Genetic testing and counselling
Introduced| English | Meaning |
|---|---|
| karyotype analysis | karyotype analysis |
| balanced translocations | balanced translocations |
| chromosomal microarray | chromosomal microarray |
| fluorescence in situ hybridization | fluorescence in situ hybridization |
| sequencing/ˈsiːkwənsɪŋ/ | sequencing |
| cascade testing | cascade testing |
| incidental findings | incidental findings |
Four tests, four views
- The same child can have four genetic tests and get four different answers, because each test sees the genome at a different scale.
- Choosing the test that can answer the clinical question is the first decision, before any consent form.
Karyotype
- Karyotype analysis 核型分析 looks at every chromosome under the microscope. It sees the whole genome, but only changes of about 5–10 Mb or more.
- It is the test that shows balanced translocations 平衡易位: pieces swapped between chromosomes with nothing lost.
Microarray and FISH
- A chromosomal microarray 染色体微阵列 (CMA) measures copy number across the genome, down to about 50–100 kb. It misses balanced changes, because nothing is gained or lost.
- Fluorescence in situ hybridization 荧光原位杂交 (FISH) uses one glowing probe for one place: fast, but it only answers the question it is asked.
Which test can show a balanced translocation?
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Nothing is gained or lost in a balanced translocation, so copy-number tests miss it; the karyotype sees the swapped pieces.
Sequencing
- Sequencing 测序 reads single bases. Sanger sequencing checks one known spot; gene panels, exomes and genomes read more and more of the genome.
- More reading finds more variants, including more VUS and findings nobody was looking for.
Put the tests in order, from the coarsest view to the finest.
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Each step down trades whole-genome structure for finer detail.
The question picks the test
- A suspected trisomy: a rapid test (FISH or QF-PCR), then a karyotype. Developmental delay without a clear cause: CMA first. A known family variant: a targeted test for that variant.
- Repeat diseases such as fragile X and Huntington need repeat-sizing tests, which ordinary sequencing reads poorly.
Match each clinical question to the first test.
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Each test answers a different question; the question chooses.
Cascade testing
- Once a pathogenic variant is found in the proband, relatives can be tested for that exact variant: cascade testing 级联检测. For a dominant variant, each first-degree relative has a 1/2 chance.
- A relative who tests negative returns to the population risk, which is lower but not zero.
A man carries a dominant pathogenic variant. What is the chance, as a percentage, that both his daughter and his sister carry it?
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Each has a 1/2 chance, independently, so 1/2 × 1/2 = 1/4 = 25%.
A relative who tests negative for the family's pathogenic variant has no risk of that cancer.
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They return to the population risk, which is lower but not zero.
Consent and incidental findings
- Wide tests can find incidental findings 偶然发现, such as an adult-onset cancer risk found while looking for the cause of delay. Consent before the test decides what will be reported.
- Children are tested only for conditions where knowing changes care in childhood; adult-onset results wait until they can choose.
A child's genome, sequenced for developmental delay, shows an adult-onset cancer risk. What is usually done?
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Children are tested for conditions that change childhood care; consent decides what is returned.
Worked example: a family variant
- (Fictional) A woman has a pathogenic BRCA1 variant. Her sister and her son each have a 1/2 chance of carrying it.
- Her sister tests negative and returns to the population risk of breast cancer. Her son is offered testing as an adult, because the screening it would lead to starts in adulthood.
Worked example: why the karyotype still matters
- (Fictional) A newborn has features of Down syndrome; a rapid test confirms three copies of chromosome 21 within two days.
- A karyotype is still done: in about 4% of cases the extra 21 is attached to another chromosome by a translocation, which a parent may carry in balanced form. That changes the recurrence risk.
A rapid test confirms trisomy 21 in a newborn. Why is a karyotype still done?
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In about 4% of cases the extra 21 is carried by a translocation; a parent may carry it in balanced form.
Three common slips
- "The microarray was normal, so there is no translocation." CMA cannot see balanced rearrangements.
- "Tested negative means no risk." It means population risk.
- Testing children for adult-onset conditions. Unless childhood care changes, it waits.
Recap
- Karyotype: whole genome, about 5–10 Mb, sees balanced changes. CMA: copy number to about 50–100 kb, blind to balanced changes.
- FISH: one targeted probe. Sequencing: single bases, from one spot to the whole genome.
- The question picks the test; cascade testing spreads one result through a family; consent sets what is returned.