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 

 

The Genome and Whole Genome Sequencing

WHAT IS IT?

  • The genome is the collective total of an individual’s DNA, including all genes
    •  The human genome is composed of over 3 billion base pairs
    • Genes that code for proteins or other functional molecules only constitute a fraction of total DNA
    • Research is ongoing to look at all regions of the genome and their complex interactions
  • The Human Genome Project (completed 2003) established an overall ‘human’ consensus genome, though every individual has variations from the consensus in their personal genome
    • Most of an individual’s gene variations have no impact on gene function
    • Some variations that will impact gene function have an important role in disease causation
    • It can be unclear in some instances what the impact of certain genetic variations is, and whether or not they contribute to clinical findings
      • These are referred to as variants of uncertain significance (VUS)

Whole Genome Sequencing (WGS)

  • Analysis of the genome is typically performed using DNA sequencing technologies and often referred to as Whole Genome Sequencing (WGS)
  • WGS is generally considered in individuals with rare diseases or syndromes for whom testing of specific potentially disease-causing genes have not identified any disease causing gene mutations
  • WGS will not detect all types of genetic changes, such as large deletions of genes/DNA regions, and possibly smaller DNA insertions and deletions

KEY POINTS:

  • WGS analysis will generally require a blood sample
    • Requirements will vary by laboratory
  • Results from WGS will not always yield definitive, actionable results that confirm a diagnosis
    • Findings may indicate a Variant of Uncertain Significance (VUS) and further follow up may be required over time to determine whether or not the variant is benign or pathogenic
    • WGS testing may often be most informative when an individual’s family members are also tested or willing to be tested to clarify result interpretation
  • Genetic counseling is recommended pre- and post-WGS analysis
  • Thorough informed consent process is imperative given the potential for results that may or may not be definitive

Learn More – Primary Sources:

National Human Genome Research Institute Fact Sheets

ACMG: Points to Consider for Informed Consent for Genome/Exome Sequencing

Locate a Genetic Counselor or Genetics services:

Genetic Services Locator-ACMG

Genetic Services Locator-NSGC

Genetic Services Locator-CAGC