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PubMed This is a summary of 22 peer-reviewed journal articles Updated
Clinical Genetics

Understanding Your Genetic Report

At a Glance

Genetic reports explain whether a DNA change may account for developmental delay, intellectual disability, or skeletal differences and whether it was inherited. A negative or uncertain result does not always rule out a genetic cause; parental testing and later reanalysis may clarify the diagnosis.

Genetic testing is the process of reading an individual’s “biological instruction manual” to find the specific change causing their symptoms. For conditions involving both developmental and skeletal challenges, this often requires a multi-step approach using different types of “genetic magnifying glasses” [1][2].

The Tools of Discovery: Types of Tests

No single genetic test can find every type of change. The medical team may recommend one or more of the following:

  • Chromosomal Microarray (CMA): This test looks for large “missing” or “extra” pieces of genetic material, known as copy number variants (CNVs) [3]. It is often an important step for developmental delays or physical differences [2].
  • Whole Exome Sequencing (WES): This test “spells out” the protein-coding parts of the DNA (the exome) [4]. It has a diagnostic yield of about 36–37% for unexplained developmental disorders [4][5].
  • Whole Genome Sequencing (WGS): The most comprehensive test, WGS reads almost all of a person’s DNA, including the non-coding regions [1][6].

A negative or unresolved result does not rule out a genetic cause. It may mean the right test hasn’t been done yet, or the gene hasn’t been discovered, and reanalysis later may be indicated.

The Importance of “Trio” Testing

Whenever possible, doctors prefer to test both biological parents alongside the affected individual—this is called trio sequencing [7]. By comparing the DNA to the parents, scientists can see which changes are unique (de novo) and which were passed down (inherited) [8]. This context is vital, but interpretation is complex: an inherited change in a healthy parent does not automatically rule it out, as factors like reduced penetrance, mosaicism, or X-linked effects play a role [9][10].

Reading the Results: Classification Categories

When a lab finds a genetic variant, they assign it to one of several categories based on available evidence (such as the ACMG guidelines) [11]:

  1. Pathogenic: There is strong evidence that this variant causes disease. If the clinical features fit, this confirms the diagnosis [11].
  2. Likely Pathogenic: There is a high probability that this variant causes disease, though more research may be helpful [11].
  3. Variant of Uncertain Significance (VUS): This is the most common “grey area” result. It means the lab found a change, but they don’t yet know if it’s a harmless quirk or a cause of disease [12]. A VUS should not ordinarily be used to make medical decisions [12][13].
  4. Likely Benign / Benign: These are considered normal variations that do not cause the symptoms and are often not reported as the cause [14][15].

Understanding Inheritance Terms

  • De novo: A brand-new change that occurred in the individual and was not inherited from either parent [16].
  • Inherited: The change was passed down from a parent. This may mean the parent is a “carrier” or has a very mild form of the condition [17][18].
  • Mosaicism: The change is only present in some of the body’s cells, not all of them. This can sometimes lead to milder symptoms [19][20].

Your Genetic Report Checklist

To advocate effectively and join research registries, ensure your report includes these critical data points (note that not all fields apply to every type of test, like CNVs) [21][22]:

  • [ ] Gene Name: The official symbol (e.g., SON, NSD2, MTSS2).
  • [ ] HGVS Notation (c.): The “coding” description (e.g., c.5234G>A), which identifies the exact spot in the DNA.
  • [ ] HGVS Notation (p.): The “protein” description (e.g., p.Arg1745His), which shows how the protein was changed.
  • [ ] Zygosity: Whether there is one change (heterozygous), two (homozygous), compound heterozygous, hemizygous, or a copy-number change.
  • [ ] Transcript / Reference Sequence: The specific version of the gene used (e.g., NM_003103.3) and the Genome Build.
  • [ ] Inheritance Status: Explicitly stating if the variant is de novo, inherited, or unknown.
  • [ ] Test Limitations: What the test could and could not detect.

Common questions in this guide

What does a pathogenic or likely pathogenic variant mean?
A pathogenic variant has strong evidence of causing disease, while a likely pathogenic variant has a high probability of doing so. When the person's clinical features fit, either result may support or help confirm the diagnosis.
What does a VUS mean on a genetic report?
A variant of uncertain significance, or VUS, is a DNA change whose effect is not yet known. It should not ordinarily be used by itself to make medical decisions, and its interpretation may change as evidence accumulates.
Why are both parents tested with the patient?
Trio sequencing compares DNA from the affected person with DNA from both biological parents. It can show whether a variant is new or inherited, although a change from a healthy parent may still be relevant because some conditions do not affect everyone who carries the change.
Can a negative genetic test still leave a genetic cause?
Yes. A negative or unresolved result can mean that the test did not detect the relevant type of change, the responsible gene is not yet known, or the data need to be reviewed again. A genetics team may recommend another test or reanalysis later.
What information should my genetic report include?
A complete report may list the gene, exact DNA and protein change using HGVS notation, zygosity, reference sequence and genome build, inheritance, and test limitations. Keeping these details can help specialists interpret the result and support registry or research participation.
How do chromosomal microarray, exome, and genome sequencing differ?
Chromosomal microarray looks for larger missing or extra DNA segments. Whole exome sequencing examines protein-coding regions, while whole genome sequencing reads nearly all DNA, including non-coding regions; each test can miss changes another test may detect.

Questions For You

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Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.Based on this report, is the diagnosis confirmed (Pathogenic/Likely Pathogenic) or is it still uncertain (VUS)?
  2. 2.If the result is a VUS, what specific 'next steps' (like testing parents or doing RNA studies) do you recommend to clarify the result?
  3. 3.Was the testing performed as a 'trio' (including both parents), and if not, would adding parental samples change the interpretation?
  4. 4.Does this lab report include a search for 'copy number variants' (deletions or duplications) as well as single-letter changes?
  5. 5.When do you recommend we schedule a 'reanalysis' of this data, since genetic knowledge is constantly evolving?

References

References (22)
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    Manickam K, McClain MR, Demmer LA, et al.

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    Genetic and metabolic investigations for neurodevelopmental disorders: position statement of the Canadian College of Medical Geneticists (CCMG).

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    Diagnostic Yield and Clinical Utility of Chromosomal Microarray Analysis (CMA) in Children With Developmental Delay, Intellectual Disability, and Autism Spectrum Disorder: A Systematic Review.

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This page explains genetic reports for informational purposes only and does not constitute medical advice. A clinical geneticist or genetic counselor should interpret your individual results and guide medical decisions.