ISPD, SMFM and PQF Release a Joint Position Statement on Fetal Genome-Wide Sequencing

SUMMARY:  

The technological advances in genetics and genomics now allows the full sequencing of exons and even the entire human genome (see ‘Related ObG Topics’ below).  While WES and WGS have led to great advances in research and clinical genetics, use in pregnancy has remained controversial. While there is ongoing research on the topic of sequencing during pregnancy, the ISPD, SMFM and PQF have released a joint statement to provide guidance in the clinical prenatal setting.

Summary of Key Recommendations 

The routine use of prenatal sequencing is not recommended, including cases where fetal DNA has already been obtained via amniocentesis, CVS or cordocentesis   

  • Clinical validation data are currently insufficient and prospective studies are required to determine clinical utility and risks vs harms 

The following are appropriate circumstances to consider prenatal sequencing in a non-research setting on a case-by-case basis 

  • Fetal anomalies or a single major anomaly suggestive of a genetic disorder, but microarray is negative   
  • No microarray result is available, but the fetus exhibits anomalies strongly suggestive of a single gene disorder (multidisciplinary review required)  
  • Previous undiagnosed fetus (or child) from either parent, with single or multiple anomalies suspicious for a genetic syndrome that has now recurred in the current pregnancy  
    • Karyotype and microarray in the current pregnancy have not yielded a diagnosis    
    • Make every effort to obtain a sample from the current pregnancy or previously affected offspring  
    • If samples are unavailable from previously affected offspring or the current pregnancy, consider offering parents sequencing to determine if they may be carriers for an autosomal recessive disorder  
  • History of recurrent stillbirths with negative karyotype and/or microarray, where the fetus is exhibiting a similar pattern of anomalies 

Key Points:  

  • Ideally, diagnostic sequencing should include a trio of samples – both parents and the fetus  
    • Aids in interpretation and turnaround time  
  • There is limited genotype-phenotype correlation for many genetic disorders 
    • Correlation between how a disorder manifests and the underlying variant is even more challenging in the prenatal setting 
    • Ultrasound even in expert hands may not always provide a complete picture when compared to a physical exam combined with other laboratory and imaging studies 
    • Debate remains if the same interpretation rules should be used for prenatal sequencing or should be limited to variants that explain the fetal findings 

Education, Counseling and Consent   

Consider the following minimal elements when providing education, counseling and informed consent  

  • It is best to individualize pre-test education and counseling and include both parents when possible  
  • Educational tools and materials to supplement or replace direct patient counseling need to be evaluated prior to clinical use   
  • If possible, both parents should provide consent but a woman can provide consent alone for all invasive prenatal diagnostic testing, including sequencing 
  • If trio testing is offered, parents should individually consent for their personal sample testing    

If providing pre-test counseling and informed consent, include the following in the discussion

  • Whose genome will be analyzed  
    • Fetus, one or both parents    
  • What type of variants may appear in the lab report
    • Known variants only, or will the report also include ‘likely’ benign or pathogenic variants and/or VUS   
  • Manage patient expectations appropriately  
    • How realistic is it that clinically useful variants will be obtained 
    • What is the expected turnaround time  
    • What is the possibility that no result will be obtained (e.g., related to DNA quality or quantity)  
    • Will the result be available prior to the birth of the fetus in the case of an ongoing pregnancy 

Reporting & Post-Test Considerations  

  • Include a discussion of whether or not the report will include incidental findings  
    • Childhood genetic disorders (unexpected based on medical/family history)  
    • Adult-onset conditions in the fetus 
  • Make patients aware that testing could uncover non-paternity or an incestuous relationship between the biological parents 
  • Genetics/Genomics is constantly evolving and results and post-test counseling will reflect the most current knowledge but this may evolve over time  
    • Data re-analysis strategies should be discussed  
  • ISPD, SMFM, and PQF endorse the ACMG opinion that data sharing is crucial to drive research and clinical advances  
    • If available, explain to patients the benefits of data sharing and provide appropriate consent if they opt for data sharing and/or storage  
    • Explain clearly who will have access and what the purpose of such storage  
  • Professionals who provide fetal sequencing and related education, counseling and reporting must be well versed in the benefits and risks to the fetus related to sequencing 
    • Interpretation of results and post-test counseling may be complicated and best performed in consultation with a multidisciplinary team with expertise in clinical and laboratory genetics/genomics  
  • Counsel and return results based on documented patient choices prior to testing 
  • All individuals should receive post-test counseling regardless of clinical usefulness of the results 

Learn More – Primary Sources:  

Joint Position Statement from the International Society of Prenatal Diagnosis (ISPD), the Society of Maternal Fetal Medicine (SMFM) and the Perinatal Quality Foundation (PQF) on the use of genome-wide sequencing for fetal diagnosis 

 

Practical obstetrics info for your women's healthcare practice

Understanding Transposition of the Great Arteries

WHAT IS IT?

In a normal heart, the pulmonary artery carries deoxygenated blood to the lungs. Oxygenated blood returns to the left side of the heart and the aorta then pumps the oxygenated blood to the rest of the body. In Transposition of the Great Arteries (TGA), the pulmonary artery and aorta have changed places (i.e., they are transposed). Therefore:

  • The pulmonary artery, which usually arises from the right side of the heart and carries deoxygenated blood to the lungs, will now connect to the left side of the heart and send oxygenated blood back to the lungs
  • The aorta, which usually arises from the left (oxygenated) side of the heart, is now exiting the right side and therefore will carry deoxygenated blood to the rest of the body, bypassing the lungs
  • 5 out of 10,000 babies are born with TGA
  • TGA is referred to as a ‘cyanotic’ (lacking oxygen) defect leading to babies with bluish discoloration and shortness of breath, with symptoms dependent on whether there is any ability for the deoxygenated and oxygenated blood to mix and be delivered to the rest of the body
  • Surgery is often necessary shortly after birth, especially in the case of complete TGA (also known as d-TGA referring to ‘dextroposition’) which is considered a ‘critical congenital heart defect’
Transposition of the Great Arteries

Image credit: Centers for Disease Control and Prevention, National Center on Birth Defects and Developmental Disabilities

KEY POINTS:

  • While TGA can be diagnosed prenatally on ultrasound, it may not always be detected
  • In the majority of cases, a cause is not readily apparent
  • In some cases, TGA can be associated with genetic abnormalities and therefore, if a prenatal diagnosis is made or suspected, referral for genetic counseling is recommended, in addition to high risk obstetrical services, neonatology and pediatric cardiology
  • TGA is sometimes referred to as Transposition of the Great Vessels (TGV)

Learn More – Primary Sources:

CDC: Facts about dextro-Transposition of the Great Arteries (d-TGA)

Circulation-AHA journal: Transposition of the Great Arteries

CDC: Facts about Critical Congenital Heart Defects

Current diagnosis and treatments for critical congenital heart defects

Fetal Growth and Neurodevelopmental Outcome in Congenital Heart Disease

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