What is expanded carrier screening and is it recommended for the parents of a young Ashkenazi‑Jewish child with familial dysautonomia (hereditary sensory and autonomic neuropathy type III)?

What is Expanded Carrier Screening?

Expanded carrier screening (ECS) is a genetic test that simultaneously screens for carrier status of multiple autosomal recessive and X-linked genetic disorders—typically dozens to hundreds of conditions—using next-generation sequencing technology, allowing identification of at-risk couples regardless of ancestry or ethnicity. 1

Definition and Technology

• ECS detects whether individuals unknowingly carry gene variants associated with genetic conditions that may be passed to their children, performed by analyzing a blood sample 2
• The technology has evolved from traditional single-disease, ancestry-based screening to multi-disease, pan-ethnic screening facilitated by next-generation sequencing (NGS) 1, 3
• Modern ECS panels test for anywhere from 100 to over 600 genes simultaneously, though there is no consensus on which specific panel of genes should be included 2, 4
• NGS technology enables identification of both common founder mutations and rare/novel variants, unlike older array-based methods that only detected known pathogenic variants 1

Clinical Purpose and Mechanism

• The goal is to identify couples at risk of transmitting genetic disorders to facilitate informed reproductive decision-making before or during pregnancy 1, 5
• For autosomal recessive conditions, both parents must be carriers for a child to be affected, creating a 25% risk per pregnancy when both partners carry variants in the same gene 6, 2
• Carriers themselves are asymptomatic and healthy but can pass the gene variant to offspring 1

Application to Your Specific Case

For the parents of a child with familial dysautonomia, expanded carrier screening is absolutely recommended and should have been offered ideally before pregnancy. 1

Why This Matters for Ashkenazi Jewish Families

• Familial dysautonomia occurs almost exclusively in the Ashkenazi Jewish population with a carrier frequency of 1 in 29 6
• The ACMG and ACOG specifically recommend that couples of Ashkenazi Jewish ancestry be offered screening for familial dysautonomia along with Tay-Sachs disease, Canavan disease, and cystic fibrosis as standard practice 6
• The cumulative carrier rate is substantial: between 1 in 4 and 1 in 5 Ashkenazi Jews carry a mutation for any one of these disorders 1, 6

Screening Approach for This Family

• Both parents should undergo carrier screening for the expanded Ashkenazi Jewish panel, which includes familial dysautonomia and at least 8 other conditions 1
• If only one parent is Ashkenazi Jewish, that partner should be tested first; if positive, the other partner should then be screened for that specific disorder 1
• The founder mutation phenomenon in Jewish genetic disorders means that 1-3 mutations account for the vast majority of cases, making molecular screening highly effective with >95% detection rates 1, 6
• For familial dysautonomia specifically, mutation detection rates exceed 99.4%, with residual carrier risk after negative testing being approximately 1 in 5000 1

Critical Counseling Points

• Screening should occur in every generation because carriers are asymptomatic, and the success of historical screening programs has created the misperception that these genes are no longer present in the population 1
• Formal genetic counseling should be readily available, particularly for carrier-positive results, to discuss reproductive options and family implications 1
• Even with excellent detection rates, a residual risk remains after negative testing, which must be explained during counseling 1
• Carrier-positive individuals should be encouraged to share their status with at-risk relatives 1

Expanded vs. Traditional Screening

• Traditional carrier screening focused on specific ethnic populations at increased risk for particular disorders (e.g., Ashkenazi Jews for Tay-Sachs) 1
• Recent studies demonstrate that pan-ethnic screening for a large number of conditions more effectively identifies at-risk couples across all races/ethnicities compared with ethnicity-restricted screening 1
• However, for Ashkenazi Jewish individuals, targeted screening for the core panel remains highly effective due to founder mutations and well-established carrier frequencies 1, 6

Important Caveats

• Not all ECS panels test the same genes, and some may include conditions that do not cause serious disease or manifest only in later life 2
• Understanding screening results is complicated and requires support from appropriately trained professionals 2
• The ACMG recommends that conditions included in screening panels should have well-understood natural history with significant morbidity/mortality and either ≥90% detection rate or ≥1% allele frequency in the target population 1
• Technical limitations include the potential for sample mix-ups, genotyping errors from trace PCR contamination, and rare polymorphisms that interfere with analysis 1