Professional Guidance on the Role of NIPS as a First Tier Screening Test

The ACOG/SMFM practice bulletin that addresses prenatal screening for fetal chromosomal anomalies clearly states that both aneuploidy screening and diagnostic testing “should be discussed and offered to all patients regardless of maternal age or risk for chromosomal abnormality”

  • Aneuploidy screening
    • Serum screening with or without NT ultrasound or
    • cfDNA screening
  • Diagnostic testing (CVS or amniocentesis)

Notes

  • Standard serum screening remains a first-line option along with cell-free DNA screening, also known as noninvasive prenatal screening (NIPS), because additional chromosomal and single gene defects may be picked up with NT and performance may be more comparable to NIPS if the higher NIPS test failure rates are considered
  • While younger women may have a higher risk for fetal microdeletion syndromes than aneuploidy, ACOG does not recommend NIPS for microdeletions | Women who want information regarding microdeletions should be offered microarray testing using CVS or amniocentesis  

What Is NIPS?

NIPS is a blood test that utilizes cell-free DNA technology (cfDNA) to predict the risk for fetal genetic disorders during pregnancy. In 2011, NIPS was introduced as a screen for T21 (trisomy 21 or Down syndrome). Today, NIPS cover the most common aneuploidies (T21, T13 and T18), as well as sex chromosomes and may also include some microdeletions and single gene genetic disorders

How Does It Work?

  • DNA fragments (outside of cells) can be found floating in the blood of all individuals
  • In every pregnant woman, there are fragments from
    • Her own DNA
    • Fragments of placental DNA (generally thought to derive from the outer cytotrophoblast rather than the inner mesenchymal layer)
  • A maternal blood sample is obtained ≥10 weeks (with some labs offering testing beginning at 9 weeks) of pregnancy
    • Usually performed at 11 to 13 weeks
  • Fetal Fraction
    • The percentage of fetal DNA found in maternal blood is known as the fetal fraction | Typical range 3 to 13% of maternal cfDNA
    • The fetal fraction is critical to the success of NIPS | Minimum required approximately 2 to 4%
    • Sensitivity drops with lower fetal fraction and if too low, test failure will result

Technologies

  • Generally, NIPS utilizes next generation sequencing and bioinformatics algorithms to interrogate DNA fragments that have been extracted from maternal samples
    • SNP-based: Bioinformatic algorithms combine risk from individual targeted single nucleotide polymorphisms (SNPs) to differentiate maternal from placental DNA fragments
      • SNP is the only analysis that can report on zygosity and individual fetal fractions in the case of twins (dependent on laboratory)
    • Quantification method: Bioinformatic algorithms determine the amount of DNA from chromosomal regions of interest | E.g. if too much chromosome 21 DNA is detected, then a ‘screen positive’ result for T21 will be generated

What Disorders Are Included?

  • T13, T18 and T21
    • Most effective at screening for T21
  • Chromosomes X and Y (fetal sex usually available)
  • Sex chromosome conditions (depending on the lab)
    • Monosomy X (Turner syndrome)
    • 47,XXX (Triple X syndrome)
    • 47,XXY (Klinefelter syndrome)
    • 47,XYY (Jacob’s syndrome)
  • Microdeletions (also known as copy number variants or CNVs) are available with more extensive panels | CNVs occur in 0.4% of pregnancies and are not related to maternal age
    • 22q11.2 deletion syndrome (DiGeorge syndrome) | 1,3000 to 1,4000 live births | May be more prevalent prenatally and cases may be missed at birth (see ‘Related ObG Topics)
    • 1p36 deletion syndrome | 1 in 5,000 to 1 in 10,000 live births
    • 4p16.3 deletion syndrome (Wolf-Hirschhorn syndrome) | 1 in 50,000 live births
    • 5p15.2 deletion syndrome (Cri du Chat syndrome) | 1 in 20,000 to 1 in 50,000 live births
    • 15q11.2 deletion syndrome (Angelman syndrome/Prader-Willi syndrome) |1 in 12,000 to 20,000 (AS) | 1 in 10,000 to 30,000 (PWS)

SYNOPSIS:

The preferred nomenclature is NIPS (‘S’ for screening) to emphasize that this test is used for screening only and not diagnostic. Cell-free DNA (cfDNA) is also commonly used with an understanding that the DNA is derived from placenta and not the fetus. NIPS utilizes next generation sequencing and bioinformatics algorithms to look at the DNA fragments in the mother and fetus, as a way of determining the likelihood of certain genetic conditions in the fetus.  While there are multiple panels available, there is consensus regarding the clinical utility of NIPS screening for T13, T18 and T21. Patient education, especially around the concept of positive predictive value (PPV) is a priority. Calculator tools are available from professional societies (see ‘Learn More – Primary Sources’ below) or ideally laboratories should be able to provide obstetric professionals with real world test performance results.

NIPS Screening Performance

Detection rates

  • The following detection rates are based on recent meta-analysis (see ‘Learn More -Primary Resources’ below)
    • T21: >99% detection rate for T21
    • 98% detection rate for T18
    • 99% detection rate for T13
  • Combined false positive rate of 0.13%
    • cfDNA is the most sensitive and specific screen for T21, T18 and T13
  • Sensitivity and specificity are superior to standard screening for T21 and other common aneuploidies

Positive Predictive Value (PPV)

Trisomies

  • NIPS generally has very high negative predictive values (NPV) | From ages 20 to 45, NPV is >99% (PQF NSGC calculator)
  • PPV is also generally high but can vary based on age | Lower background risk will lower PPV | PQF NSGC calculator can be used to determine PPVs
    • PPVs have been reported up to approximately 90% for T21 but tend to be lower for T18, T13 and monosomy X
    • Abnormal ultrasound will increase PPV

Microdeletions

  • NIPS for microdeletion syndromes can have high sensitivity and specificity but still have very low PPV because the particular syndrome is a priori so rare | For example
    •  Cri du Chat Syndrome (Using PQF calculator – see ‘Learn More – Primary Sources’ below)
      • Even if sensitivity and specificity are both >99%, the chance of a positive results being a true positive (i.e. PPV) is ≤1%
      • Negative predictive value will generally always be high for a rare disorder
    • 22q11.2 deletion syndrome (22q11.2DS) is the most common microdeletion syndrome, found in 1 in 3000 to 4000 live births | Appears to be more common prenatally with a prevalence of approximately 1 in 1000 of otherwise normal pregnancies (see ‘Learn More – Related Entries)
      • PPV in a low risk population (see ‘Learn More – Primary Sources’) has been reported to be approximately 1 in 20 and higher in pregnancies at higher risk (e.g. congenital heart disease consistent with 22q11.2DS)

Note: NIPS is a screening test and not diagnostic | Regardless of PPV, screen positive results require patients be offered invasive diagnostic testing to confirm results

  • Some women may opt for a cfDNA screen after a positive serum analyte screen instead of an invasive test. This is a valid option for patients who do not want an invasive test
    • However, patients should be counseled that a cfDNA screen will not give a diagnosis and may delay a formal diagnosis
    • cfDNA will not identify all babies with chromosomal abnormalities
    • Residual risk of a chromosomal abnormality after an abnormal traditional screen followed by a normal cfDNA screen is around 2%

Reasons for a False Positive Result

  • There is a high likelihood that a positive T21 NIPS screen is truly positive (approximately 90%)
  • However, confirmatory testing is necessary because false positive results are possible
    • Confined placental mosaicism (since NIPS only looks at the placental DNA)
    • Vanishing twin that was aneuploid but surviving twin is normal
    • Maternal condition such as cancer (NIPS results will usually show multiple chromosomal aneuploidies)
    • Unknown

NIPS Test Failure

  • Low fetal fraction
    • BMI: 10% of patients >250 lbs will have a fetal fraction <4% | May be caused by (1) dilutional effect or (2) elevation in maternal DNA due to inflammatory processes
    • Early Gestational age <9 weeks
  • Other reasons for no result include
    • Laboratory failure | IVF pregnancy | Maternal drug exposure to LMWH | Racial background (e.g. Black and South Asian vs white) | Fetal aneuploidy (e.g. T13 or T18 and sex chromosome aneuploidies)

Follow-Up for ‘No Call Result’

  • Inform patients that there is an increased risk of aneuploidy | Effect may be due to smaller placentas  
  • Offer genetic counseling, detailed ultrasound evaluation and diagnostic testing
  • Repeat screening “may be considered’
    • Success rate 75 to 80% (less with high BMI)
  • Repeat screening is not advised for the following
    • Ultrasound anomalies present
    • Later gestational age where further delay may complicate access to reproductive options

Note: It is preferred that the laboratory report the fetal fraction

Other Practice Guidelines: ACMG

  • All patients should be offered the option of fetal aneuploidy screening or diagnostic testing
    • NIPS is an appropriate option vs standard ultrasound/serum marker screening
  • The choice to accept or decline remains that of the patient
  • Patients should be provided with adequate information to make an informed decision including
    • Risks
    • Benefits
    • Alternatives
    • An understanding that (1) a positive screening result does not necessarily mean the pregnancy is affected and (2) false negatives are possible
    • There is a baseline risk for birth defects despite testing (approximately 3 to 4%)
  • Post-test genetic counseling should be available to patients especially if there is a ‘screen positive’ result
    • Confirmation with CVS or amnio should be offered whether the patient has a screen positive result with NIPS or standard screening
    • Because CVS assesses placental tissue, there is a risk for confined placental mosaicism and follow-up with amniocentesis may be required (especially for T13 or monosomy X)

In addition, the ACMG

  • Recommends against testing for other aneuploidies (all other non-sex chromosomes aside from 21, 18 and 13)
  • Recommends patients be informed that NIPS can screen for sex aneuploidies
  • Recommends informing patients that microdeletion syndrome screening is available with NIPS if the following are discussed with the patient
    • Benefit and risks for use of screening vs diagnostic testing, especially if a patient wants the most fetal genetic information possible
    • Higher chance for false-positive and false-negative results compared to NIPS for common aneuploidies  
    • Prognosis for some of the resultant findings may not be clear
  • Recommends the following regarding reports

Laboratory requisitions and pretest counseling information should specify the DR, SPEC, PPV, and NPV of each CNV screened. This material should state whether PPV and NPV are modeled or derived from clinical utility studies (natural population or sample with known prevalence).

Single Gene and NIPS

  • NIPS also has the capability to identify single gene disorders
    • Ability to identify single gene variants that would likely not be detected with carrier testing
    • Generally serious autosomal dominant disorders that may be absent in the parents, but pathogenic variants may spontaneously occur in the fetus (de novo) such as Cornelia de Lange syndrome or Achondroplasia
    • Some of these conditions are associated with advanced paternal age (≥40 at time of conception)
  • Single gene screening is clinically available, although currently not recommended by ACOG

Note: ACMG provides healthcare professionals with open access ‘ACT Sheets’ to guide next steps following a positive NIPS report (see ‘Learn More – Primary Sources’ below)  

Learn More – Primary Sources: 

ACOG Practice Bulletin 226: Screening for Fetal Chromosomal Abnormalities

ACOG Practice Advisory: Cell-free DNA to Screen for Single-Gene Disorders

ACOG Statement on FDA Warning on Genetic Non-Invasive Prenatal Screening Tests | ACOG

ACMG ACT Sheets and Algorithms

Analysis of cell‐free DNA in maternal blood in screening for aneuploidies: updated meta‐analysis

Screening for trisomies by cfDNA testing of maternal blood in twin pregnancy: update of The Fetal Medicine Foundation results and meta‐analysis

NIPT/Cell Free DNA Screening Predictive Value Calculator

GHR: What is noninvasive prenatal testing (NIPT) and what disorders can it screen for?

Locate a Genetic Counselor or Genetics Services:  

Genetic Services Locator-ACMG

Genetic Services Locator-NSGC  

Genetic Services Locator-CAGC  

Locate a Maternal Fetal Medicine Specialist  

Maternal Fetal Medicine Specialist Locator-SMFM   

What is the Best Strategy for Fetal Aneuploidy Screening?

BACKGROUND AND PURPOSE:

  • Multiple strategies for aneuploidy screening are currently being evaluated
  • cfDNA has superior performance characteristics compared to standard first trimester screening (NT + markers) but may miss fetal anatomic/chromosomal anomalies that can be initially detected on ultrasound
  • Kagan et al. (Ultrasound Obstet Gynecol, 2017) compared the performance of first trimester standard combined screening with an approach that uses the combination of a detailed ultrasound exam and cfDNA analysis

METHODS:

  • Prospective randomized control trial of normal first-trimester ultrasound exam at 11 to 13 weeks’ gestation (2015-2016)
  • Subjects were randomized into two groups of assessing aneuploidy risk
    • Standard screening
    • Ultrasound and cfDNA screening if ultrasound is normal
  • Blood was retained for standard serum markers in case the cfDNA result was inconclusive
  • Primary outcome
    • Number of false positives in screening for trisomy 21
    • False positive defined as normal karyotype if risk for trisomy 21 was >1:100, irrespective of the method of risk calculation

RESULTS:

  • 688 women with normal first-trimester ultrasounds were randomized into each group (1) Standard screening cohort and (2) ultrasound + cfDNA cohort
  • All 7 cases of DS were detected on ultrasound based on enlarged NT or fetal anomalies, as were trisomy 13 and 18 cases
  • When comparing risk assessment using standard screening vs ultrasound + cfDNA cohorts, there were no major demographic differences
  • The ultrasound + cfDNA cohort median risk for trisomy 21 was 1 in 10,000
    • None of the cases had a risk above 1:100 [95% CI 0.0 – 0.5%]
  • The standard screening cohort median risk for trisomy 21 was 1 in 3,786
    • > 1:100 risk was identified in 17 (2.5%) pregnancies (95% CI 1.5 – 3.9%)

CONCLUSION:

  • A first-trimester screening for trisomy 21 using ultrasound, NT measurement, and cfDNA in women without ultrasound anomalies is associated with a significant reduction in the false positive rate compared to standard screening
  • This study suggests first trimester serum markers (β-hCG and PAPPA) should not be used
  • By including a detailed ultrasound, disadvantages of cfDNA only testing only are overcome
    • Anatomic assessment provided by ultrasound
    • Saving blood for markers if necessary can address the problem of inconclusive cfDNA results

Learn More – Primary Sources:

First trimester screening based on ultrasound and cfDNA vs. first-trimester combined screening – a randomized controlled study.

What Is the Best Follow-Up Diagnostic Test After a High-Risk NIPT Result?

BACKGROUND AND PURPOSE:

  • DNA that circulates in the maternal compartment is mostly derived from placenta (cytotrophoblast layer) and not the fetus
  • Fetal and placental cells both originate from the fertilized oocyte, but diverge early in pregnancy into distinct tissues
    • Placenta can tolerate different cell lines (mosaicism) and may not perfectly match the fetal chromosomal complement, resulting in false positive and negative NIPS results
  • There are other causes that may result in false positive and negative NIPS reports, such as vanishing twin or maternal chromosomal anomalies
  • Therefore, there is universal agreement that a positive cfDNA report requires confirmation based on invasive testing with either CVS or amniocentesis
  • Grati et al. (Prenatal Diagnosis, 2015) used an extensive database to determine how often placental DNA (CVS results) matched fetal DNA (amniocentesis results), broken out by chromosome and cellular layer, to determine whether amniocentesis and/or CVS is the more appropriate confirmatory test.

METHODS:

  • Data on 52,673 karyotypes were analyzed to determine frequency of mosaicism involving cytophoblasts, for trisomies 21 (T21), 18 (T18), 13 (T13) and monsomy X (MX)
  • Karyotypes were obtained from cytorophoblast (outer layer, DNA source for NIPS), mesenchyme and confirmatory amniocentesis

RESULTS:

Using cytotrophoblast karyotype as a proxy for NIPS, authors posited the following

  • After a high-risk NIPS result, mosaicism on confirmatory CVS requiring a follow up amniocentesis would be:
    • 2% in T21
    • 4% in T18
    • 22% in T13
    • 59% in MX
  • When mosaicism is detected by CVS, the likelihood of fetal confirmation by amniocentesis would be:
    • 44% in T21
    • 14% in T18
    • 4% in T13
    • 26% in MX

CONCLUSION:

  • For T21/18, confirmatory CVS may still be an option, especially if there is a clinical indication to obtain early results
    • Small but still real risk for inconclusive results
  • For MX/T13, amniocentesis seems most appropriate for follow-up after high risk cfDNA result due to high likelihood of a mosaic result on confirmatory CVS
  • The authors state “If an ultrasound anomaly suggesting the suspected karyotype anomaly is found, CVS could be offered to the patient regardless of risk of need for a secondary procedure because an early diagnosis may be preferable.”

Learn More – Primary Sources:

The type of feto-placental aneuploidy detected by cfDNA testing may influence the choice of confirmatory diagnostic procedure

Diagnostic cytogenetic testing following positive noninvasive prenatal screening results: a clinical laboratory practice resource of the American College of Medical Genetics and Genomics (ACMG)

NIPS vs. Microarray for Pathogenic Results

PURPOSE:

This study by Sotiriadis et al. (Prenatal Diagnosis, 2017) sought to calculate the proportion of pathogenic results that would be picked up by array comparative genomic hybridization (aCGH) compared to NIPS.

METHODS:

Comparative Retrospective Study

RESULTS:

This study included 2,779 fetuses that underwent invasive prenatal diagnosis using aCGH, with indications including large NT, standard 1st and 2nd trimester screening, fetal anomalies, maternal age, personal or family history of genetic issues, patient request or other (e.g. infection). Patients who were referred for screen positive NIPS were excluded. The investigators assumed a simulated NIPS panel comprised of common aneuploidies, trisomies 21, 18, 13, but also sex chromosome aneuploidies including monosomy X, 47, XXX, 47, XYY, and 47, XXY. NIPS would detect 28.0% (95% CI 14.3-47.6) of detectable aCGH pathogenic results for NT between 95th to 99th centile, 14.3% (95% 5.0-34.6) for NT > 99th centile, 34.2% (95% CI 21.1-50.1) for high-risk first-trimester results, 52.4% (95% CI 32.4-71.7) for second-trimester markers and 50.0% (95% CI 26.8-73.2) for advanced maternal age. Overall, the rate of aCGH pathogenic/likely pathogenic results was 5.0% of which 44.0% (95% CI 36.0-52.2) would have been missed by NIPS alone. This paper yet again reinforces the fact that NIPS is a screening test only and, particularly in the age of aCGH, approximately half of pathogenic findings detectable with invasive testing will be missed.

Learn More – Primary Sources:

Non-invasive prenatal screening versus prenatal diagnosis by array comparative genomic hybridization: a comparative retrospective study

Does cfDNA in First Trimester Signal Subsequent Preeclampsia?

PURPOSE:

This study by Silver et al. (American Journal of Perinatology, 2017) sought to determine if a relationship exists between first trimester cell-free total DNA in maternal plasma and the development of preeclampsia.

METHODS:

Nested Case-Control Study

RESULTS:

Data on 350 women, 50% with and 50% without preeclampsia, who were enrolled in the Combined Antioxidant and Preeclampsia Prediction Studies, were analyzed. While some women did have higher cell-free total DNA than others (Black and Hispanic women had higher levels than white women), there was no correlation between levels and subsequent development of preeclampsia. The authors conclude that cfDNA is not a good prenatal risk assessment marker for preeclampsia.

Learn More – Primary Sources:

Cell-Free Total and Fetal DNA in First Trimester Maternal Serum and Subsequent Development of Preeclampsia

SMFM Guidance – The Role of Prenatal Ultrasound and NIPT 

SUMMARY:

SMFM has released, as part of their Consult Series, a document on the role of prenatal ultrasound in the context of cfDNA screening.  The summary recommendations are as follows:

  • Negative cfDNA at 11-14 weeks: (evidence level 1B)
    • First trimester ultrasound only for NT measurement not recommended
  • Negative cfDNA and isolated ‘soft marker’: (evidence level 2B)
    • Diagnostic testing is not recommended solely for this indication
    • Describe ‘soft marker’ finding as ‘not clinically significant’ or ‘normal variant’
  • Negative 1st or 2nd trimester screen and isolated ‘soft marker’: (evidence level 2B)
    • Describe ‘soft marker’ finding as ‘not clinically significant’ or ‘normal variant’
  • Structural abnormality on ultrasound (evidence level 1A)
    • Offer diagnostic testing using microarray
  • Do not offer routine screening for microdeletions using cfDNA (evidence level 1B)

Key Points:

  • Examples of  ‘soft marker’ include echogenic intracardiac focus or choroid plexus cysts
  • ‘Isolated’ implies a single finding and the absence of any other pathology
  • If multiple ‘soft markers’ are identified
    • Refer for genetic counseling, consideration of diagnostic testing
    • prenatal risk assessment should be limited to expert centers and individuals

Levels of Evidence:

  • 1A: Strong recommendation; high-quality evidence
  • 1B: Strong recommendation; moderate-quality evidence
  • 2B: Weak recommendation; moderate-quality evidence

Learn More – Primary Sources:

SMFM Consult Series #42: The role of ultrasound in women who undergo cell-free DNA screening

ACOG Committee Opinion 682: Microarrays and Next-Generation Sequencing Technology: The Use of Advanced Genetic Diagnostic Tools in Obstetrics and Gynecology

ACOG Practice Bulletin 226: Screening for Fetal Chromosomal Abnormalities

ACOG Practice Bulletin 162: Prenatal Diagnostic Testing for Genetic Disorders

ACOG Practice Bulletin 175: Ultrasound in Pregnancy

Locate a Genetic Counselor or Genetics services:

Genetic Services Locator-ACMG

Genetic Services Locator-NSGC

Genetic Services Locator-CAGC

Locate a Maternal Fetal Medicine Specialist

Maternal Fetal Medicine Specialist Locator-SMFM

Counseling Women with NIPT Results Suggesting Cancer

PURPOSE:

This study by Giles et al. (Prenatal Diagnosis, 2016) surveyed genetic counselors on their current methods and management needs for counseling women whose prenatal cfDNA screening indicate maternal neoplasm.

METHODS:

Anonymous Online Survey Answered by Board-Eligible/Certified Genetic Counselors through the NSGC.

RESULTS:

343 participants completed the entire survey. Despite the fact that 95% of participants previously knew that NIPT could be used to uncover maternal neoplasm, the majority (51.8%) did not feel adequately prepared or comfortable discussing the ramifications of a test report suggesting an increased risk for maternal neoplasm based on NIPT findings. This study substantiates the urgent need for management guidelines on this topic.

Learn More – Primary Sources:

Prenatal cfDNA screening results indicative of maternal neoplasm: survey of current practice and management needs

 

Down Syndrome / Trisomy 21: Clinical Findings and Prenatal Considerations

WHAT IS IT?

  • Down syndrome is the most common chromosomal cause of intellectual disability
  • May affect almost every organ system but the following findings are particularly common and may be identified on prenatal sonogram:
    • Increased nuchal translucency (first trimester) and/or nuchal fold (second trimester) or cystic hygroma
    • Congenital heart disease (50%), particularly AV canal defects
    • Duodenal atresia (double bubble sign) usually identified in 3rd trimester
    • Prenatal ultrasound markers include: short femurs, echogenic intracardiac foci, dilated renal pelviectasis, mild ventriculomegaly
  • Other findings may not be apparent until postnatal life:
    • Dysmorphic features: epicanthal folds, single palmar crease, low set ears
    • Decreased muscle tone
    • Intellectual disability: usually in the mild (IQ ~70) to moderate range (IQ ~50)
      • Most individuals with Down syndrome can participate in numerous group and individuals activities, but may need some level of supervision throughout their lives
      • Individualized education programs can help children with Down syndrome reach their potential
      • Special education services at school can range from inclusion in the typical classroom with extra help to small group instruction
    • Hearing loss (up to 75%)
    • Sleep apnea (50-75%)
    • Eye disease, such as cataracts (50-70%)
    • Endocrine disease: thyroid, diabetes
    • Hirschsprung disease
    • Leukemia is slightly increased in this population, typically requiring lower doses of chemotherapy treatments
    • Plaques are frequently seen in older adults with Down syndrome (50+ years) but their presence does not mean that Alzheimer’s disease will necessarily develop – other treatable causes of decline are investigated first

CAUSE:

Down syndrome (DS) is a condition caused by the presence of an extra chromosome (#21) at the time of conception. In 90% of cases, it is the result of nondisjunction during meiosis (Trisomy 21), which is usually a sporadic occurrence. In 4-5% of DS affected individuals a chromosomal imbalance is the cause, inherited from a parent who has a balanced karyotype (i.e. Robertsonian translocation). A small proportion of affected individuals, < 1%, are diagnosed with mosaic DS.

KEY POINTS:

  • ACOG requires all women be offered prenatal screening (biochemical/cfDNA) or invasive testing (amniocentesis;CVS) to detect an increased risk for DS, or to diagnosis it, respectively
  • Children with Down syndrome are more similar to other children than they are different
  • Overall, this condition is present in approximately 1 in 800 live births. Risk increases with maternal age
    • At maternal age 25, the risk is 1/1250
    • At maternal age 35, the risk is 1/365
    • At maternal age 40, the risk is 1/110
    • At maternal age 45, the risk is 1/32
  • If there is a family history or previous DS pregnancy, refer for genetic counseling
  • Data is limited on obstetrical management of an ongoing pregnancy with trisomy 21
    • Increased risk of fetal loss (5.9%), growth restriction (17.5%) and anomalies (75.0%)
    • Non-reassuring fetal surveillance (35.9%) appears to be associated with placental insufficiency and not necessarily related to structural anomalies
    • Data suggests a role for antepartum surveillance

Note: ACMG provides healthcare professionals with open access ‘ACT Sheets’ to guide next steps following a positive NIPS report for trisomy 21 (see ‘Learn More – Primary Sources’ below) 


Learn More – Primary Sources:

ACOG Practice Bulletin 226: Screening for Fetal Chromosomal Abnormalities

ACMG: Noninvasive Prenatal Screening via Cell-Free DNA [Trisomy 21: Positive Cell Free DNA Screen]

Antepartum management and obstetric outcomes among pregnancies with Down syndrome from diagnosis to delivery

CDC: Facts about Down syndrome

lettercase.org: Understanding a Down syndrome Diagnosis

Practice Guidelines for Communicating a Prenatal or Postnatal Diagnosis of Down Syndrome: Recommendations of the National Society of Genetic Counselors

Locate a Genetic Counselor or Genetics Services:

Genetic Services Locator-ACMG

Genetic Services Locator-NSGC

Genetic Services Locator-CAGC

Klinefelter Syndrome: A Wide Range of Clinical Findings

WHAT IS IT?

  • Klinefelter syndrome is also known as XXY syndrome
    • Present in 1 in 500 to 1 in 1000 newborn males
  • A sex chromosome abnormality that involves the presence of two or more X chromosomes and one Y chromosome
    • Majority are 47,XXY karyotype
    • Remaining cases are 48, XXXY or mosaic 46,XY/47,XXY
  • Prenatally, usually no obvious physical features detectable on ultrasound
  • In infancy, possible minor findings:
    • Hypospadias and small or undescended testes
  • Clinical features may be subtle and often a diagnosis is not made until adolescence, adulthood, or not at all:
    • Tall stature
    • Small and atrophic testes
    • Gynecomastia (excess breast tissue)
    • Evidence of androgen deficiency such as decreased body hair
    • Increased risk for breast cancer and autoimmune disorders (e.g. lupus)
  • Intellectual development:
    • Individuals who have a 47,XXY karyotype usually have normal intelligence
    • Starting in childhood, educational support may be needed to address learning disabilities, delayed speech and language development
    • Individuals who have more than two X chromosomes are likely to have more severe symptoms
  • Treatment:
    • Testosterone replacement is available and is usually started in early puberty
      • Treatment should be under the care of an endocrinologist and ideally with the collaboration of a multidisciplinary team
      • Recent data suggest treatment early in childhood may have a positive impact on neurodevelopment and social behaviors
    • Removal of excess breast tissue is an option for cosmetic reasons and to reduce the risk for breast cancer
    • Fertility treatment now available using assisted reproductive technology (ART), including testicular sperm extraction with intercytoplasmic sperm injection (TESE-ICSI)
    • Academic educational support to assist with language-based learning disabilities (LLD) and motor planning issues

CAUSE:

Klinefelter syndrome is a condition caused by an abnormal karyotype (2 or more X chromosomes and one Y chromosome) that is present at the time of conception. It usually is the result of non-disjunction during meiosis and is either of maternal (55%) or paternal (45%) origin. It is a sporadic condition, not inherited.

KEY POINTS:

  • ACOG requires all women be offered prenatal screening (biochemical/cfDNA) or invasive testing (amniocentesis; CVS) to detect an increased risk or to diagnose aneuploidy, respectively
  • Currently, the only way to prenatally diagnose Klinefelter syndrome is through invasive testing (amniocentesis or CVS)
  • Klinefelter syndrome is now included on some cfDNA screening tests
    Invasive testing is necessary to confirm any positive result on screening using cfDNA
  • If there is a history of Klinefelter syndrome, refer for genetic counseling

Learn More – Primary Sources:

NIH GARD –Klinefelter syndrome

NICHD – Klinefelter syndrome

US NLM – Genetics Home Reference: Klinefelter syndrome

Management of Klinefelter syndrome During Transition

Neurodevelopmental outcome of prenatally diagnosed boys with 47,XXY (Klinefelter syndrome) and the potential influence of early hormonal therapy

Oxandrolone Treatment Results in an Increased Risk of Gonadarche in Prepubertal Boys With Klinefelter Syndrome

Locate a Genetic Counselor or Genetics Services:

Genetic Services Locator-ACMG

Genetic Services Locator-NSGC

Genetic Services Locator-CAGC

Turner Syndrome – 45,X Explained

WHAT IS IT?

  • Also known as 45,X ; monosomy X; Turner’s syndrome; Ullrich-Turner syndrome
  • A sex chromosome abnormality that involves the presence of one functional X chromosome and no other X or Y chromosome
    • All cells can be monosomy X (having a single X chromosome) or 
    • There can be a mix of cell lines, where some cells are normal (46,XX) and others have only one X chromosome (mosaic Turner syndrome)
  • Common findings on prenatal ultrasound:
    • Increased nuchal translucency (1st trimester), nuchal fold (2nd trimester), or cystic hygroma
    • Cardiac defects
      • Bicuspid aortic valve and coarctation of the aorta
    • Renal defects (i.e. horseshoe kidney)
  • Other findings may not be apparent until postnatal life
    • Short stature is usually the most consistent finding, approximately 8 inches less than what would be expected for her family
      • Genetic mechanism resulting in short stature still unknown, however the absence of the SHOX gene, located on short arm of X chromosome, which helps coordinate bone development, is likely an important factor
    • Wide or webbed neck
    • Low-set ears
    • Low hairline at the back of the head
    • Broad chest with widely spaced nipples
    • Lymphedema, especially of the hands and feet
    • Absent, delayed, or partial spontaneous pubertal development (30%)
    • Absent or decreased fertility, depending on what percentage of cells have only one X chromosome, as two X chromosomes are required for ovarian development and function
  • Intellectual development:
    • Females who have a 45,X karyotype usually have normal intelligence although there may be some learning disabilities, particularly with mathematical and spatial concepts, some difficulty in social situations
  • Treatment and monitoring:
    • Cardiology monitoring
    • Growth hormone and hormone replacement therapy
    • Academic support for potential learning challenges
    • Fertility assessment

CAUSE:

Turner syndrome (45,X) is a condition caused by an abnormal karyotype that is present at the time of conception and results from a sperm or egg that is capable of undergoing fertilization, but has no X chromosome. As this appears to be a random event, Turner syndrome is generally not inherited and risk of recurrence in subsequent pregnancies is minimal.

KEY POINTS:

  • ACOG requires all women be offered prenatal screening (biochemical/ cfDNA) or invasive diagnostic testing (amniocentesis/ CVS)
    • Turner (45,X) syndrome is included on some cfDNA screening panels but is associated with a higher false positive rate compared to Down syndrome
    • Confirmatory testing (amniocentesis or CVS) should be offered all women with a positive cfDNA screening report
      • Presently, invasive testing is the only way to diagnose fetal Turner syndrome
      • There is data supporting the use of amniocentesis rather than CVS for confirmation
  • Present in 1/1500- 1/2500 live births
  • Estimated to account for 3% of all conceptions
  • Despite relatively functional outcomes, approximately 99% of cases are miscarried or stillborn
    • Mosaic Turner syndrome has a better chance of survival
  • ACMG provides ACT sheets to assist healthcare professionals with ‘next steps’ following a positive NIPS report for 45,X (see ‘Learn More – Primary Sources’ below)

Learn More – Primary Sources:

ACMG: Noninvasive Prenatal Screening via Cell-Free DNA ACT Sheet [45,X: Positive Cell Free DNA Screen]

NHGRI: Turner syndrome

US NLM- Genetics Home Reference

The type of feto-placental aneuploidy detected by cfDNA testing may influence the choice of confirmatory diagnostic procedure

ACOG Practice Bulletin 226: Screening for Fetal Chromosomal Abnormalities

Locate a Genetic Counselor or Genetics services:

Genetic Services Locator-ACMG

Genetic Services Locator-NSGC

Genetic Services Locator-CAGC

Practice management info for your women's healthcare practice

Can a Laboratory Patent Non-Invasive Prenatal Screening?

In March 2016, Sequenom asked the United States Supreme Court to review a US Federal Court ruling that Sequenom’s patent (U.S. Patent No. 6,258,540) for noninvasive prenatal diagnosis analyzing cell-free fetal DNA (cfDNA/NIPS/NIPT) in maternal blood did not meet the U.S. Supreme Court’s criteria for patent eligibility.

Following a major case involving Mayo Collaborative Services and Prometheus Laboratories, patents using methods that start and end with “a naturally occurring phenomenon” will not be patent eligible if the methods used to measure a sample are routine, conventional and well understood laboratory applications.  In other words the federal court did not find Sequenom’s patent “new and useful”.

As technology advances, the courts will have to continue to wrestle with how to interpret patent eligibility criteria. Their interpretation will lead to limited or expansive criteria. The full effects on the development of new medical diagnostics remain to be seen, but with the hope that these new technologies will continue to enable healthier lives.

Learn More – Primary Sources:

Sequenom and Noninvasive Prenatal Diagnosis Patent Case

Developments in global non-invasive prenatal testing (NIPT) market