SUMMARY:

The ACMG provides guidance on preconception and prenatal carrier screening. Multiple factors were taken into consideration for this document, including optimal panel size and which genes should be included. This document divides carrier screening into 4 tiers (see below). In addition, the committee addresses the question of making panels panethnic vs separating these tests out by race and/or ethnicity

Definitions

• Carrier screening
  • Molecular testing used to identify individuals and couples at risk for a child with an autosomal recessive or X-linked genetic disorder
  • Generally, carriers are healthy | However, there may be circumstances where individuals may have medical issues (e.g., Fragile X carriers may have risk for premature ovarian failure)
  • Carrier screening provides patients with knowledge regarding her pregnancy so that she can make informed choices regarding reproductive options and management plans
• Carrier
  • “…Specifically refers to individuals who are heterozygous for a pathogenic or likely pathogenic variant in an autosomal recessive or X-linked condition”

Pre-Test Counseling Requirements

• Testing is optional | A patient can decline but request screening at another time
• Preconception screening is recommended over prenatal screening
  • Less stress
  • Opens up additional options such as PGT
• Concurrent partner testing should be offered if testing done during pregnancy
• Check to ensure if there is a new reproductive partner | If new partner, carrier screening should be readdressed as couple’s risk will have changed
• Only a minority of all genetic disorders are tested in carrier screening panels
• Genetic variants detected on screening panels usually will have been in families for generations
• Carrier screening cannot detect de novo (new) mutations in the fetus
• Requirements for newborn screening are unchanged
  • Carrier screening looks at the parents’ DNA to determine risk for certain genetic conditions in the offspring
  • Newborn screening is a test that assesses offspring directly for specific medical and genetic conditions
• Consanguinity increases risk for autosomal recessive disorders | Couples from certain communities, while not immediate first cousins, may also have increased risk
• Residual Risk
  • Critical to ensure patients understand  that “a negative test reduces the chance to have an affected child but does not eliminate the risk”

What Disorders Should be Tested?

ACMG Has Developed a Tiered Approach to Screening

• Tier 1
  • CF | SMA | Risk Based Screening
• Tier 2
  • ≥1/100 carrier frequency (includes Tier 1)
• Tier 3:  RECOMMENDED
  • ≥1/200 carrier frequency (includes Tier 2) and X-linked conditions
• Tier 4: <1/200 carrier frequency (includes Tier 3) | Genes/conditions will vary by lab

ACMG Recommendations

• Carrier screening paradigms should be ethnic and population neutral and more inclusive of diverse populations to promote equity and inclusion
• All pregnant patients and those planning a pregnancy should be offered Tier 3 carrier screening
• Tier 4 screening should be considered
  • When a pregnancy arises from a known or possible consanguineous relationship (second cousins or closer)
  • When a family or personal medical history warrants further risk assessment
• ACMG does not recommend
  • Offering Tier 1 and/or Tier 2 screening, because these do not provide equitable evaluation of all racial/ethnic groups
  • Routine offering of Tier 4 panels

Note: ACMG provides a robust explanation for selection of Tier 3 as the recommended panel | Research demonstrates a carrier frequencies of <1/200 adds a “diminishingly small” number of at risk couples (see ‘Learn More – Primary Care Sources’ below)

KEY POINTS:

• Tier 3 is recommended and includes
  • 97 autosomal recessive genes
  • 16 X-linked genes, including DMD and Fragile X
• Genetic testing can alter risk but cannot rule out the presence of a disorder
  • Other genes may cause a condition but may not yet be known
  • The test may not cover all genes or some causative variants
  • The technology may not be able to test for all causative variants
  • Analysis of the sequence may be difficult or the algorithms used by a specific lab may misclassify the pathogenicity of a particular variant
• Family history is still valuable
  • Not all genetic disorders are included in prenatal screening panels
  • Consider referral to genetic professionals if family history suggests the need to examine additional genes beyond what is available on a screening panel
• The word ‘expanded’ in ‘expanded carrier screening’ is unclear
  • The word ‘expanded ‘should be dropped and replaced with  ‘carrier testing’
• Partner testing
  • Male partners may be offered Tier 3 carrier screening (for autosomal recessive conditions) if carrier screening is being performed at the same time with female partner
• Laboratory report requirements are also addressed in the guideline and include among other recommendations the following
  • Labs “should not report residual risk estimates because carrier frequency and the detection rate of all genes is not established”
  • “Content of carrier screening panels and the corresponding ACMG tier must be described in the laboratory reports”
• The recommendations will likely evolve as more data becomes available

Learn More – Primary Sources:

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

Estimating yields of prenatal carrier screening and implications for design of expanded carrier screening panels

Systematic Classification of Disease Severity for Evaluation of Expanded Carrier Screening Panels

Related ObG Topics:

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

ACOG Opinion on Expanded Carrier Screening

Spinal Muscular Atrophy: Genetic Concepts and Carrier Screening 

Prenatal & Preconception Carrier Screening for Fragile X: Clinical and Genetic Essentials

Newborn Screening: NBS Basics for Healthcare Professionals