What is the role of carrier screening for genetic disorders in pregnancy or preconception?

Carrier Screening for Genetic Disorders in Pregnancy or Preconception

All pregnant patients and those planning pregnancy should be offered tier 3 carrier screening, which includes screening for 97 autosomal recessive genes and 16 X-linked genes with carrier frequencies ≥1/200, regardless of ethnicity or family history. 1

Understanding Carrier Screening

Carrier screening identifies individuals who carry genetic mutations that could cause serious genetic disorders in their children. These are typically:

• Autosomal recessive conditions (both parents must be carriers)
• X-linked conditions (primarily carried by mothers and affecting male offspring)

Evolution of Carrier Screening Approaches

Carrier screening has evolved significantly:

1. Traditional approach: Targeted specific ethnic populations (e.g., Ashkenazi Jewish individuals for Tay-Sachs disease) 1
2. Current approach: Pan-ethnic screening using next-generation sequencing (NGS) technology that more effectively identifies at-risk couples across all ethnicities 1, 2

ACMG Tiered Screening Recommendations

The American College of Medical Genetics and Genomics (ACMG) recommends a tiered approach to carrier screening 1:

• Tier 1: Cystic fibrosis, spinal muscular atrophy, and risk-based screening
• Tier 2: Conditions with carrier frequency ≥1/100 (includes Tier 1)
• Tier 3: Conditions with carrier frequency ≥1/200 (includes Tier 2) and selected X-linked conditions
• Tier 4: Conditions with carrier frequency <1/200 (includes Tier 3)

Optimal Timing for Carrier Screening

Preconception screening is strongly preferred as it provides couples with the most comprehensive range of reproductive options 1, 3:

• Preimplantation genetic diagnosis
• Use of donor gametes
• Adoption
• Preparation for potential medical interventions

If preconception screening isn't possible, screening should be performed as early as possible in pregnancy 1.

Testing Protocols

Sequential vs. Concurrent Testing

• Early pregnancy (<14 weeks): Sequential testing is acceptable (test mother first, then father if mother is positive)
• Later pregnancy (≥14 weeks): Concurrent testing of both partners is recommended due to time constraints 1
• Family history: Testing may be initiated with the partner who has relevant family history 1

When One Partner Tests Positive

If one partner is found to be a carrier for an autosomal recessive condition:

• The other partner should be offered testing to assess risk to offspring 1, 3
• If both partners are carriers, genetic counseling should be offered 3
• Prenatal diagnosis options should be discussed 1

Technical Approaches to Carrier Screening

Modern carrier screening utilizes several technologies 1:

1. Targeted Gene Panels (TGPs):

   • Focus on specific genes of interest
   • Higher coverage depth for targeted regions
   • May require supplementary testing for certain variants

2. Virtual Gene Panels from Exome/Genome Sequencing:

   • Analyze specific genes from broader sequencing data
   • May have less uniform coverage than targeted panels
   • Can detect a wider range of variant types

Clinical Implementation Considerations

Reporting Results

• All pathogenic/likely pathogenic variants in tier 3 genes should be reported 1
• Variants of uncertain significance (VUS) represent a challenge for large-scale implementation 1

Technical Challenges

Some clinically important genes require special testing approaches due to:

• Pseudogenes (e.g., GBA for Gaucher disease)
• Repeat expansions (e.g., FMR1 for Fragile X syndrome)
• DNA structural variations 1

Communicating with Patients

When a carrier is identified:

• Encourage informing relatives about their risk and screening availability 3
• Discuss implications for future pregnancies
• Provide genetic counseling if both partners are carriers 3

Common Pitfalls and Caveats

1. Residual risk: A negative test doesn't eliminate carrier risk completely due to limitations in detection rates
2. Ethnic-specific considerations: Detection rates vary by ethnicity for some conditions 1
3. Insurance coverage: Coverage for paternal testing may be inconsistent, potentially delaying critical information 1
4. Limited time in pregnancy: Late testing may restrict reproductive options
5. Interpretation challenges: NGS can identify numerous variants of uncertain significance 1

Moving Toward Universal Expanded Carrier Screening

Recent evidence supports moving away from ethnicity-based screening toward universal expanded carrier screening for all patients planning pregnancy or already pregnant 2, 4. This approach:

• Identifies at-risk couples more effectively and equitably
• Reduces systemic inequalities in medical practice
• Aligns with recommendations from multiple professional societies