patients and providers11 Thus some womenassume that a pregnancy is affected based on apositive screening result before receiving posttestcounseling An online calculator developed by thePerinatal Quality Foundation and the National Societyof Genetic Counselors is available to assist clinicians inunderstanding cfDNA results and is available at httpswwwperinatalqualityorgVendorsNSGCNIPT

Initially cfDNA was utilized only as a screening testfor Down syndrome but it quickly advanced to in-clude other chromosomal conditions such as trisomy13 and 18 The ability to assess the X and Y chro-mosomes allows for determination of increased prob-ability of sex chromosome variations such as Turnersyndrome or Klinefelter syndrome and also allows forthe prediction of fetal sex15 Fetal sex determination asearly as 10 weeks has proven to be a successful sell-ing point for cfDNA testing however professional so-cieties such as the American College of Obstetriciansand Gynecologists (ACOG) Society of Maternal-FetalMedicine (SMFM) and the American College of Genet-

ics and Genomics (ACMG) advise that cfDNA screeningshould not be utilized for this purpose alone101315 Ad-ditionally many laboratories promote the use of cfDNAfor the detection of rare microdeletion and microdupli-cation syndromes however given the low prevalenceof these conditions and increased possibility of false-positive results inclusion in general screening is notrecommended5710

Current professional guidelines from ACOG andACMG support screening for aneuploidy for all preg-nant women in the context of pretest counseling andinformed consent713 It is not advised for women to un-dergo both cfDNA and analyte screening concurrentlyduring pregnancy and which test is optimal for eachwoman may be determined on a number of factors in-cluding maternal age and relative risk for aneuploidygestational age maternal body mass index and insur-ance coverage710 In addition cost and insurance cov-erage typically factors into which test is ultimately se-lected with currently evolving reimbursement trendslikely affecting future practice patterns

CARRIER SCREENINGCarrier screening identifies healthy women and partnerswho have an increased chance to have offspring withgenetic disorders16 Research estimates that each personis a carrier of 28 severe recessive disorders with inher-ited disorders accounting for 20 of infant mortality17

With autosomal recessive inheritance carriers are typ-ically healthy individuals who ldquocarryrdquo a deleterious

Box 1 Terminology for understanding screening testsab

Term Definition Example

Sensitivity Proportion of affected pregnancies thatare correctly identified as having thecondition (true positive)

Percentage of fetuses with trisomy 21with a positive result

Specificity Proportion of unaffected pregnanciesthat are correctly identified as NOThaving the condition (true negatives)

Percentage of fetuses that do not havetrisomy 21 with a negative result

Positive predictive value (PPV) Ratio of true positives to combinedtrue and false positives

The percentage of all positive resultsthat are true positives (fetusesactually have trisomy 21)

Negative predictive value(NPV)

Ratio of true negatives to combinedtrue and false negatives

The percentage of all negative resultsthat are true negatives (fetuses donot have trisomy 21)

aExplanation A positive screening test for trisomy 21 includes true-positive results (fetus has trisomy 21) and false-positive results (the fetus does not havetrisomy 21) The PPV allows you to determine the likelihood that a positive result is a true positive (the fetus actually has trisomy 21) The PPV is dependenton the prevalence of the disorder in a population The prevalence of trisomy 21 (and other aneuploidy conditions) increases with maternal age The PPV of ascreening test for trisomy 21 is therefore higher with increasing maternal age as the prevalence of trisomy 21 also increasesExample A cfDNA screening test for trisomy 21 in women who are 40 years of age has a PPV of approximately 90 while the PPV in 20-year-old women isapproximately 50 This means that in 40-year-old women approximately 9 out of 10 cases with a positive screen for trisomy 21 can be expected to be atrue positive while 20-year-old woman would have a 50-50 chance that a positive result is either a true-positive or false-positive result (Based on trisomy 21prevalence at 16 weeksrsquo gestational age with a screening test that has 99 sensitivity and 999 specificity for trisomy 21)bFrom Lutgendorf and Stoll11



mutation in a single copy of a gene If both membersof a couple carry a mutation in the same gene for thesame recessive disorder there is a 1 in 4 or 25 chancethat their child is affected with each pregnancy as notedin Figure 11819

If one member is found to be a carrier and the part-ner is unavailable or unknown refinement of recur-rence risk and option of prenatal diagnosis options arelimited as identification of a single variant will not dif-ferentiate between a fetus that is an unaffected carrierand one that may be affected

Todayrsquos carrier screening options span ethnic groupsand geographical boundaries20 Improved technologyalong with an increasing inability to categorize individ-uals into a single ethnic group has propelled offeringscreening for multiple disorders at one time16 AlthoughACOG and ACMG have carrier screening guidelines forspecific disorders most laboratory panels are set bycommercial entities1621 While panels with more op-tions may appeal to a diverse society disorders with lesswell-defined phenotypes and imprecise residual risksmake counseling difficult12 and do not replace currentpractice guidelines21

Carrier screening can be divided into 3 primarycategories pan-ethnic (universal) ethnicndashbased andexpanded carrier screening panels2021 Two profes-

sional organizations recommend pan-ethnic screeningfor cystic fibrosis and spinal muscular atrophy8162223

Screening for disorders based on an individualrsquos eth-nic background include disorders observed more fre-quently in the Ashkenazi Jewish population as wellas hemoglobinopathies2425 Expanded carrier screeningpanels typically screen for more than 100 disorders aswell as other recessive and X-linked conditions1620 Inaddition professional guidelines for screening for frag-ile X syndrome currently exist on the basis of the anal-ysis of personal or family history26 Current professionalguidelines are outlined in Box 2

Pan-ethnic carrier screening Cystic fibrosis

Cystic fibrosis is the most common life-limiting reces-sive disorder in Caucasians though recent treatmentadvances have extended average life expectancy withmedian survival now predicted to exceed 50 years ofage27 This type of carrier screening is offered regard-less of age race or ethnicity23 Cystic fibrosis is causedby mutations in the cystic fibrosis transmembrane con-ductance regulator (CFTR) gene Although more than2000 pathogenic variants have been identified currentscreening recommendations include a core panel of 23of the most common variants19

Figure 1 Autosomal recessive inheritance Used with permission from Genetic SupportFoundation18 (wwwgeneticsupportfoundationorg)



Box 2 Carrier screening guidelines based on Current ACOGACMG recommendationsa

DisorderACOGACMG

recommendation What to order

Cystic fibrosis (CF) Pan-ethnic screening Include 23 core mutation panel

Spinal muscular atrophy (SMA) Pan-ethnic screening Dosage analysis of SMN1 gene

Individuals of Ashkenazi Jewishancestry

Ethnicity-based Initially offer Tay-Sachs disease Canavan disease familialdysautonomia Cystic fibrosis

Screening considered Niemann-Pick (type A) Bloomsyndrome Fanconi anemia (group C) Mucolipidosis IVGaucher disease familial hyperinsulinism glycogenstorage disease type 1 Joubert syndrome maple syrupurine disease Usher syndrome

Individuals of French Canadian orCajun descent

Ethnicity-based Tay-Sachs disease

Hemoglobinopathies Ethnicity-based Complete blood cell count for all pregnant womenHemoglobin electrophoresis if African SE Asian or

Mediterranean descent

Fragile X syndrome Personalfamily history Personal history of premature ovarian insufficiency (POI)Family history of intellectual disability or autism

aFrom references 5 8 16 19 23 29 30

Pan-ethnic carrier screening Spinal muscular

atrophy

Women are offered preconception or prenatal carrierscreening for spinal muscular atrophy822 This disorderis the most common genetic cause of mortality in chil-dren younger than 2 years and affects approximately1 in 10 000 live births2228 Characterized by degener-ation of spinal motor neuron cells progressive mus-cle weakness and atrophy eventually evolve22 Othercommon complications include poor weight gain withgrowth and respiratory failure scoliosis and joint con-tractures Onset ranges from prenatal to young adult-hood with increasing severity in earlier-onset forms of

the disease as noted in Table 18192229 Treatment in-cludes gene therapy to limit disease progression andsurgical intervention to improve nutrition and respira-tory function1929

Spinal muscle atrophy is caused by mutations inthe SMN1 gene with approximately 95 of patientshaving inherited homozygous deletions of exon 7 inboth copies of the SMN1 gene29 In addition a pseu-dogene residing near SMN1 known as SMN2 can al-ter the clinical severity of this disorder when presentin multiple copies22 Statistics demonstrate that an esti-mated 1 in 40 to 60 people are unaffected carriers ofSMA29 Carrier testing can be complicated by multiple

Table 1 Types of spinal muscular atrophya

Type Age of onset Description

0 (congenital SMA) Prenatal Decreased fetal movements severe hypotonia andweakness at birth life expectancy sim6 mo

I (Werdnig-Hoffmandisease)

lt6 mo Severe weakness and hypotonia motor delaysproblems feeding failure to thrive respiratoryissues life expectancy sim24 mo

II (Dubowitz disease) 6-18 mo Low muscle tone but make developmental progressscoliosis progressive respiratory muscle weaknesslife expectancy teensmdash3rd4th decade

III (Kugelberg-Welanderdisease)

gt18 mo Initial ability to walk but lose this over time legs moreaffected than arms life expectancy is same asgeneral population

IV Adulthood Onset of muscle weakness 2ndmdash3rd decade lifeexpectancy is the same as general population

aFrom American College of Obstetricians and Gynecologists8 King JR Klugman19 Prior and Finanger29 and Sykes27



factors including de novo (new) mutations not inher-ited from a parent and mutations not detected by carrierscreening29 Given these nuances carrier status is con-firmed only when both parents are shown to carry asingle pathogenic variant in one of two copies of theSMN1 gene29

Ethnic-based screening Hemoglobinopathies

Hemoglobinopathies are a group of disorders that arecharacterized by abnormal hemoglobin When thereis an abnormality in the alpha globin genes (HBA1and HBA2) or beta globin gene (HBB) hemoglobinis not produced effectively resulting in anemia andother health problems The hemoglobinopathies in-clude structural hemoglobin variants as well as thethalassemias24 Testing for hemoglobinopathies is con-sidered in certain ethnic groups and in pregnancy withthe presence of anemia and normal iron studies24 Atesting flow chart is provided in Figure 2

Sickle cell disease (SCD) is characterized by abnor-mally shaped red blood cells resulting in obstructedblood flow and decreased oxygenation throughout theorgan systems More than 100 000 people in the UnitedStates are affected with SCD with most individuals be-ing of black or African-American descent30 Treatmentfor SCD includes managing symptoms to relieve painand prevent infections

Sickle cell disease is caused by a specific muta-tion in the HBB gene resulting in a variant known ashemoglobin S1930 Approximately 1 in 10 African Amer-icans are known to be carriers of hemoglobin S andthus said to have sickle cell trait8 Hemoglobin S is alsoseen more frequently in individuals of Greek Italian(particularly Sicillian) Turks Arabs Southern Iraniansand Asian Indians8 Sickle cell disease may also resultfrom coinheritance of hemoglobin S along with a sec-

Figure 2 Screening for hemoglobinopathies AbbreviationsHb = hemoglobin MCH = mean corpus hemoglobin MCV= mean corpus volume From American College of Ob-stetricians and Gynecologists24 Prior and Finanger29 andSykes27

ond HBB variant such as hemoglobin C D or E or betathalassemia

Beta thalassemia is caused by multiple pathogenicvariants in the HBB gene which in turn indicatesthe amount of beta chain (hemoglobin A) producedfrom each gene19 Persons with beta thalassemia majorhave alterations in both copies of the HBB gene andpresent within the first 2 years of life with severe ane-mia and extramedullary erythropoiesis poor growthand jaundice19 Death typically occurs by the age of 10years unless treated with periodic blood transfusions orbone marrow transplantation19 While individuals withbeta thalassemia intermedia also have 2 mutations inthe HBB gene these variants are typically less severeallowing some production of beta chains and thus vari-able amounts of hemoglobin A19 Beta thalassemia mi-nor or trait refers to individuals with a single mutation inthe HBB gene resulting in a mild asymptomatic anemiaBeta thalassemia occurs more frequently in individualsof Greek (Mediterranean) Middle Eastern Asian His-panic and West Indian descent19

Two genes are responsible for alpha thalassemia al-pha globin genes HBA1 and HBA2 Each individualhas 2 copies of a HBA1 gene and 2 copies of a HBA2gene one each on separate strands of chromosome 16for a total of 4 alpha globin genes19 How an individ-ual is affected by alpha thalassemia depends on howmany of the alpha globin genes are deleted as noted inFigure 319

Occasionally a point mutation rather than a dele-tion may be the underlying genetic factor in alpha tha-lassemia and when coupled with alpha thalassemiatrait may result in more significant disease24

Conditions more common in individuals of

Ashkenazi Jewish ancestry

People of Ashkenazi Jewish descent are primarily ofEastern European origin and make up the majority ofJewish individuals in the United States31 Carrier fre-quencies for certain recessive disorders like TSD areincreased in this population secondary to a foundereffect in which a mutation occurred in a single indi-vidual within a small community that then underwentsignificant population expansion The single mutationis then inherited by multiple members thus increasingthe carrier frequency and disorder incidence2532 Cur-rent guidelines indicate that carrier screening is offeredto persons where one or both members are of Ashke-nazi Jewish descent8 If only one member is Jewish andtesting confirms their carrier status partner testing isoffered8

Tay-Sachs disease is a severe progressive neurode-generative lysosomal storage disease resulting in build-up of GM2 gangliosides in the central nervous system



Figure 3 Possible outcomes for alpha thalassemia Normalhemoglobin Individuals with 4 working copies of the alphaglobin genes (no deletions) have normal hemoglobin levelsand are not affected nor carriers for alpha thalassemia Silentcarriers individuals with 3 working copies and one deletiontypically have no health problems and normal hemoglobinlevels Alpha thalassemia trait 2 working copies and 2 dele-tions typically have no health concerns but can demonstratemild anemia Individuals of Southeast Asian descent typi-cally have both deletions on the same chromosome (cis asshown) and thus are at risk to have a child with hemoglobinBartrsquos disease individuals of African descent have a dele-tion on each chromosome (trans not shown) Hemoglobin(Hb) H disease one working copy and 3 deletions typicallydevelop mild to severe health concerns such as moderate-severe anemia hepatosplenomegaly mild jaundice chronicfatigue and bone changes and may require frequent bloodtransfusions Hemoglobin Bartrsquos disease (Hb Barts) dele-tions in all 4 alpha globin genes typically have fetal onset ofedema pleural and pericardial effusions resulting in hydropsfetalis and severe anemia typically resulting in death in thenewborn period From American College of Obstetriciansand Gynecologists824 King and Klugman19

(CNS) causing early childhood death8 Through com-munity education and screening programs the inci-dence of TSD in the Jewish population has declined dra-matically with most affected children now being bornto non-Jewish parents2531 Carrier screening for otherdisorders in the Ashkenazi Jewish population is alsorecommended8 A brief description of each is providedin Table 282033ndash40

Fragile X syndrome and FMR1-related disorders

Fragile X syndrome is the most common inherited formof intellectual disability occurring in approximately 1 in3600 males and 1 in 4000ndash6000 females8 The diseasespectrum has expanded to include learning disabilitiesattention-deficithyperactivity disorder and autism inboth genders Although not known to be associatedwith structural birth defects a characteristic pattern offeatures in affected males has been described40

Fragile X syndrome is caused by an altered FMR1gene located on the X-chromosome and follows an X-linked pattern of inheritance as noted in Figure 441

The most common alteration involves expansion of atrinucleotide repeat with an associated effect on methy-

lation In the presence of a family history of intellectualdisability carrier frequency is approximately 1 in 86while the risk is lower 1 in 257 for females with noknown risk factors8

Current guidelines advise against routine carrierscreening for fragile X syndrome unless requested bya woman8 Women considering pregnancy or alreadypregnant with a family history of fragile X-related disor-ders intellectual disability or autism are offered fragileX carrier screening8 Additionally women with unex-plained premature ovarian insufficiency or an elevatedfollicle stimulating hormone before 40 years or malesand females over age 50 years with fragile X-associatedtremorataxia syndrome (FXTAS intention tremor andataxia difficulties with memory and cognitive declineatrophy and Parkinson-like features)40 are also offeredscreening to identify those who may be premutationcarriers for FMR1-related disorders

Expanded carrier screening panels

Expanded carrier screening panels which can vary insize include an ability to screen for multiple disorderssimultaneously regardless of personal or family historyor ethnic background21 While appealing to patients andhealthcare providers expanded carrier screening panelshave several limitations as outlined in Table 3

When a larger number of disorders are included onthe panel there is a greater chance of identification of acarrier of one or more disorders42 The chance that bothindividuals are carriers for the same disorder is greatestwith consanguinity or within the same ethnic group5

When carrier status is identified for the same disorderprenatal diagnosis through CVS or amniocentesis is typ-ically offered

DIAGNOSTIC TESTINGDiagnostic tests provide definitive information a yes-or-no answer about diagnosis of a chromosomal or singlegene condition in the fetus Diagnostic testing includeschorionic villi sampling (CVS) or amniocentesis43 Eachprocedure allows for assessment of the number ofchromosomes present in a fetus also known as akaryotype43 Initially diagnostic testing was only offeredto women who were believed to have a higher chanceof a genetic or chromosomal condition with most pro-cedures performed for advancing maternal age Cur-rent professional recommendations state that all womenmay be offered assessment for fetal aneuploidy throughscreening or diagnostic testing regardless of age743

Amniocentesis

Amniocentesis for prenatal genetic testing is usuallyperformed between 15 and 20 weeksrsquo gestation12 Am-niotic fluid contains fetal cells (amniocytes) which



Table 2 Carrier screening for disorders seen more frequently in Ashkenazi Jewish populationa

Disorders DescriptionCarrier

frequency

Genetic analysisfor Ashkenazi Jewish

individuals

Cystic fibrosis Chronic respiratory infectionspancreatic insufficiency infertility inmales secondary to CAVD

124 Gene CFTR 23 coremutation panel (5mutations detect 97 ofcarriers)

Canavan disease Degenerative neurologic disorder withonset in infancy with macrocephalyhypotonia developmental delays(DD)intellectual disabilities (ID) lifeexpectancy is childhood oradolescence

141 Gene ASPA 2 mutationsdetect 974 of carriers

Familialdysautonomia

Disorder of the sensory and autonomicnervous system resulting inabnormal suck feeding difficultiesepisodic vomiting temperatureinsensitivity abnormal sweating

132 Gene IKBKAP 2 mutationsincluding IVS20(+6T-gtC)which accounts for 99

Tay-Sachs disease Severe progressiveneurodegenerative lysosomalstorage disease resulting in build-upof GM2 gangliosides in the centralnervous system causing death inearly childhood

130 Gene HEXA 3 mutationsdetect 92ndash99 ofcarriers Enzymatic analysisof hexosaminidase Ademonstrates low activityin carriersb

Fanconi anemia(Group C)

May exhibit short stature skeletalanomalies (upperlower extremities)pigmentary differences bonemarrow failure with increased risk ofmalignancy and solid tumorsc

189 Gene FANCC one mutation(IVS4+4AgtT) detectsgt99 of carriers

Niemann-Pick type A Cherry red spot in eye failure to thrivehepatosplenomegaly neurologicdeterioration life expectancy is earlychildhood

190 Gene SMPD1 3 mutationsdetect sim90 of carriers

Bloom syndrome Short stature skin rash during sunexposure increased risk for cancerlearning disabilities (LD)

1107 Gene BLM 1 mutation(2281del6ins7) gt99 ofcarriers

Mucolipidosis typeIV

Severe developmental delays withprogressive visual impairment

1127 Gene MCOLN1 2 mutationsaccount for 95 of carriers

Gaucher disease Various types withhepatosplenomegaly anemiathrombocytopenia bone diseasewith types 2 and 3 alsodemonstrating CNS findings

115 Gene GBA 4 mutationsaccount for sim90 ofcarriers

Familialhyperinsulinism

Increased levels of insulin resulting inhypoglycemia can present withseizures hypotonia Unless treatedresults in brain damage

168 Gene ABCC8 2 mutationsaccount for 97 of carriers

Glycogen storagedisease type 1

Organ malfunction secondary tobuild-up of glycogen in cells Age ofonset typically 3ndash4 months

170 Genes G6PC and SLC37A4one mutation in G6PCaccounts for the majority ofcarriers

Joubert syndrome Hypotonia ataxia abnormal breathingIDDD and presence of ldquomolar toothsignrdquo on MRI

192 ndash 1100 Multiple genes associatedwith JS but one mutation(pArg73Leu) in TMEM216gene observed morefrequently in AJ descent

(continues)




(Continued)


frequency


individuals

Maple syrup urinedisease

Urine smells ldquosweetrdquo in infants poorfeeding lethargy and DD Lifeexpectancy=lethal withouttreatment

197 Genes BCKDHA BCKDHBDBT 3 mutations in theBCKDHB gene account forthe majority of carriers

Usher syndrome Type I congenital profound hearingloss vestibular difficulties andretinitis pigmentosa (RP) Type IIIpostlingual hearing loss variablevestibular difficulties late-onset RP

178 ndash 1120 Genes PCDH15 (type 1F)one mutation (R245X)detects 95 of carriers andCLRN1 (type III) onemutation (N48K) detects75 of carriers

aFrom references 8 19 31-39bEnzymatic analysis of hexosaminidase A is the preferred screening method for TSD in those of non-Jewish descent as this assay detects sim98 of carriersregardless of ethnic background8 Enzymatic testing performed in serum with the exception of pregnant womenthose taking oral contraceptives whereanalysis is best in leukocytes to minimize the occurrence of false-positive resultscSome individuals do not show any physical symptoms

are primarily sloughed from fetal skin and the uri-nary tract and used for genetic testing Biochemi-cal studies on amniotic fluid can also be performedto evaluate markers such as alpha fetoprotein and

acetylcholinesterase to diagnose open neural tubedefects1 Risk of miscarriage associated with amnio-centesis is reported as 011 or approximately 1in 90044

Figure 4 X-linked recessive inheritance Used with permission from GeneticSupport Foundation41 (wwwgeneticsupportfoundationorg)



Table 3 Limitations of expanded carrier screening panelsa

Not comprehensive ECS panels do not screen for all genetic disordersVary by laboratory ECS panels vary by laboratory and typically incorporate a variety of genetic analyses

when screening for disorders This analysis includes assessing for commonmutations thus missing mutations that may be specific to certain ethnic groupsor those with a positive family history A ldquonegativerdquo result is therefore of littlesignificance if testing was not tailored to the patientrsquos ethnicity or family history

Degrees of severity ECS panels include disorders with various degrees of severity from lethal disordersin childhood to those with treatable conditions Some disorders may demonstratehigh phenotypic variability even when the same underlying mutation is presentmaking counseling regarding potential outcome difficult to estimate

Residual risk A negative carrier screen reduces but does not eliminate the chance that anindividual is a carrier for a disorder A residual carrier risk will remain in the settingof a negative result

Diagnostic ECS panels may identify 2 pathogenic variants for a disorder thus diagnosing anindividual rather than determining their carrier status

Rare disorders ECS panels include rare disorders where the carrier frequency is unknown Whenone member of a couple is found to be a carrier of a rare disorder it may bedifficult to calculate accurate recurrence risks given the inability of knowing thecarrier frequency in the general population

aFrom references 5 16 20 21

Chorionic villus sampling

Chorionic villus sampling (CVS) is commonly per-formed between 10 and 13 weeksrsquo gestation andinvolves aspirating placental villi transcervically ortransabdominally12 The genetic make-up of the chori-onic villi is usually congruent with the fetus there-fore aneuploidy or other genetic mutations identifiedby CVS can be diagnostic of chromosomal or geneticconditions1 In rare situations incongruence of a chro-mosomal abnormality between the placenta and the fe-tus can occur due to non-disjunction early in embry-onic development leading to placental mosaicism4546

Miscarriage rate is currently estimated to be 1 in 455 or02244

While CVS is considered a diagnostic test cautionmust be given when used as a follow-up test to high-riskcfDNA results as both rely on placental cell analysis5

Confined placental mosaicism the possibility that ab-normal cells may only reside in a placenta and not inthe fetus is a phenomenon that may suggest that a fe-tus with an abnormal cfDNA and CVS result is trulyaffected when actually the abnormal cells are onlypresent in placenta25

Chromosome microarray analysis

Karyotype analysis was the gold standard for diagnos-tic aneuploidy testing for decades but is now often for-gone for the newer technology of chromosome microar-ray analysis Chromosomal microarray allows detectionof chromosomal deletions and duplications that are toosmall to be seen by traditional karyotype analysis47

Deletions and duplications are known as ldquocopy numbervariantsrdquo and can cause varying degrees of health con-cerns and severity including birth defects and intellec-tual disabilities47 Previous studies estimate that approx-imately 6 of fetuses with structural abnormalities arefound to carry copy number variants of clinical signifi-cance versus 1ndash2 of fetuses with normal ultrasoundevaluations48

A leading professional organization recommendsthat microarray testing be offered in place of fetalkaryotyping when a structural anomaly is detected onultrasound47 For indications such as advanced mater-nal age or an abnormal first trimester screen either CMAtesting or karyotyping can be offered47 Additional stud-ies such as whole exome sequencing (WES) and genetictesting for single gene disorders on amniocytes are alsopossible when there are unique concerns based on ul-trasound findings or family history43

FETAL IMAGINGImaging modalities such as ultrasound and fetal mag-netic resonance imaging (MRI) may aid in screeningand diagnosis of fetal placental and maternal abnor-malities including birth defects Like screening testshowever imaging cannot detect an underlying geneticetiology but can provide information that may altermedical management or birth route While deemed safeduring pregnancy the use of these devices is ldquoexpectedto answer a relevant clinical question or otherwise pro-vide medical benefit to the patientrdquo49(e210)



Ultrasound

Ultrasonography is a readily available fetal imagingmethod used throughout pregnancy During the firsttrimester a fluid-filled area at the back of a fetal neckis measured and referred to as nuchal translucency El-evated values raise concern for a fetal aneuploidy (egtrisomy 21) or a major structural anomaly (eg cardiacdefect)50

Second-trimester ultrasound has become a routineassessment for fetal anatomy Typically performed be-tween 18 and 22 weeksrsquo gestation ultrasound focuseson detecting structural fetal anomalies soft markersfor aneuploidy placental location and fetal size50 Softmarkers such as a thickened nuchal fold or an absentnasal bone in the presence of an increased risk on ma-ternal serum or cfDNA screen can further raise con-cern for an underlying aneuploidy Identification of softmarkers or a major structural anomaly typically promptsreferral for maternal-fetal medicine and genetic counsel-ing to allow for further discussion of prenatal diagnosisoptions and in some cases such as with open neuraltube defects fetal surgical intervention

Magnetic resonance imaging

Magnetic resonance imaging (MRI) of a fetus can pro-vide additional details of a suspected or ill-definedstructural fetal anomaly after the first trimester Al-though initially too slow to capture a moving fetusnew MRI scanners offer single-shot images that allowfor optimal imaging without using fetal sedation51 Ben-efits include higher quality of imaging not reliant onoperator experience and enhanced imaging of softtissue that can be performed without using ionizingradiation47 Limitations include availability gestationalage and that fetal anatomy and pathology can differthan that of a newborn51

Fetal MRI may be most beneficial when assessingspecific structural anomalies Abnormalities of the CNSincluding ventriculomegaly may be the most commonreason for imaging but clarification of the extent of fetalmasses such as teratomas can also be helpful52 Forcongenital anomalies requiring surgery such as openneural tube defects or congenital diaphragmatic herniaMRI may assist with candidacy for fetal surgery andestimating likelihood of survival

DISCUSSIONPrior to 2007 healthcare providers had limited prena-tal genetic testing options to review with a defined setof women considered to be at increased risk653 Infor-mation could be reviewed during obstetric visits withformal genetic counseling requested in the setting ofabnormal test results With the recommendation to of-

fer prenatal genetic screening options to all women re-gardless of age or other risk factors and the explosionof available genetic tests healthcare providers may findthemselves limited in their understanding of testing op-tions and what information they can provide during anobstetric visit26 This coupled with an estimated 2500clinical genetic counselors currently in practice in theUnited States covering all specialty areas it is impracti-cal to refer all pregnant women for genetic counseling54

Thus healthcare providers other than genetic coun-selors must have the information and skill set necessaryto help guide patients through navigating the myriad oftesting options

The American College of Obstetricians and Gynecol-ogists recommends that pretest counseling occur at theinitial obstetric visit and be a ldquoprocess of shared de-cision makingrdquo including a discussion of the womanrsquosrisks for genetic disorders and the differences betweenscreening and diagnostic tests2(e112) Informing womenthat there is no genetic test that can guarantee the birthof a healthy baby is imperative along with documen-tation in the medical record of her decision to pursueor decline testing Discussion of risks for aneuploidy orcarrier status may need to be presented in numerical(eg fractions percentages) or with pictorial images tomeet various learning styles

Effective counseling begins with healthcareproviders having a clear understanding of avail-able prenatal genetic testing options as well as thebenefits and limitations of the tests being offered55

Information discussed is centered around a womanrsquosneeds level of apprehension regarding abnormalor inconclusive results test limitations and partnerinvolvement for carrier screening56 Providing possiblescenarios may help patients understand how theirdecisions to pursue or decline testing can affectpregnancy For example an apprehensive patient whowould refuse diagnostic testing regardless of screeningresults may wish to decline prenatal screening teststo minimize the emotional impact of an abnormalresult Alternatively a woman who voices concerns foraneuploidy or a known familial diagnosis may electto pursue diagnostic testing directly When time isdedicated to providing pretest counseling women aremore inclined to make autonomous decisions and havedecreased anxiety when receiving abnormal results57ndash59

As testing should not be considered routine and in-formed consent always obtained alternative strategiesto address the complexity of testing options in a shorttime period may need to be considered55 Group coun-seling has been employed by some clinics to addressbenefits and limitations of testing to multiple patientsin one setting thus removing discussions from the ini-tial obstetric visit5355575860 Flow charts brochures and



Table 4 Genetic counseling resources

Resource Description URL

Video series produced byGenetic SupportFoundation and theWashington StateDepartment of Healthregarding prenatal genetictesting to support patienteducation and pretestgenetic counseling

A series of 7 educationalvideos for patients eachapproximately 3ndash4 min inlength on the topics such ascfDNA screening analytescreening ultrasound andamniocentesis Available inSpanish and English

httpsgeneticsupportfoundationorgvideos

Cell Free DNA ScreeningInfographic produced bythe American College ofObstetricians andGynecologists

A printable 2-page infographicdescribing cfDNAscreening for patients withexplanation of predictivevalue

httpswwwacogorgPatientsFAQsCell-free-DNA-Prenatal-Screening-Test-Infographic

Provider talking pointsregarding positive cfDNAscreening results producedby the National Society ofGenetic Counselors

A resource for providers withdetails on how to interpretand communicate withpatients about a positivecfDNA screen

httpswwwnsgcorgpageabnormal-non-invasive-prenatal-testing-results

NIPTCell Free DNAScreening Predictive ValueCalculator Developed bythe Perinatal QualityFoundation and theNational Society of GeneticCounselors

An online calculator to assessthe positive and predictivevalue for conditionsincluded on cfDNAscreening panels

httpswwwperinatalqualityorgVendorsNSGCNIPT

videos developed by professional organizations (notcommercial laboratories with competing interests) canalso provide supplemental unbiased information to pa-tients regarding prenatal screening options535561 Ac-cessing electronic or web-based tools prior to the initialobstetric visit can provide an overview of available test-ing options allowing time during the visit for patient-centered counseling5355 Examples of various resourcesto assist providers with counseling are included inTable 4

Healthcare providers delivering abnormal screeningtest results require awareness that this information mayevoke anxiety and confusion in women about what theresult may actually mean4262 In situations in which awoman is unaware that testing was performed or forthose with limited health education or a previous childwith aneuploidy extended posttest counseling with vi-sual aids may help clarify confusion and concerns62 Itis crucial that any abnormal results are interpreted inthe context of the patient the pregnancy and her fam-ily history and referral for genetic counseling should beconsidered

CONCLUSIONPrenatal genetic testing options are numerous and com-plex It is essential that healthcare providers allow time

for review of various options including discussion ofbenefits and limitations so women have an opportunityto make informed independent decisions Knowledgeregarding what tests are available current professionalrecommendations and a general understanding of thenuances of testing are imperative to providing accurateinformation to women and their families

References1 Wilson KL Czerwinski JL Hoskovec JM et al NSGC Practice

Guideline prenatal screening and diagnostic testing optionsfor chromosome aneuploidy J Genet Counsel 2013224ndash15doi101007s10897-012-9545-3

2 American College of Obstetricians and Gynecologists Com-mittee on Genetics Society for Maternal Fetal Medicine Com-mittee Opinion No 682 microarrays and next generationsequencing technology the use of advanced genetic diag-nostic tools in obstetrics and gynecology Obstet Gynecol2016128e262ndash268

3 Lewis C Hill M Chitty LS A qualitative study looking atinformed choice in the context of non-invasive prenatal test-ing for aneuploidy Prenat Diagn 201636875ndash881 doi101002pd4879

4 Johnston J Farrell R Parens E Supporting womenrsquos auton-omy in prenatal testing N Engl J Med 2017377(6)505ndash507doi101056NEJMp1703425

5 Fonda Allen J Stoll K Bernhardt BA Pre- and post-test genetic counseling for chromosomal and mendeliandisorders Semin Perinatol 201640(1)44ndash55 doi101053jsemperi201511007



6 Minkoff H Berkowitz R The case of universal prenatal ge-netic counseling Obstet Gynecol 2014123(6)1335ndash1338

7 American College of Obstetricians and Gynecologists Prac-tice Bulletin 163 screening for fetal aneuploidy ObstetGynecol 2016127(5)e123ndashe137 doi101097AOG0000000000001406

8 American College of Obstetricians and Gynecologists Com-mittee Opinion No 691 carrier screening for genetic condi-tions Obstet Gynecol 2017129e41ndashe55

9 Chasen ST Maternal serum analyte screening for fetal aneu-ploidy Clin Obstet Gynecol 201457(1)182ndash188 doi101097GRF0000000000000017

10 American College of Obstetricians and Gynecologists andSociety for Maternal-Fetal Medicine Committee Opinion 640Cell-Free DNA screening for fetal aneuploidy Obstet Gynecol2015126(3)e31ndashe37

11 Lutgendorf MA Stoll KA Why 99 may not be as goodas you think it is limitations of screening for rare dis-eases J Matern Fetal Neonatal Med 201629(7)1187ndash1189doi1031091476705820151039977

12 Livergood MC LeChien KA Trudell AS Obesity and cell-freeDNA ldquono callsrdquo is there an optimal gestational age at time ofsampling Am J Obstet Gynecol 2017216(4)413e1ndash413e9doi101016jajog201701011

13 Gregg AR Skotko BG Benkendorf JL et al Noninvasiveprenatal screening for fetal aneuploidy 2016 update a po-sition statement of the American College of Medical Ge-netics and Genomics Genet Med 201618(10)1056ndash1065doi101038gim201697

14 Norton ME Jacobsson B Swamy GK et al Cell-free DNAanalysis for noninvasive examination of trisomy N Engl JMed 2015372(17)1589ndash1597 doi101056NEJMoa1407349

15 Benn P Borrell A Chiu R et al Position statement fromthe chromosome abnormality screening committee on be-half of the board of the International Society for PrenatalDiagnosis Prenat Diagn 201535(8)725ndash734 doi101002pd4606

16 Edwards JG Feldman G Goldberg J et al Expanded carrierscreening in reproductive medicine-points to consider ObstetGynecol 2015125(3)653ndash662

17 Bell CJ Dinwiddie DL Miller NA et al Carrier test-ing for severe childhood recessive diseases by next-generation sequencing Sci Transl Med 20113(65)65ra4doi101126scitranslmed3001756

18 Autosomal recessive inheritance Genetic Support Founda-tion Web site httpswwwgeneticsupportorggenetics-101inheritance-patternsautosomal-recessive Updated April 72017

19 King JR Klugman S Ethnicity-based carrier screening ObstetGynecol Clin N Am 20184583ndash101 httpsdoiorg101016jogc201710010

20 Rose NC Wick M Carrier screening for single gene disor-ders Semin Fetal Neonatal Med 20171ndash7 httpdxdoiorg101016jsiny201706001

21 American College of Obstetricians and Gynecologists Com-mittee Opinion No 690 carrier screening in the age of ge-nomic medicine Obstet Gynecol 2017129e35ndashe40

22 Prior TW Carrier screening for spinal muscular atrophyGenet Med 200810(11)840ndash842

23 American College of Obstetricians and Gynecologists Com-mittee Opinion No 486 update on carrier screening for cysticfibrosis Obstet Gynecol 2011117(4)1028ndash1031

24 American College of Obstetricians and Gynecologists Prac-tice Bulletin No 78 hemoglobinopathies in pregnancy Ob-stet Gynecol 2007109(1)229ndash237

25 Gross SJ Pletcher BA Monaghan KG Carrier screeningin individuals of Ashkenazi Jewish descent Genet Med200810(1)54ndash56 doi101097GIM0b013e31815f247c

26 American College of Obstetricians and Gynecologists Com-mittee Opinion No 469 carrier screening for fragile X syn-drome Obstet Gynecol 2010116(4)1008ndash1010

27 Sykes J Stanojevic S Goss CH et al A standardized approachto estimating survival statistics for population-based cysticfibrosis registry cohorts J Clin Epidemiol 201670206ndash213doi101016jjclinepi201508026

28 Hendrickson BC Donohoe C Akmaev VR et al Differ-ences in SMN1 allele frequencies among ethnic groupsin within North America J Med Genet 200946641ndash644doi101136jmg2009066969

29 Prior TW Finanger E Spinal muscular atrophy In AdamMP Ardinger HH Pagon RA et al eds GeneReviews Rcopy[Internet] Seattle WA University of Washington 1993ndash2018 httpswwwncbinlmnihgovbooksNBK1352 Up-dated December 22 2016

30 Bender MA Sickle cell disease In Adam MP ArdingerHH Pagon RA et al eds GeneReviews Rcopy [Internet] SeattleWA University of Washington Seattle 1993ndash2018 httpswwwncbinlmnihgovbooksNBK1377 Updated August17 2017

31 Klugman S Gross SJ Ashkenazi Jewish screening in thetwenty-first century Obstet Gynecol Clin N Am 20103737ndash46 doi101016jogc201001001

32 Schrijver I Klum M Gardner PI et al Comprehensivearrayed primer extension array for the detection of 59sequence variants in 15 conditions prevalent among the(Ashkenazi) Jewish population J Mol Diagn 20079(2)228ndash236

33 Bali DS Chen YT Austin S et al Glycogen storage dis-ease type I In Adam MP Ardinger HH Pagon RA et aleds GeneReviews Rcopy [Internet] Seattle WA University ofWashington Seattle 1993-2018 httpswwwncbinlmnihgovbooksNBK1312 Updated August 25 2016

34 Mehta PA Tolar J Fanconi anemia In Adam MP ArdingerHH Pagon RA et al eds GeneReviews Rcopy [Internet] SeattleWA University of Washington Seattle 1993-2018 httpswwwncbinlmnihgovbooksNBK1401 Updated March 82018

35 Ong T Marshall SG Karczeski BA et al Cystic fibrosisand congenital absence of the vas deferens In Adam MPArdinger HH Pagon RA et al eds GeneReviews Rcopy [Internet]Seattle WA University of Washington Seattle 1993-2018httpswwwncbinlmnihgovbooksNBK1250 UpdatedFebruary 2 2017

36 Parisi M Glass I Joubert syndrome In Adam MP ArdingerHH Pagon RA et al eds GeneReviews Rcopy [Internet]Seattle WA University of Washington Seattle 1993-2018httpswwwncbinlmnihgovbooksNBK1325 UpdatedJune 29 2017

37 Pastores GM Hughes DA Gaucher disease In Adam MPArdinger HH Pagon RA et al eds GeneReviews Rcopy [Inter-net] Seattle WA University of Washington Seattle 1993-2018 httpswwwncbinlmnihgovbooksNBK1269 Up-dated June 21 2018

38 Schiffmann R Grishchuk Y Goldin E Mucolipidosis IVIn Adam MP Ardinger HH Pagon RA et al edsGeneReviews Rcopy [Internet] Seattle WA University of Wash-ington Seattle 1993-2018 httpswwwncbinlmnihgovbooksNBK1214 Updated July 30 2015

39 Wasserstein MP Schuchman EH Acid sphingomyelinase de-ficiency In Adam MP Ardinger HH Pagon RA et aleds GeneReviews Rcopy [Internet] Seattle WA University ofWashington Seattle 1993-2018 httpswwwncbinlmnihgovbooksNBK1370 Updated June 18 2015

40 Saul RA Tarleton JC FMR1-related disorders In Adam MPArdinger HH Pagon RA et al eds GeneReviews Rcopy [Internet]Seattle WA University of Washington Seattle 1993-2018



httpswwwncbinlmnihgovbooksNBK1384 UpdatedApril 26 2012

41 X-linked inheritance Genetic Support Foundation Web sitehttpswwwgeneticsupportorggenetics-101inheritance-patternsx-linked Updated July 19 2018

42 Rothwell E Johnson E Mathiesen A et al Experiencesamong women with positive prenatal expanded carrierscreening results J Genet Counsel 201726(4)690ndash696doi101007s10897-016-0037-8

43 American College of Obstetricians and Gynecologists Prac-tice Bulletin No 162 prenatal diagnostic testing for geneticdisorders Obstet Gynecol 2016127(5)e108ndashe122

44 Akolekar R Beta J Picciarelli G Ogilvie C DrsquoAntonioF Procedure-related risk of miscarriage following amnio-centesis and chorionic villus sampling a systematic re-view and meta-analysis Ultrasound Obstet Gynecol 20154516ndash26

45 Hahnemann JM Vejerslev LO Accuracy of cytogenetic find-ings on chorionic villus sampling (CVS)mdashdiagnostic conse-quences of CVS mosaicism and non-mosaic discrepancy incentres contributing to EUCROMIC 1986-1992 Prenat Diagn199717(9)801ndash820

46 Grati FR Chromosomal mosaicism in human feto-placentaldevelopment implications for prenatal diagnosis [Review] JClin Med 20143(3)809ndash837 doi103390jcm3030809

47 American College of Obstetricians and Gynecologists Com-mittee on Genetics Society for Maternal Fetal Medicine Com-mittee Opinion No 581 the use of chromosomal microarrayanalysis in prenatal diagnosis Obstet Gynecol 2013122(6)1374ndash1377

48 Wapner RJ Martin CL Levy B et al Chromosomal microar-ray versus karyotyping for prenatal diagnosis N Engl J Med20123672175ndash2184

49 American College of Obstetricians and Gynecologists Com-mittee Opinion No 723 guidelines for diagnostic imagingduring pregnancy and lactation Obstet Gynecol 2017130(4)e210ndashe216

50 Edwards L Hui L First and second trimester screeningfor fetal structural anomalies Semin Fetal Neonatal Med201823102ndash111

51 Ertl-Wagner B Lienemann A Strauss A Reiser M Fetal mag-netic resonance imaging indications technique anatomicalconsiderations and a review of fetal abnormalities Eur Ra-diol 2002121931ndash1940

52 Verburg B Fink AM Reidy K Palma-Dias R The contribu-

tion of MRI after fetal anomalies have been diagnosed byultrasound correlation with postnatal outcomes Fetal DiagnTher 201538186ndash194 doi101159000380821

53 Stoll K Kubendran S Cohen S The past present and fu-ture of service delivery in genetic counseling keeping up inthe era of precision medicine Am J Med Genet 20181ndash14doi101002ajmgc31602

54 Hoskovec JM Bennett RL Carey ME et al Projecting thesupply and demand for certified genetic counselors a work-force study J Genet Counsel 201727(1)16ndash20 doi101007s10897-017-0158-8

55 Metcalfe SA Genetic counseling patient education and in-formed decision-making in the genomic era Semin FetalNeonatal Med 20171ndash8 doi101016jsiny201711010

56 Agatisa PK Mercer MB Coleridge M Farrell RM Geneticcounselorsrsquo perspective about cell-free DNA experienceschallenges and expectations for obstetricians J Genet Couns20181ndash12 httpsdoiorg101007s10897-018-0268-y

57 Gammon BL Otto L Wick M Borowski K Allyese M Imple-menting group prenatal counseling for expanded noninva-sive screening options J Genet Couns 20171ndash8 httpsdoiorg101007s10897-017-0178-4

58 Hunter AG Cappelli M Humphreys L et al A randomizedtrial comparing alternative approaches to prenatal diagnosiscounseling in advancing maternal age patients Clin Genet200567(4)303ndash313

59 Cloutier M Gallagher L Goldsmith C Akiki S BarrowmanN Morrison S Group genetic counseling an alternate ser-vice delivery model in a high risk prenatal screening pop-ulation Prenat Diagn 201737(11)1112ndash1119 doi101002pd5149

60 Knutzen DM Stoll KA McClellan MW Deering SH Foglia LMImproving knowledge about prenatal screening options cangroup education make a difference J Matern Fetal NeonatalMed 201326(18)1799ndash1803

61 Kloza EM Haddow PK Halliday JV Orsquobrien BM Lambert-messerlian GM Palomaki GE Evaluation of patient edu-cation materials the example of circulating cell free DNAtesting for aneuploidy J Genet Couns 201424(2)259ndash266doi101007s10897-014-9758-8

62 Van Schendel RV Lieve Page-Christiaens GCM Beulen Let al Womenrsquos experiences with non-invasive prenatal test-ing and emotional well-being and satisfaction after test-results J Genet Couns 2017261348ndash1356 doi101007s10897-017-0118-3

The CE test for this article is available online only Log onto the journal website wwwjpnnjournalcomor to wwwNursingCentercomCEJPNN to access the test For more than 15 additional continuingeducation articles related to neonatal topics go to NursingCentercomCE

Instructions Read the article The test for this CE activity is to be taken

online at wwwNursingCentercomCEJPNN You will need to create (its free) and login to your per-

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This activity is also provider approved by the California Boardof Registered Nursing Provider Number CEP 11749 LippincottProfessional Development is also an approved provider of continu-ing nursing education by the District of Columbia Board of Nursing50-1223 Florida Board of Nursing 50-1223 and Georgia Boardof Nursing CE Broker 50-1223

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considered for a genetic diagnosis In addition somewomen decline prenatal testing because results will notchange pregnancy management if a genetic conditionis identified thus screening may evoke unwanted anx-iety The purpose of this article was to incorporate anoverview of currently available prenatal genetic screen-ing and diagnostic tests with guidance on critical ele-ments of pre- and posttest genetic counseling

OVERVIEW OF GENETIC TESTINGTo help women navigate various prenatal genetic test-ing options within established appointment time lim-its clinicians are obligated to understand differencesamong available tests as well as risks and benefits be-fore counseling patients Generally prenatal genetictesting is divided into 2 categories screening tests anddiagnostic tests17 Diagnostic testing during pregnancyinvolves a procedure such as amniocentesis or chori-onic villus sampling (CVS) to allow for direct testingon fetal or placental cells2 These tests provide defini-tive information about a diagnosis of a chromosomal orsingle gene condition in the fetus In contrast screen-ing tests such as maternal serum and prenatal cell freeDNA testing can only determine if there is a higheror lower chance of a chromosomal or genetic condi-tion in the pregnancy but cannot provide a definitivediagnosis17 Imaging modalities such as ultrasound andfetal magnetic resonance imaging (MRI) can providediagnostic information regarding birth defects but likescreening tests cannot diagnose an underlying geneticetiology17 Finally carrier screening for recessive dis-orders can identify those couples at increased risk tohave a child with a genetic condition however a diag-nostic procedure and test are needed to identify thosefetuses that are affected8 Both screening and diagnos-tic tests are typically available to pregnant women butthe amount of information desired by women can varysignificantly

ANEUPLOIDY SCREENINGGiven that diagnostic invasive procedures carry a riskof miscarriage screening tests performed on mater-nal blood allow for a mechanism to identify womenwho have a higher probability of a pregnancy affectedwith aneuploidy (eg conditions caused by the pres-ence or absence of chromosomal material)7 There aregenerally 2 types of screening for aneuploidy maternalserum screening and cell free DNA screening (cfDNAscreening) Each type of aneuploidy screen has multi-ple versions offered by a number of laboratories witheach modality demonstrating different strengths andweaknesses7

Maternal serum screening

Maternal serum screening for fetal aneuploidy requiresmeasurement of specific analytes detected in preg-nancy The data obtained from these analyte measure-ments are then used to calculate a posttest probabilityfor aneuploidy based on specific analyte values mater-nal age and other factors7 For example lower than av-erage levels of maternal serum alpha-fetoprotein duringthe second trimester of pregnancy are associated witha higher probability of trisomy 21 (Down syndrome)9

Through discovery of new analytes and an associationto aneuploidy risk maternal serum screening has gonethrough many updates (eg triple quad first trimestersequential and integrated screening) and now includesevaluation of multiple maternal analytes in the first andsecond trimesters to screen for trisomy 21 trisomy 18and in some cases trisomy 13 and Smith-Lemli-Opitzsyndrome17 Analyte screening also screens for con-ditions other than aneuploidy including neural tubeand abdominal wall defects given the association ofthese conditions with elevated maternal serum alpha-fetoprotein17

Prenatal cell free DNA

Also referred to as noninvasive prenatal screening ornoninvasive prenatal testing this clinical test involvesmeasurement of cell-free fragments of DNA in mater-nal serum for trisomy 13 18 21 and sex chromosomevariations71011 During pregnancy shedding placentalcells which usually have the same genetic make-up asthe fetus enter the maternal bloodstream710 These pla-cental DNA fragments can be detected and measuredfrom about 10 weeksrsquo gestation through the remain-der of the pregnancy710 Next-generation sequencingallows for amplification of cell-free DNA with analysisto determine if genetic material is over- or underrep-resented relative to what would be expected and thuscan predict if there is a higher or lower chance for ane-uploidy in the pregnancy1011

The relative amount of placental cfDNA to mater-nal cfDNA is known as the fetal fraction710 In somecases the fetal fraction is insufficient for the test tobe performed resulting in a ldquono-callrdquo result7 Fetal frac-tion is inversely correlated to maternal body mass indexand obese women are more likely to have a ldquono-callrdquoresult12 In addition no call results have been associ-ated with a higher likelihood of fetal aneuploidy710

Thus it is recommended that women with a no-call re-sult be offered genetic counseling and consideration ofdiagnostic testing1013

The positive and negative predictive values for ane-uploidy most notably Down syndrome are higherwith cfDNA screening than seen with maternal serum




































DisorderACOGACMG














atrophy













































Amniocentesis






frequency


individuals






























(continues)




(Continued)


frequency


individuals
































Ultrasound






















































































































































DisorderACOGACMG














atrophy













































Amniocentesis






frequency


individuals






























(continues)




(Continued)


frequency


individuals
































Ultrasound

































































































































DisorderACOGACMG














atrophy













































Amniocentesis






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individuals






























(continues)




(Continued)


frequency


individuals
































Ultrasound






















































































































DisorderACOGACMG














atrophy













































Amniocentesis






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individuals






























(continues)




(Continued)


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individuals
































Ultrasound


















































































































































Amniocentesis






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individuals






























(continues)




(Continued)


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Amniocentesis






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individuals






























(continues)




(Continued)


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Ultrasound























































































































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(continues)




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Documents

Beyond the Brochure - CEConnection · for fetal diagnosis of trisomy 21 and other chromosomal conditions, while carrier screening was available for a handful of single gene disorders