New CDC Interim Guidance on Infants with Possible Zika &#038; Perinatal Review (Oct 2017)

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Spinal Muscular Atrophy: Genetic Concepts and Carrier Screening

WHAT IS IT?

ACOG recommends that screening for spinal muscular atrophy (SMA) be offered to all women who are considering or who are currently pregnant. SMA is a severe progressive neuromuscular disorder caused by loss of alpha motor neurons in the spinal cord, with the loss of muscle strength, leading to paralysis.

This disorder is common, with carrier frequencies in one study of 1/47 in Caucasians; 1/67 in Ashkenazi Jewish; 1/59 in Asian; 1/68 Hispanic; 1/52 Asian Indian; and 1/72 African American. In the overall US panethnic population, the carrier frequency was 1/54 with a detection rate of over 90%. SMA affects all population groups and is only second to cystic fibrosis as a cause of death from an autosomal recessive condition.

Childhood SMA is divided into 4 clinical groups but span a continuum without clear delineation

Type 0: Congenital SMA
- Presents at birth
- Death by 6 months of age
Type I: Severe SMA (Werdnig-Hoffmann disease)
- Onset < 6 months
- Median survival 2 years of age
Type II: Intermediate SMA (Dubowitz disease)
- Onset 6-18 months
- Children can sit but not stand unaided but lose ability by mid-teens
- Life expectancy not known with certainty – adolescence to 3^rd or 4^th decade
Type III: Juvenile SMA (Kugelberg-Welander disease)
- Onset > 18 months
- Patients learn to walk unaided but most will lose ability with age
- Life expectancy that of normal population

KEY POINTS:

Genetics

There are two related, almost identical genes on the long arm of chromosome 5, SMN1 and SMN2
- SMN1 is the SMA-determining gene
- Exon 7 in SMN1 is absent in both gene copies (maternal and paternal) in over 95% of affected individuals
- In a few individuals, exon 7 is absent in one gene copy and there is a smaller mutation in the other gene copy
- Some individuals have additional copies of SMN2 and their presence seem to lessen the severity of SMA

Limitations to Carrier Testing – False Negatives

De novo mutation: In 2% of cases, SMA results from a de novo mutation and therefore in this particular situation, screening parents will not detect the pathogenic variant (usually paternal)
Silent Carrier (2 + 0): Healthy individuals can carry 2 copies of SMN1 on a single chromosome and no copies on their other chromosome
- The % of ‘silent carriers’ varies from approximately 30% in African Americans to 5% in Caucasians
- The standard carrier screening tests are based on gene dosage and result in a false negative because 2 normal copies will be detected and therefore total amount of SMN1 will be interpreted as ‘normal’
- The (2+0) individual is a carrier because there is a 50% chance he/she will pass the abnormal (missing SMN1) chromosome to the fetus
- There are variants that track with silent carriers (i.e., found on chromosomes with duplications and not single-copy alleles) that can be incorporated into clinical carrier screening tests to improve residual risk estimates

Medication now available for SMA

Nusinersen

The FDA approved the first medication (nusinersen) in 2016, to treat children and adults with spinal muscular atrophy (SMA)
The FDA approval was based on a clinical trial in 121 patients with infantile-onset SMA who were diagnosed before 6 months of age and who were less than 7 months old at the time of their first dose
- Patients were randomized to receive an injection of nusinersen into the fluid surrounding the spinal cord, or undergo a mock procedure without drug injection (a skin prick)
- Forty percent of patients treated with nusinersen achieved improvement in motor milestones as defined in the study, whereas none of the control patients did

Onasemnogene abeparvovec-xioi

Indicated for the treatment of children with SMA <2 years
Gene therapy
- Adeno-associated virus vector-based gene therapy
- Vector delivers a fully functional copy of human SMN gene into the target motor neuron cells
- One-time IV administration
Studies
- Primary evidence of effectiveness from ongoing clinical trial
- Compared to the natural history of patients with infantile-onset SMA patients in treatment arm demonstrated significant improvement in their ability to reach developmental motor milestones (e.g., head control and the ability to sit without support)

Learn More – Primary Sources:

ACOG Committee Opinion 691: Carrier Screening for Genetic Conditions

FDA approves innovative gene therapy to treat pediatric patients with spinal muscular atrophy, a rare disease and leading genetic cause of infant mortality

GeneReviews: Spinal Muscular Atrophy

FDA approves first drug for spinal muscular atrophy

ACMG: Screening for autosomal recessive and X-linked conditions during pregnancy and preconception: a practice resource of the American College of Medical Genetics and Genomics

ACMG: Carrier screening for spinal muscular atrophy

Pan-ethnic carrier screening and prenatal diagnosis for spinal muscular atrophy: clinical laboratory analysis of >72,400 specimens

An Ashkenazi Jewish SMN1 haplotype specific to duplication alleles improves pan-ethnic carrier screening for spinal muscular atrophy

NIH Guidance: Early Introduction of Peanuts to Prevent Severe Allergy

SUMMARY:

The prevalence of peanut allergy in the US has more than doubled between 1997 to 2008 and is a leading cause of death due to food related allergic reactions. 26 professional organizations, including the NIH, have issued new clinical guidelines to prevent peanut allergy. In 2010, an expert panel determined that there was insufficient evidence to advise the delay of introducing peanuts into children’s diets. Based on strong evidence, to prevent severe peanut allergy the latest guidelines now promote early introduction of peanuts, which for most infants will be between 4 to 6 months of age.

Infants at high risk for peanut allergy—based on severe eczema and/or egg allergy—are suggested to begin consuming peanut-enriched foods between 4 to 6 months of age, but only after parents check with their health care providers.

Infants already showing signs of peanut sensitivity in blood and/or skin-prick tests should try peanuts for the first time under the supervision of their doctor or allergist. In some cases, test results indicating a strong reaction to peanut protein might lead a specialist to recommend that a particular child avoid peanuts.

Infants with mild to moderate eczema should incorporate peanut-containing foods into their diets by about 6 months of age. It’s generally OK for them to have those first bites of peanut at home and without prior testing.

Infants without eczema or any other food allergy aren’t likely to develop an allergy to peanuts. To be on the safe side, it’s still a good idea for them to start eating peanuts from an early age.

Following the safe introduction of peanuts, continue regular exposure
Those at greatest risk for allergies are advised to consume 2 grams of peanut protein (2 teaspoons of peanut butter) 3 times per week
Avoid whole peanuts in infants to prevent choking

FDA Statement (September 7, 2017)

The FDA has released a statement regarding food labeling based on the above NIH recommendations and the Du Toit et al. (NEJM, 2015) study. Aside from the current messaging on food that provides information on whether food contains peanuts or peanut residue

Recognizing the importance of science-based food decisions, the FDA has responded to a petition for a new qualified health claim that states “for most infants with severe eczema and/or egg allergy who are already eating solid foods, introducing foods containing ground peanuts between 4 and 10 months of age and continuing consumption may reduce the risk of developing peanut allergy by 5 years of age.” This is the first time the FDA has recognized a qualified health claim to prevent a food allergy. Our goal is to make sure parents are abreast of the latest science and can make informed decisions about how they choose to approach these challenging issues. The new claim on food labels will recommend that parents check with their infant’s healthcare provider before introducing foods containing ground peanuts.

Learn More – Primary Sources:

Addendum guidelines for the prevention of peanut allergy in the United States: Report of the National Institute of Allergy and Infectious Diseases – sponsored expert panel

NIH Director’s Blog: Peanut Allergy: Early Exposure Is Key to Prevention

NEJM: Randomized Trial of Peanut Consumption in Infants at Risk for Peanut Allergy

Statement from FDA Commissioner Scott Gottlieb, M.D., on a new qualified health claim advising that early introduction of peanuts to certain high-risk infants may reduce risk of peanut allergy

AAP: New guidelines detail use of ‘infant-safe’ peanut to prevent allergy

Zika virus: transmission, symptoms and management

Zika virus disease is a nationally notifiable condition:

Healthcare providers should report suspected Zika virus disease cases to their state, local, or territorial health department, who will report to the CDC.

WHAT IS IT?

The Zika virus (ZIKV) was first discovered in 1947, but has only become a global public health threat in the last decade with marked geographic spread in the last 5 years
The Zika virus is named after the Zika forest in Uganda where it was first found, is a Flavivirus and is related to similar viruses such as dengue, West Nile and Japanese encephalitis
The infectious viral particle (virion) is primarily composed of a single strand of RNA which is released into the infected cell’s cytoplasm, overtakes the infected cell’s genetic and cellular machinery, leading to replication and release of additional Zika virus
ZIKV, typical for a Flavirus, is predominantly spread via mosquito vectors, however transmission via blood transfusion and sexual contact can occur

KEY POINTS:

Clinical symptoms appear 3 to 14 days after a mosquito bite and should resolve within 2 to 7 days
Most people will be asymptomatic
20% will have typical viral signs and symptoms, usually of a mild nature
- Fever
- Maculopaular rash
- Conjunctivitis
- Arthralgias
- Headache
Management is that of typical viral illness and includes:
- Rest
- Antipyretics
  - Note: current drug labels state that NSAIDs should not be used by pregnant women in their third trimester of pregnancy because of the risk of premature closure of the ductus arteriosus in the fetus
- Nutrition and adequate fluids
- Monitor for signs and symptoms of severe infection such as coagulopathies and organ damage – ICU care is rare but any concern should be escalated
- Guillain-Barré syndrome, an autoimmune neurological disorder, has been reported and while uncommon should generate a referral for diagnosis and management

Learn More – Primary Sources:

CDC: Zika Virus For Healthcare Providers

CDC: Areas with Risk of Zika

ACOG Committee Opinion 784: Management of Patients in the Context of Zika Virus

ACOG Zika Tool Kit

FDA Drug Safety Communication: FDA has reviewed possible risks of pain medicine use during pregnancy

ACOG and Universal Screening for Cystic Fibrosis – What You Need to Know

CLINICAL ACTIONS:

Genetic screening for Cystic Fibrosis (CF) has been recommended by ACOG and ACMG for over a decade.

Offer CF screening to all women of reproductive age, not just those in higher risk groups
Document previous CF screening results
- Genetic testing does not need to be repeated in subsequent pregnancies if already on record
Expanded mutation panels beyond the ‘ACMG 23’ can be considered to increase sensitivity
- DNA sequencing of the CFTR gene is not considered ‘appropriate’ for routine carrier screening and should be reserved for particular circumstances in conjunction with genetic counseling (see below in key points)
Refer for genetic counseling if both partners are CF carriers
- CF is an autosomal recessive disorder and if both partners are affected, the risk to offspring is ¼ or 25%

SYNOPSIS:

Initially, prenatal screening for CF was limited to women from high risk groups, non-Hispanic whites and those of Ashkenazi Jewish background. However, as it becomes more difficult to identify specific racial groups and ethnicities, ACOG guidance is clear that all women of reproductive age should be screened to determine their carrier status. There are several genetic tests currently available that can sequence the entire CFTR gene, providing a clinical report for hundreds of CF disease causing mutations. While Committee Opinion 691 still mentions the original ACMG 23 mutation panel, expanded mutation panel analysis can be considered to help improve test sensitivity particularly among non-Caucasians.

KEY POINTS:

Full gene sequencing of the CFTR gene should be reserved for patients who meet the following criteria:
- Personal history of CF
- Family history of CF
- Males with CBAVD
- Newborns with positive newborn screening results when mutation panel testing is negative
Newborn screening for CF in newborns does not replace maternal screening
- A negative newborn screen for CF cannot identify parental carriers

Learn More – Primary Sources:

ACOG Committee Opinion 690: Carrier Screening in the Age of Genomic Medicine

ACOG Committee Opinion 691: Carrier Screening for Genetic Conditions

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FDA bans the use of powdered surgical gloves

SUMMARY:

The FDA has recently released an official ban on powdered surgeon’s gloves, powdered patient examination gloves, and absorbable powder for lubricating a surgeon’s glove. Many providers have already transitioned to powderless gloves. Powdered gloves are associated with asthma, lung inflammation and surgical adhesions. It is important to note, these products not only pose risks to patients, but providers as well. The rule, published on December 19, 2016, is available in the link below.

Learn More – Primary Sources:

Federal Register: Banned Devices; Powdered Surgeon’s Gloves, Powdered Patient Examination Gloves, and Absorbable Powder for Lubricating a Surgeon’s Glove

ACOG Response to FDA Communication on Anesthesia in Pregnancy

SUMMARY:

In 2016, the FDA released a warning stating that repeated or lengthy use of general anesthetic or sedation drugs in children less than 3 years of age or in pregnant women in their 3^rd trimester may be harmful to children’s brain development. The FDA issued an update (2017) requiring warnings to be added to labels of these medications. The FDA does point out in the update that the concern relates to procedures >3 hours and that most surgeries in the 3rd trimester are generally well within that time frame. Therefore, the FDA safety communication states

We are advising that in these situations, pregnant women should not delay or avoid surgeries or procedures during pregnancy, as doing so can negatively affect themselves and their infants

In response to the initial warning, ACOG released a practice advisory (2016) making the following important points

The data used to derive this warning were obtained from a pediatric study only – no pregnant women were included
There are potential negative clinical implications if healthcare professionals hesitate in providing appropriate care and management
The FDA did not seek input from ACOG and obsetetrician-gynecologists were not involved in the development of this warning

As a result of the above and based on current evidence

ACOG continues to recommend that women in any trimester of pregnancy should be counseled regarding evidence-based benefits and risks of any proposed interventions which may involve the use of general anesthetic or sedative agents, and no woman should be denied a medically indicated surgery or procedure which may involve the use of these agents

ACOG and the American Society for Anesthesiologists (2019) confirmed the above in their committee opinion and state that presently there is “no evidence that in utero human exposure to anesthetic or sedative drugs has any effect on the developing fetal brain.”

Learn More – Primary Sources:

ACOG / American Society of Anesthesiologists Committee Opinion 775: Nonobstetric Surgery During Pregnancy

FDA Drug Safety Communication: FDA approves label changes for use of general anesthetic and sedation drugs in young children

Does General Anesthesia Exposure in Infancy Impact Neurodevelopment?

Trisomy 18 – Key Findings, Prenatal Screening and Prognosis

WHAT IS IT?

Trisomy 18 (47,XX,+18 or 47,XY,+18) is also referred to as Edwards syndrome
Second most common trisomy after Down syndrome
- Present in approximately 1/5000 live births
- Prevalence during pregnancy is considerably higher: 1/2500-1/2600 due to the high frequency of fetal loss and pregnancy termination after prenatal diagnosis
- Approximately 72% of trisomy 18 pregnancies result in loss between 12 weeks to term
- 50% survive longer than one week
- 5% to 10% of infants will survive past the first year
- There are individuals who have survived into adulthood but require significant care
  - Intellectual disability is profound and overall, the developmental age in older children is 6-8 months
May affect almost every organ system but the following findings are particularly common and may be identified on prenatal ultrasound. Most affected fetuses have multiple findings:
- Prenatal/postnatal growth deficiency
- Cleft lip and palate
- Congenital heart defects (80-100%), most commonly one of the following:
  - Ventricular septal defect (VSD)
  - Atrial septal defect (ASD)
  - Patent ductus arteriosis (PDA)
  - Polyvalvular disease
- Major limb malformations (5-10%): radial ray anomalies and other preaxial limb defects
- Abnormal limb posture: clenched fists, clubbing, rocker bottom feet
- Horseshoe kidney
- CNS structural defects:
  - Cerebellar hypoplasia
  - Agenesis of the corpus callosum
  - Hydrocephalus with or without an open neural tube defect
Other findings may not be apparent until postnatal life, such as feeding difficulties

SYNOPSIS:

Trisomy 18 (Edwards syndrome) is a condition caused by an extra chromosome 18 that is present at the time of conception. Most cases (90%) are the result of nondisjunction during meiosis, which is typically a sporadic occurrence. In some affected individuals a chromosomal imbalance is the cause, inherited from a parent who has a balanced karyotype (i.e. Robertsonian translocation). There is also a small portion of affected individuals that have partial Trisomy 18 which may be the result of a parental translocation. A small proportion of affected individuals are diagnosed with mosaic Trisomy 18.

KEY POINTS:

Risk increases with maternal age
ACOG requires all women be offered prenatal screening (biochemical/ cfDNA) or invasive testing (amniocentesis / CVS)
- Screening tests used to detect fetal Down syndrome also include risk assessment for Trisomy 18
- Offer confirmatory testing following a positive screening test for Trisomy 18 due to the potential for false positive results
  - Strongly consider a false positive screening test if the prenatal ultrasound is normal as most affected fetuses will have multiple anomalies
If there is a family history or previous Trisomy 18 pregnancy, refer for genetic counseling

Note: ACMG provides healthcare professionals with open access ‘ACT Sheets’ to guide next steps following a positive NIPS report for trisomy 18 (see ‘Learn More – Primary Sources’ below)

Learn More – Primary Sources:

ACOG Practice Bulletin No. 226: Screening for Fetal Chromosomal Abnormalities

ACMG: Noninvasive Prenatal Screening via Cell-Free DNA [Trisomy 18: Positive Cell Free DNA Screen]

GHR: Trisomy 18

The Trisomy 18 Syndrome

NIH-GARD: Trisomy 18

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Maternal Fetal Medicine Specialist Locator-SMFM

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Should Amniocentesis or Chorionic Villus Sampling Be Offered to All Pregnant Women?

CLINICAL ACTIONS:

Invasive prenatal diagnostic testing usually refers to amniocentesis (analysis of amniotic fluid cells) or chorionic villus sampling (placental cells). Prenatal healthcare providers should

Offer all patients the option of prenatal invasive testing or prenatal screening
Counsel patients that unlike invasive tests which cover all chromosomal abnormalities, traditional screening tests or even the newer cfDNA (NIPS / NIPT) tests will only screen for specific and limited chromosomal abnormalities
- although cfDNA has superior detection for Down syndrome, traditional first-trimester combined screening can detect additional structural and anatomical anomalies because of the ultrasound component of the test
Identify the following risk factors for fetal aneuploidy and consider referral to genetic counseling and high risk OB services if patient requires more in depth counseling or has additional concerns
- Maternal age of 35 or older at EDD: the risk for chromosomal aneuploidy increases throughout the reproductive lifespan, not just after age 35
- If either parent of the fetus has an unusual chromosome makeup or aneuploidy, such as an additional X or Y chromosome
ACOG states

A patient’s baseline risk for chromosomal abnormalities should not limit testing options; serum screening with or without NT ultrasound or cell-free DNA screening and diagnostic testing (CVS or amniocentesis) should be discussed and offered to all patients regardless of maternal age or risk for chromosomal abnormality

ACMG recommends

Allowing patients to select diagnostic or screening approaches for the detection of fetal aneuploidy and/or genomic changes that are consistent with their personal goals and preferences

Informing all pregnant women that diagnostic testing (CVS or amniocentesis) is an option for the detection of chromosome abnormalities and clinically significant CNVs

SYNOPSIS:

The cells obtained from amniocentesis or CVS are analyzed to determine if the number of chromosomes are correct (46) and whether there are structural changes such as deletions or duplications. Routine karyotyping is done using light microscopy. If changes are smaller than the resolution of a microscope, then molecular techniques are required and these small alterations are called microduplications or microdeletions (see ‘Related ObG Topics’ below). Presently, despite major advances in screening technologies, diagnosis of fetal aneuploidy still requires an invasive test.

KEY POINTS:

Miscarriage Risks

In expert hands, there is a 0.1 to 0.3% chance of miscarriage associated with invasive prenatal testing
Cochrane Review (Alfirevic et al., 2017) has released its review on amnio/CVS safety
- 2nd trimester amnio increased risk of pregnancy loss, but it was not possible to quantify the loss rate, based on one study that is now over 30 years old
- Early amnio (11w0d-12w6d) is associated with pregnancy loss and clubfoot compared to 2nd trimester amnio (15w0d-16w6d)
- Transcervical CVS may be associated with higher loss rate compared to 2nd trimester amnio but the quality of the evidence was downgraded due to heterogeneity between studies
Wulff et al. (Ultrasound Obstet Gynecol, 2016)
- Using propensity scoring on a nationwide database of approximately 150,000 women, did not find an increased risk of miscarriage or stillbirth due to amnio or CVS when indications for the procedures were taken in to account (see Related OBG Topics below for review of this paper and other recent papers on this subject of procedure related fetal loss)
Salomon et al. (Ultrasound Obstet Gynecol, 2019)
- Estimated procedure-related risk of miscarriage after amniocentesis and chorionic villus sampling (CVS)
- Performed a systematic review and meta-analysis, covering 20 controlled studies
- The authors concluded

…amniocentesis is associated with a procedure-related risk of 1:300 at most, or more likely, no significant increase in risk

With regard to CVS, our results demonstrate that, there is no significant procedure-related risk associated with undertaking this procedure

Routine Karyotyping or Microarray?

Abnormal prenatal ultrasound with structural abnormality
- A chromosomal microarray analysis that can detect submicroscopic changes is recommended
- Standard karyotype may miss 6% of important chromosome changes
Normal prenatal ultrasound
- A chromosomal microarray can be offered because 1.7% of significant chromosome changes will not be detected on a standard karyotype approach

Microarray limitations to discuss with patients (see ‘Related ObG Topics’ below for more on the benefits and limitations of microarray analysis)
- In a small number of cases, the laboratory may identify copy number variants of uncertain significance (VUS), also referred to as variants of uncertain significance (VOUS)
  - Over time, as databases grow, VUSs can be re-categorized as benign or pathogenic
- Microarrays cannot detect low levels of mosaicism (more than one cell line) or balanced translocations
  - Small risk that while overall DNA appears balanced on a microarray, the breaks involved in the translocation may have disrupted a gene and lead to abnormal protein production

Additional Considerations

A patient who would not terminate a pregnancy
- Important information that may impact the management of a pregnancy may be obtained on invasive testing beyond termination of pregnancy
- Therefore, all patients should be offered the option of screening or invasive testing and have the option of accepting or declining testing irrespective of future reproductive choices
Diagnosis code: diagnosis code will vary depending on indication
- Procedure codes: amniocentesis- 59000; sono guidance for amniocentesis- 76946
- Procedure codes: CVS- 59015; sono guidance for CVS-76945

Learn More – Primary Sources:

ACOG Practice Bulletin No. 226: Screening for Fetal Chromosomal Abnormalities

ACOG Practice Bulletin No. 162: Prenatal Diagnostic Testing for Genetic Disorders

ACOG Committee Opinion No. 682: Microarrays and Next-Generation Sequencing Technology: The Use of Advanced Genetic Diagnostic Tools in Obstetrics and Gynecology

Amniocentesis and chorionic villus sampling for prenatal diagnosis

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

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Maternal Fetal Medicine Specialist Locator-SMFM

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Genetic Carrier Screening in Ashkenazi Jewish Patients

CLINICAL ACTIONS:

Offering carrier screening for various autosomal recessive conditions to patients of Ashkenazi Jewish or Central/Eastern European Jewish heritage has been a longstanding recommendation. ACOG describes a targeted panel. ACMG endorses panethnic prenatal carrier screening rather than direct larger panels toward specific high risk groups (see ‘Related ObG Topics’ below)

ACOG guidelines recommend, at a minimum, screening for the following disorders when offering genetic testing to those of Ashkenazi Jewish background

Tay Sachs Disease (1/30 carrier frequency)
- Serum analysis in non-pregnant female, not taking oral contraceptives
- Leukocyte analysis in pregnant female or female patient taking oral contraceptives
Cystic Fibrosis (1/29 carrier frequency)
Canavan disease (1/40 carrier frequency)
Familial Dysautonomia (1/32 carrier frequency)

ACOG includes the following disorders where screening ‘should be considered’

Mucolipidosis IV (1/127 carrier frequency)
Niemann-Pick disease type A (1/90 carrier frequency)
Fanconi anemia group C (1/90 carrier frequency)
Bloom syndrome (1/100 carrier frequency)
Gaucher disease type I (1/15 carrier frequency)
Familial hyperinsulinism (1/68 carrier frequency)
Glycogen storage disease type 1 (1/64 carrier frequency)
Joubert Syndrome (1/110 carrier frequency)
Maple syrup urine disease (1/97 carrier frequency)
Usher Syndrome (type 1F: 1/147 | type III; 1/120)

Additional Clinical Considerations

Simultaneous testing of both partners can be considered if the patient is pregnant and timing is a concern
If the patient is pregnant and only one member of the couple is Ashkenazi Jewish, it is best to test that individual first, if possible
One Jewish grandparent is sufficient for testing
- If patient is unsure of background, always offer testing
Even if a patient reports being screening previously, without documentation, she needs to be screened again

SYNOPSIS:

A positive family history may not always be present for autosomal recessive conditions, even when there is a high carrier frequency in the Ashkenazi population. Therefore, carrier screening should be offered to those who identify as having Eastern European Jewish/Ashkenazi ancestry. Guidelines have tended toward genetic screening for conditions that have a high carrier frequency in this population. However, due to technological advances, more disorders have been added to genetic screening panels and while some diseases have relatively high carrier rates, others may be less frequent but are considered severe conditions.

KEY POINTS:

Informed consent for genetic testing at a minimum should include

A general description of the disorders
Some of these disorders may not always be severe
- For example, cystic fibrosis can have relatively mild signs and symptoms
Residual risk for a disorder exists even if both partners have a negative carrier screening result, although less risk than prior to testing
A carrier of an autosomal recessive disorder is healthy but has a risk of passing the mutation to her offspring
Genetic counseling should be available for anyone who requests further information

When both partners are identified as carriers, there is a 25% chance that the fetus is carrying both mutations

Prenatal diagnosis with amniocentesis or chorionic villus sampling should be offered
Preimplantation Genetic Diagnosis (PGD) could be considered in couples when both are carriers for the same condition
Encourage patient to inform family members when they are confirmed carriers for any of the conditions for which they were tested

Testing for those of Jewish but non-Ashkenazi heritage

There are no guidelines specifically for Jews of Sephardic (descending from the Iberian/Spanish peninsula) or Mizrahi (Middle East, North Africa, Central Asia) heritage
Genetic testing panels that are comprehensive for Jewish individuals, regardless of area of origin, are now available and include over 90 disorders but most of these do not appear in the recommended ACOG list at this time

SMA variant in the Ashkenazi Jewish population

ACOG recommends that all women who are pregnant or considering pregnancy should be offered screening for SMA (see ‘Related ObG Topics’ below)
There are variants that tracks with silent carriers (i.e., found on chromosomes with duplications and not single-copy alleles) that can be incorporated into clinical carrier screening tests to improve residual risk estimates across all populations
Testing for one of these variants is available commercially in many laboratories and is especially effective in the Ashkenazi Jewish population to identify silent carriers

Learn More – Primary Sources:

ACOG Committee Opinion 690: Carrier Screening for Genetic Conditions

ACOG Committee Opinion 691: Carrier Screening in the Age of Genomic Medicine

Expanded Carrier Screening in Reproductive Medicine—Points to Consider: A Joint Statement of the ACMG, ACOG, NSGC, PQF, and SMFM

ACMG Practice Guidelines : Carrier Screening in Individuals of Ashkenazi Jewish Descent

An Ashkenazi Jewish SMN1 haplotype specific to duplication alleles improves pan-ethnic carrier screening for spinal muscular atrophy

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