Autism genetic testing results explained: positive, negative, and uncertain

The five results a lab can hand you

Most parents expect two outcomes from a genetic test: positive or negative. There are actually five.

In 2015, the two US professional groups that set the rules for clinical genetics labs — the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology — agreed on one shared scale that US clinical labs now use as the standard for sequence variants: pathogenic, likely pathogenic, uncertain significance, likely benign, and benign (Richards 2015).

Your report will usually collapse these five into plainer language:

• Pathogenic or likely pathogenic — the lab is confident this DNA change explains part of your child’s medical picture. Reports typically call this “positive.”
• Uncertain significance — the lab found a real change but cannot yet say whether it matters. This is its own category, not a maybe-positive. Reports usually spell out “variant of uncertain significance,” often shortened to VUS.
• Likely benign or benign — an ordinary, harmless variation. Most labs do not even list these on the report a family receives.

Ask your clinician to read you the exact word on the report — “positive,” “negative,” or “uncertain” secondhand is not the same as hearing “likely pathogenic” or “variant of uncertain significance” in full. The wording changes what happens next.

A positive result: what it explains, and what it does not

A positive result — pathogenic or likely pathogenic — means the lab is confident a specific DNA change plays a real role in your child’s medical picture. It does not mean the gene is the whole story, and it does not replace your child’s autism diagnosis, which comes from clinical evaluation, not from a blood draw.

De novo or inherited. The report will usually say one of two things: the variant is de novo (new in your child, not found in either parent’s DNA) or inherited (passed down from a parent, who may or may not share related traits). Neither is “worse.” De novo variants are a well-studied source of genetic changes linked to autism (Sanders 2015); inherited variants simply mean the change has been in the family longer, sometimes unnoticed.

What a positive result can change:

• Screening. Many named genetic conditions come with a known pattern of related health issues — heart, kidney, vision, hearing, or seizure findings tied to that specific gene. A positive result often turns guesswork into a written screening schedule.
• Management. Some conditions point toward a specific next step for your child’s medical team, rather than only more watching and waiting.
• Research. A named condition can connect you to a gene- or syndrome-specific parent community and research registry that a general autism diagnosis does not.
• Family information. Some genetic findings carry a known chance that a sibling or a future pregnancy could carry the same variant — recurrence information you can bring to a genetic counselor on your own timeline, not something you have to decide about today.

A full walkthrough of what testing can do for your child, for you, and for your child’s medical team is on genetic testing, explained.

A negative result does not close the door

If nothing came back, you are in the majority. In one study, 258 children with autism all had a chromosomal microarray, and 24 of them — 9.3% — got an explanation from it. Ninety-five of those children also had whole exome sequencing, which explained 8 more (8.4%). Across that 95-child group, the two tests together explained an estimated 15.8% of cases — meaning roughly 84% of that group tested negative on both (Tammimies 2015). A separate pooled analysis across 14 autism sequencing studies found an overall diagnostic yield of 17.1% (Stefanski 2021). Most children who get tested get a negative result. That is ordinary, not a sign the test failed.

A negative result means the specific genes and variant types this test can see did not turn up an answer. It does not mean genetics played no part at all. Autism’s genetic contribution is not always one gene doing all the work — often it involves many common variants, each with a small effect, adding up together. Researchers call this polygenic: instead of one clear single-gene change, many ordinary variants across the genome combine. Current clinical tests are built to catch single strong-effect changes, not this kind of combined, spread-out signal, so a negative result on a standard test says nothing about whether a polygenic pattern is present.

Should you retest later? Maybe, eventually. Gene discovery moves quickly — a variant with no clear category today can be reclassified as more families are tested and more data accumulates. If your child had an older or more limited test, such as a chromosomal microarray alone, ask whether whole exome sequencing would add anything now — see whole exome sequencing for what a broader test finds, and chromosomal microarray for how the two differ. If your child already had exome or genome sequencing, ask instead about re-analysis of the same data, covered below, rather than an entirely new sample.

A variant of uncertain significance

Every person’s DNA differs from the reference sequence — the shared comparison point — at millions of places; a test that reads only the protein-coding genes still turns up tens of thousands. Most are harmless background variation. A handful, in the wrong gene, cause disease. The lab’s job is to sort every variant it finds into one of the five categories from Richards 2015 — and for a meaningful number of variants, there simply is not enough evidence yet to sort it confidently into “clearly harmless” or “clearly disease-causing.” That gap is a variant of uncertain significance, or VUS.

A VUS happens because the change is rare enough, or new enough to genetic databases, that nobody has yet gathered the population data, computational modeling, or family evidence needed to classify it with confidence (Richards 2015). It is not a filing error, and it is not a maybe-positive result in disguise. It means: not enough is known yet.

What not to do with a VUS. Do not treat it as a diagnosis. Do not start, stop, or change anything about your child’s medical care because of it alone. Do not assume it explains your child’s autism — that has not been established. Genetics teams are consistent on this point: an uncertain result should not drive decisions on its own.

Reclassification. A VUS is not permanent. As more people are tested and more evidence accumulates — new families found with the same variant, new lab studies, updated public databases — a lab can move a variant into a firmer category. One study systematically re-analyzed 40 previously nondiagnostic clinical exomes using then-current software and literature, and reached a definitive diagnosis in 4 of them (10%) — each traced to a variant that had not had strong enough evidence to call at the time of the original report (Wenger 2017). Wenger’s team put the rate at roughly 250 new gene-disease links and 9,200 new variant-disease links a year (Wenger 2017), which is part of why yesterday’s uncertain result can become tomorrow’s answer.

Ask your lab or clinic:

• Is this lab’s classification the most current one, or could it have changed since the report was issued?
• Does this lab offer automatic re-analysis, or does a family need to request it?
• Is there a cost to requesting re-analysis, and how often is it reasonable to ask?

Put the answer in writing, and put a reminder on your own calendar — six months, a year — rather than counting on the lab to reach out first.

Secondary findings and the choice to opt out

Broader tests like whole exome or genome sequencing read thousands of genes in one pass, which means they can turn up something with nothing to do with autism at all. A current US professional guideline names 84 genes as important enough to report as a secondary finding if a lab happens to spot a pathogenic or likely pathogenic variant in one — most tied to heart-rhythm conditions or inherited cancer risk, where knowing early genuinely changes care (ACMG SF v3.3, Lee 2025).

This is optional. Most labs ask, before the blood or saliva sample is even collected, whether your family wants these results if something turns up. There is no required answer — some families want every actionable finding reported; others want only what explains the reason they tested in the first place.

The choice happens before testing, not after, because a lab cannot un-know what it has already told you. Once a result is delivered, it cannot be handed back. Deciding in advance means you choose what you are ready to hear, rather than having that decision made for you by the order the report happens to arrive in.

Ask your genetics team directly: does their lab offer this choice, how is it documented, and can it be changed later before your next test if you decide differently?

Trio testing: why the lab wants your DNA too

Sometimes a genetics team asks for a blood or saliva sample from both parents alongside your child’s — this is trio testing, as opposed to testing your child alone (proband-only).

The extra samples do one specific job: they let the lab see directly which of your child’s variants are new (de novo) and which were inherited from a parent. Without parental samples, the lab has to estimate this using population databases and computational tools. With them, it can often say with confidence.

That distinction matters most for a variant of uncertain significance. A change that is de novo — brand new, present in your child but in neither parent — carries more weight toward “this variant matters,” because it is unlikely to be common harmless background variation. A change inherited from a parent with no related traits can sometimes be reclassified toward “likely benign” faster, because the parent’s own health history becomes part of the evidence. Because the lab can see directly which variants are new and which came from a parent, trio testing usually leaves fewer results in the uncertain column than testing your child alone.

Trio testing is not always available or covered. Ask whether it is an option for your child’s test, and whether your insurance requires it to be requested up front rather than added later.

Reading the report: a short glossary

Genetic reports are written for other clinicians, not for a parent at 2am. A few words account for most of the confusion:

• Heterozygous — your child has one changed copy of a gene and one typical copy (everyone has two copies of most genes, one from each parent).
• Homozygous — your child has the same change on both copies of the gene.
• De novo — new in your child; not found in either parent’s DNA.
• Inherited — passed down from a parent’s own DNA.
• Pathogenic / likely pathogenic — the lab’s confidence level that a specific variant explains part of a medical picture (see the five results, above). “Pathogenic” means the lab is at least 99% confident; “likely pathogenic” means at least 90%. Both are usually acted on the same way.
• ClinVar — a free, public US database where labs and researchers submit what they know about specific variants. Your clinician may look up your child’s variant there directly; you can too, though the entries are written in clinical language and are best read together with your genetics team.

Keep a copy of the full report yourself, not just the after-visit summary. Future clinicians — a new pediatrician, a school evaluator years from now, your child as an adult — will want the original wording, not a paraphrase.

Telling the family, telling your child, and who else finds out

Telling the rest of the family. A positive result sometimes means other relatives carry the same variant without knowing it — a sibling, a parent, a cousin. There is no obligation to announce a result to extended family, and no single right way to share it. Some families pass along genetics’ own printed explanation rather than trying to summarize it themselves; ask your genetic counselor whether they can prepare one.

Telling your child, over time. How much a young child needs to know about a genetic result is different from what a teenager needs to know, and different again from what an adult wants to decide for themselves. There is no rule requiring you to explain everything at once. What matters is that the explanation grows honest as your child grows — the same brief answer that satisfies a five-year-old is not the conversation a fifteen-year-old needs.

Privacy. In the US, the Genetic Information Nondiscrimination Act of 2008 (GINA) has two parts. Title II, enforced by the Equal Employment Opportunity Commission, makes it illegal for an employer to use genetic information in “any aspect of employment, including hiring, firing, pay, job assignments, promotions” (EEOC). Title I bars health insurers from using genetic information in coverage and premium decisions, and is enforced by the Departments of Labor, Health and Human Services, and the Treasury rather than the EEOC. GINA does not cover life insurance, disability insurance, or long-term-care insurance — those remain outside its protection, and insurers in those categories can still ask about genetic test results depending on your state’s law. Ask your genetic counselor what your specific state adds on top of GINA before you decide who reviews a copy of the report. More on paying for testing itself is on genetic testing cost and insurance.

Related

Genetic testing, explained · Autism testing, explained · Whole exome sequencing · Chromosomal microarray · Fragile X testing · Genetic testing cost and insurance

Questions parents ask after reading this

1. Our report says “likely pathogenic.” Does that mean this one gene explains all of our child’s autism?
2. We got a negative result. Is there ever a reason to test again later?
3. The report lists a variant of uncertain significance in a gene we’ve never heard of. What should we actually do with that today?
4. Should our other children be tested too, even though they show no traits themselves?

Bring this list to your next genetics appointment. A short, direct answer to each is a complete answer.

If you only do three things

1. Find the exact classification word on your child’s report — pathogenic, likely pathogenic, uncertain significance, likely benign, or benign — and write it down in your own words.
2. If the result is uncertain, change nothing about your child’s care because of it, and ask your genetics team when re-analysis is next planned.
3. Decide, before your next appointment, who in the family gets a copy of the report and who does not.

A result you understand is more useful than a result you are still guessing about.