From one proband's pathogenic variant to a whole family tree — notifying, testing, and identifying at-risk relatives ring by ring
Cascade genetic testing begins with a single "proband" — the first person in a family identified as carrying a pathogenic or likely pathogenic variant in a gene associated with a hereditary condition. That one laboratory result carries implications far beyond the individual patient: for autosomal dominant conditions, each of the proband's first-degree relatives independently has roughly a 50% chance of carrying the same variant. Cascade testing is the structured process of working outward through the family tree — first-degree, then second-degree, then third-degree relatives — offering targeted, inexpensive single-site or panel testing to each at-risk relative in turn.
Cascade testing has its clearest historical roots in familial hypercholesterolemia (FH), an autosomal dominant disorder of LDL receptor function that causes markedly elevated cholesterol and early-onset coronary disease. Because FH is common (roughly 1 in 250 people), highly penetrant, and eminently treatable once identified, national screening programs in the Netherlands and United Kingdom pioneered systematic "cascade" identification: find one person with a known FH-causing variant, then test their relatives, then their relatives' relatives, statin-treating each newly found carrier before their first heart attack rather than after.
The same logic was independently adopted in hereditary cancer genetics. When a BRCA1/BRCA2 pathogenic variant (breast/ovarian cancer) or a Lynch syndrome mismatch-repair gene variant (MLH1, MSH2, MSH6, PMS2 — colorectal and endometrial cancer) is found in one family member, testing relatives for that exact familial variant is dramatically simpler and cheaper than sequencing each relative's whole genome from scratch — the laboratory already knows precisely which single change to look for.
Population-wide genetic screening — testing every person in a country for every actionable variant — remains prohibitively expensive and logistically enormous. Cascade testing sidesteps this problem entirely: once a variant is known in a family, testing a relative for that single specific change costs a small fraction of a full diagnostic sequencing panel, and each relative found to carry it can immediately begin proven preventive care — statins and lifestyle changes for FH, enhanced cancer screening or risk-reducing surgery for BRCA1/2, colonoscopy surveillance for Lynch syndrome.
Health-economic modeling consistently finds cascade testing among the most cost-effective interventions available in clinical genetics, often falling well under standard cost-per-QALY thresholds used by health systems to fund new interventions. The efficiency comes from concentrating testing resources exactly where the prior probability of a positive result is highest — inside a family already known to carry a pathogenic variant — rather than searching the general population at large.
Because each identified carrier can start preventive care years or decades before symptoms would otherwise appear, the downstream savings — heart attacks prevented, cancers caught early or avoided entirely — compound far beyond the modest cost of the test itself.
In most health systems, the responsibility for informing relatives falls on the proband: after genetic counseling, the patient is given a "family letter" summarizing the result and asked to share it with parents, siblings, and children themselves. This proband-mediated model respects patient autonomy and confidentiality, but it is also the single biggest bottleneck in cascade testing — many relatives are never told at all, not because anyone objects, but because disclosure is emotionally difficult, families are estranged, relatives are geographically distant, or the proband simply does not know how to start the conversation.
Multiple studies across FH, BRCA, and Lynch syndrome cohorts converge on a striking pattern: even when probands express clear intention to share their result, actual relative uptake of testing frequently falls well short of the theoretical family at risk — commonly under half of eligible first-degree relatives ever get tested through proband-mediated disclosure alone.
The reasons are rarely refusal or disagreement. They are logistical and emotional: not knowing the right words to use, fear of causing distress or being blamed for "bad news," family conflict or long-standing estrangement, uncertainty about contact information for distant relatives, or simply the diffusion of responsibility that happens when a difficult task is left open-ended with no deadline and no follow-up.
For an autosomal dominant condition, each first-degree relative of a confirmed carrier independently has approximately a 50% prior probability of carrying the same variant — a coin flip repeated once per relative, unaffected by whether siblings tested positive or negative. This is the statistical engine driving the simulation on this page: as the "Family Communication Willingness" slider is raised, more first-degree relatives are actually informed of that coin flip and given the chance to have it resolved by a test; as it is lowered, more relatives who are unknowingly living with (or without) the variant simply never learn there was ever a question to ask.
A cascade does not stop at first-degree relatives. Every relative who tests positive is themselves a new proband for their own first-degree relatives — meaning the process should, in principle, expand outward through second-degree relatives (grandparents, aunts, uncles, nieces, nephews, half-siblings) and third-degree relatives (cousins), each ring carrying its own diluted but still clinically actionable prior probability of carrying the variant. In practice, each additional hop through the family network multiplies the chances of the message failing to travel — a phenomenon visible as a steady drop-off rate ring by ring.
Because relay-based, proband-only disclosure loses relatives at every hop, a growing number of health systems now offer "direct contact" alternatives: with the proband's consent, a genetic counselor or trained patient navigator sends a formal letter directly to named relatives, or helps the proband draft and send a structured family letter with clinic contact details attached. Patient navigator programs go further — actively helping trace contact information, coordinating appointments, and following up with relatives who have not responded.
Evidence from FH and hereditary cancer cascade programs shows that these assisted-contact models can substantially increase the number of relatives who ultimately get tested compared with relying on the proband alone, particularly for second- and third-degree relatives who the proband may barely know how to reach.
Direct-contact and patient-navigator programs do not replace the proband's role — they support it, reducing the burden of a difficult conversation from "explain this alone" to "here is a letter and a person who can help."
Every ring outward in the simulation on this page multiplies two independent probabilities: whether the closer relative who was tested chooses to inform their own relatives, and whether the more distant relative then agrees to test once informed. Even modest per-hop attrition compounds quickly — which is exactly why third-degree relatives are so often the ones who never learn about a variant already known, sometimes for years, elsewhere in their own family.
Once a relative is tested, the family tree branches into two very different futures. A non-carrier result (green) ends that branch of concern — for autosomal dominant conditions, a confirmed non-carrier cannot pass the familial variant to their own children and typically needs no further surveillance beyond general population guidelines. A carrier result (red) does the opposite: it confirms the same elevated risk the proband carried, opens the door to preventive care for that relative, and — critically — makes that relative a brand-new proband, with their own untested first-degree relatives now waiting to be found.
Because roughly half of tested first-degree relatives are expected to be carriers under Mendelian inheritance, cascade programs can reasonably forecast how many new "restart points" a single proband's result will generate — informing staffing, genetic counseling capacity, and outreach budgets. A large, well-connected family with many first-degree relatives can produce a cascade that keeps generating new carrier-led branches for years, particularly when second- and third-degree relatives are actively pursued rather than left to chance.
Unlike a simple notification list, cascade testing is recursive: every carrier identified is a potential new index case for relatives who have not yet been reached at all — including relatives outside the rings already examined (in-laws' families, more distant cousins, relatives from a previous generation not yet tested). This is why sustained cascade programs, rather than a single one-time notification effort, tend to identify substantially more carriers over time than a single wave of contact ever could.
Zoomed out across an entire extended family, cascade testing's impact becomes visible as a simple ratio: how many at-risk relatives were actually identified and tested, against how many remain entirely unreached, still unknowingly living with — or without — a variant that a health system already knows the answer to. That gap sits at the center of one of clinical genetics' most persistent ethical tensions: patient confidentiality versus relatives' arguable right to know actionable health information about themselves.
Genetic information is unusual among medical data because it is inherently shared — a variant found in one person is, by definition, information about their blood relatives too. Most health systems treat the proband's result as strictly confidential, placing disclosure to relatives in the proband's own hands and requiring explicit consent before a clinician contacts anyone else. This protects patient autonomy but can leave relatives permanently uninformed about a preventable or treatable risk.
A smaller but growing body of ethical and legal opinion argues for a limited "duty to warn" in cases of serious, actionable hereditary risk — analogous to duty-to-warn precedents in other areas of medicine — allowing or requiring clinicians to directly contact at-risk relatives under defined safeguards, even without the proband's active cooperation, when the condition is both serious and something that can actually be acted upon.
No consensus position has been universally adopted. Most current direct-contact and patient-navigator programs operate squarely within the consent-based model — proband permission remains the starting point — while still working to close the reach gap that pure proband-mediated disclosure leaves behind.
The zoomed-out family tree on this page renders every relative the simulation considered "at risk" — every node that could, in principle, have been reached. Bright, colored nodes are relatives who were actually notified and tested; dim gray nodes are relatives who remain unreached under the current Family Communication Willingness and Direct Contact Program settings. Raising either slider closes that gap; a real cascade testing program spends its effort trying to do exactly the same thing, family by family.