Carrier screening has outgrown the language we still use to explain it.

For years, clinicians told patients they were either “a carrier” or “not a carrier.” But as the science has evolved, this binary approach is not only outdated; it is increasingly misleading.

Genetic carrier screening has entered a new era, and our counseling must evolve alongside it.

For decades, carrier screening was offered selectively based on ethnicity. Ashkenazi Jewish individuals were screened for Tay-Sachs disease, African Americans for sickle cell disease, and so on. While well-intentioned, this strategy left large gaps and excluded millions of people because genetic conditions do not follow racial boundaries.

Today, the American College of Medical Genetics and Genomics (ACMG) recommends pan-ethnic screening for all individuals, using a Tier 3 panel that includes:

• 113 genes in total
• 97 autosomal recessive conditions
• 16 X-linked conditions

This move toward equity is long overdue. But broader screening means more results to interpret; and a greater need for nuanced counseling.

Why a “negative” result does not mean “no risk”

Even the most comprehensive test cannot detect every variant. A negative result reduces the chance of having an affected child; it does not eliminate it. This remaining possibility is called residual risk, and patients deserve to understand it before they undergo screening, not after they receive results.

Residual risk matters most when:

• Both partners carry variants in the same autosomal recessive gene ($\approx$25 percent risk of an affected child)
• One partner carries an X-linked variant (up to 50 percent risk for male offspring)

In these scenarios, partner testing, reproductive counseling, and options for diagnostic testing (such as chorionic villus sampling (CVS) or amniocentesis) should be offered to support informed decision-making.

The new counseling burden: Genetics has become an “alphabet soup”

As a reproductive endocrinologist, I sit with individuals and couples who are overwhelmed by modern genetic reports, filled with abbreviations, variant classifications, copy-number findings, and footnotes that require a genetics glossary to decipher.

They often ask:

• “Am I supposed to worry about this?”
• “Is my baby at risk?”

The genetic screening we are throwing at patients has become an alphabet soup, and it is generating confusion, fear, and analysis paralysis, not just in the general public, but among clinicians as well. If we do not update the way we communicate, we risk undermining patient trust and adding emotional harm to what should be an empowering process.

Why some “carriers” can still have symptoms

Historically, we taught that carriers of autosomal recessive conditions are unaffected. But in reality, the presence or severity of symptoms depends on the type of variant, how it behaves in the body, and other modifying factors.

To provide accurate counseling, four core genetic concepts must be understood:

• Penetrance: How likely a person with a variant is to show symptoms. Someone may carry a variant but never develop disease.
• Variable expressivity: The same variant causing different symptoms in different people. One carrier may have mild symptoms, another may have more severe effects.
• Allelic heterogeneity: Different variants within the same gene causing a range of disease severity. Not all variants in the same gene carry the same reproductive risk.
• Locus heterogeneity: Variants in different genes causing the same condition. More than one gene may need to be assessed to determine true risk.

These principles explain why carriers may sometimes have mild or organ-specific symptoms, despite not having the full condition; and why family history can be misleading.

Why a “negative” result does not equal zero risk

• Before testing: General population risk is unknown.
• After a negative result: Risk is reduced, but not eliminated.
• Why residual risk remains: Not all variants are detectable. Some genes have limited test sensitivity. New variants continue to be discovered. Some conditions involve modifying genes or variant interactions.

Residual risk = the small chance that remains even after a negative result. This concept must be normalized in pre-test counseling, not treated as a footnote.

Why our communication must evolve

Carrier screening has advanced faster than our counseling models. If we continue explaining results using outdated frameworks, we risk:

• Over-reassuring patients with negative results
• Over-alarming patients with mild or uncertain findings
• Missing opportunities for informed reproductive choices
• Increasing mistrust in genetic testing and medical guidance

Patients deserve clarity, context, and a collaborative approach that honors both the science and the emotional impact of these results.

Where we go from here

To practice responsibly in the era of Genetic Carrier Screening 2.0, clinicians must:

• Retire the binary “carrier vs. not a carrier” language
• Explain residual risk as standard counseling practice
• Understand core genetic concepts that influence expression and risk
• Use patient-friendly language to reduce fear and confusion
• Know when to refer for genetic counseling or recommend diagnostic testing

Oluyemisi (Yemi) Famuyiwa is a renowned fertility specialist and founder, Montgomery Fertility Center, committed to guiding individuals and couples on their path to parenthood with personalized care. With a background in obstetrics and gynecology from Georgetown University Hospital and reproductive endocrinology and infertility from the National Institutes of Health, she offers cutting-edge treatments like IVF and genetic testing. She can be reached on Linktr.ee, LinkedIn, YouTube, Facebook, Instagram @montgomeryfertility, and X @MontgomeryF_C.