Genetic testing and resources - the essentials for paediatricians

The RCPCH Genomics Working Group in partnership with the Genomics Education Programme has developed this resource to support clinicians in learning more about different genetic tests, the benefits and limitations of different tests and the approach for selecting the appropriate test. The associated flowchart can be downloaded at the bottom of this page.
Last modified
12 October 2023

What are the different genetic tests, and what do they each detect and miss?

The below drop down options provides a basic overview of different genetic tests, but the techniques and analytic approach may vary in different regions and between laboratories.

See further definitions and descriptions of these tests on the Genomics Education Programme Knowledge Hub.

For further information about selecting an appropriate test and the associated pathways, download our genomic testing flowchart.

Karyotype

A cytogenetic test to visualise the number and structure of chromosomes

Detects:

  • Large deletions and duplications (>5Mb)
  • Chromosomal translocations/rearrangements
  • Aneuploidies (abnormal number of chromosomes)
  • Can detect chromosomal mosaicism ~10%

Misses:

  • Small-moderate sized deletions and duplications (~<5Mb)
  • Sequence variants, etc.
Fast-FISH

Fluorescence in situ hybridisation (FISH) is a cytogenetic test, which uses chromosome specific probes to identify the common aneuploidies

Detects:

  • 'Fast-FISH' is typically the quickest way to detect the common aneuploidies (e.g. Down Syndrome, Edwards Syndrome, Patau's Syndrome) in the post-natal setting
  • Some labs will report sex chromosome aneuploidies (e.g. Turner Syndrome, Kleinfelter Syndrome)

Misses:

  • Copy number variants (microdeletions and duplications) unless using targeted probes
  • Chromosomal translocations, sequence variants, etc.
QF-PCR

Quantitative Fluorescence PCR is a molecular genetic test which uses chromosome specific markers to identify the common aneuploidies. It is typically used in the pre-natal setting, but some labs may offer post-natally.

Detects:

  • QF-PCR is typically used in the pre-natal setting to detect the common aneuploidies (e.g. Down Syndrome, Edwards Syndrome, Patau's Syndrome) in the post-natal setting
  • Some labs will report sex chromosome aneuploidies (e.g. Turner Syndrome, Kleinfelter Syndrome)

Misses:

  • Copy number variants (microdeletions and duplications) unless using targeted probes
  • Chromosomal translocations, sequence variants, etc.
Microarray

A cytogenetic test, which uses probes across the genetic code to detect imbalances (copy number variants).

The resolution of an array (the size of deletions and duplications it can detect) varies across different regions of the genome, depending on probe density.

SNP array and array CGH are both types of microarray, but are performed using different laboratory techniques.

Detects:

  • Microdeletions (e.g. 22q11.2 microdeletion, William's syndrome) and microduplications
  • Aneuploidies
  • Can detect chromosomal mosaicism ~>10%
  • A SNP-based array can detect unipaternal isodisomy, triploidy and loss of heterozygosity

Misses:

  • Balanced translocations/rearrangements
  • Small deletions and duplications (~<50Kb)
  • Sequence variants, etc.
Exome

A molecular genetic test, which sequences the coding portion of the genetic code (~1% of the entire genome).

An exome can be analysed as a trio (child and parents analysed together) or as a singleton/duo.

The results of a trio exome are usually filtered using an "agnostic approach" (concentrating on variants which are de novo, recessive, or X-linked). A duo or singleton exome is usually filtered using one or more virtual panels.

Detects:

  • Sequence variants ("spelling mistakes") in the coding genes
  • Some exome testing techniques can detect intragenic (small) deletions and duplications
  • Some exome testing techniques can detect copy number variants

Misses:

  • A trio exome, which uses an "agnostic" filtering approach, may miss autosomal dominant inherited disorders
  • An exome which is filtered using virtual panels, may miss variants in genes not included on the panels
  • Non-coding variants, microdeletions and duplications, aneuploidies, triplet repeat disorders, disorders of methylation, mitochondrial mutations, etc.
  • An exome may miss low level mosaicism, depending on read depth
Genome

A molecular genetic test which sequences the entirety of the genetic code (~3 billion base pairs).

Typically the results of the genome are filtered using one or more virtual panels.

As above, the results of a trio genome are usually filtered using an "agnostic approach" (concentrating on variants which are de novo, recessive or X-linked).

Detects:

  • Sequence variants in both coding and non-coding areas of the genome
  • Some genome testing techniques can detect intragenic (small) deletions and duplications, and copy number variants

Misses:

  • A genome, which is filtered using virtual panels, may miss variants in genes not included on the panels
  • Triplet repeat disorders, disorders of methylation, mitochondrial mutations, etc
  • A genome may also miss low level mosaicism, depending on read depth
Condition specific tests

Some conditions will require specific assays, and will not be detected by any of the tests listed above.

Examples include:

  • Methylation disorders (e.g. Prader Willi, Angelman, Beckwith Weidemann and Russell Silver Syndrome)
  • Spinal Muscular Atrophy
  • Triplet repeat and other short tandem repeat disorders (e.g. Myotonic dystrophy, Fragile X, Friedrich ataxia, most spinocerebellar ataxias)
  • Disorders caused by variants in the mitochondrial genome
  • Uniparental disomy
  • Deep sequencing on DNA extracted from an affected tissue (e.g. somatic mosaicism in PIK3CA-related disorders)

The formal procedures for taking and documenting consent for genetic testing varies between different centres. Your local Clinical Genetics department may have a standard consent form, and/or they may use the NHS England “Record of Discussion Regarding Genomic Testing” form (PDF). Some specialised tests (eg a rapid prenatal exome, R21) will have a laboratory specific consent form. It is best to check what your local policy is for the specific test that you are requesting.

However, when taking consent for any genetic test, there are three important issues which are imperative to cover:

  1. Non-diagnosis: There is no single genetic test that can diagnose all genetic conditions. Even very extensive genetic tests (eg exome or genome sequencing) will miss underlying genetic diagnoses. A “normal” genetic test result cannot entirely rule out an underlying genetic diagnosis.
  2. “Grey results” / Variants of uncertain significance: We all carry thousands of genetic variants (“spelling mistakes”) across our genetic code. Sometimes when the lab detect a variant, it can be difficult for them to work out if the variant is causing a problem (“pathogenic”) or if it is harmless (“benign”). These “grey results” can sometimes cause additional worry or anxiety.
  3. Incidental findings, including unexpected family relationships: It is possible that genetic testing can detect variants which do not explain the original reason for the test, but are still relevant for health (an “incidental finding”). The laboratory do not usually go “looking for” incidental findings, but if they encounter an incidental finding, they may report this back. In general, the lab will only report incidental findings where something can be done (e.g. cancer screening), or where there is value in having forewarning (e.g. reproductive implications). When undertaking genetic testing of parents and children together (eg a trio exome or genome), it is also possible that the lab can detect that the family relationships are not as expected, for example, where the father is not the biological father, or that the parents are close relatives.

What is the National Genomic Test Directory and where do I find it?

The National Genomic Test Directory outlines the genetic tests which are commissioned by the NHS, in England.

The ‘Rare and inherited disease eligibility criteria’ PDF document on the Directory provides clinical criteria to help identify which patients are appropriate for a given genetic test, and which clinical speciality would be expected to request the test. These criteria are revised and updated iteratively.

If you are based in Scotland, Wales and Northern Ireland there may be local differences in test availability and eligibility criteria.

What is GeNotes and where do I find it?

GeNotes (Genomic notes for clinicians) is an educational resource being developed by NHS England’s Genomics Education Programme.

GeNotes offers clinicians ‘just in time’ educational information, designed to be used during or just before the patient appointment. Based around clinical scenarios, GeNotes covers when, why and how to request genomic testing, as well as the options available when test results come back – all aligned to NHS England’s National Genomic Test Directory.

Underpinning these ‘In the Clinic’ articles is the Knowledge Hub, packed with bitesize articles on the fundamentals of genomics, technologies, therapies, conditions and more – perfect for busy clinicians who want to continue their genomics learning.

Some GeNotes are grouped according to clinical presentations (eg Child acutely unwell in NICU or PICU, Child with developmental delay or intellectual disability, Child with macrocephaly).

RCPCH Learning also has a webinar hosted in collaboration with the Genomics Education Programme where you can find out more about paediatric GeNotes.

What is the Genomics Education Programme and where do I find it?

The Genomics Education Programme has been developed by Health Education England and is now part of NHS England. It collates a variety of educational resources relating to genetics and genomics.

Suggested content and free, online courses:

Other resources

The RCPCH hosted a webinar on the 'Beginners Guide to Genetic Testing' which is available on demand.

There is also a collection of genomics resources collated by the RCPCH Genomics Working Group

For any queries please contact genomics@rcpch.ac.uk.


We thank Dr Caoimhe McKenna, Dr Ellie Hay, Dr Melody Redman and the Genomics Working Group, partnered with the Genomics Education Programme for the creation of this resource.

Please note this document and the associated flowchart are not exhaustive and may be subject to change, and there are local/regional and laboratory variations.

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