R27 Paediatric disorders

R27 Paediatric disorders is for individuals with a likely monogenic condition, where there is a wide differential and multisystem involvement. Presentations may include congenital anomalies, neurodevelopmental and behavioural difficulties, abnormal growth parameters and a distinctive appearance. Discussion with a clinical geneticist may be beneficial, particularly if you feel that test result analysis should be prioritised. For acutely unwell children with a likely genetic condition requiring rapid testing R14 Acutely unwell infants with a likely monogenic disorder should be considered.

Testing criteria, as per the National Genomic Test Directory, is listed below.

• Congenital malformations and/or dysmorphism highly suggestive of an underlying monogenic disorder where targeted genomic testing is not possible.
• Unexplained moderate, severe or profound global developmental delay or unexplained moderate, severe or profound intellectual disability, where clinical features are highly suggestive of an underlying monogenic disorder and where targeted genomic testing is not possible.
• Craniofacial dysmorphism in combination with additional issues with health or development suggestive of a single genomic explanation, for instance intellectual disability, congenital malformation and/or organ dysfunction.
• Syndromic overgrowth, or overgrowth in combination with intellectual disability or developmental delay.
• Adults with congenital malformation and dysmorphism syndromes; however, the clinical utility of testing should be made clear on the request form, such as to inform a clinical management decision or reproductive choice.
• A fetus from a demised or terminated pregnancy, with multiple major structural abnormalities detected on fetal ultrasound or post-mortem examination and where a monogenic malformation disorder is considered highly likely.

Test results may be prioritised for analysis in situations where a molecular diagnosis is more likely to influence clinical management but where the individual is not eligible for R14 rapid trio analysis.

Typically, the test is analysed as a trio, with samples requested from the affected child and both parents. This allows bioinformatic pathways to pick out new (de novo) variants in the child, and autosomal recessive variants where both parents are carriers, increasing the chance of identifying genetic conditions. Duo or singleton analysis may be requested when parental samples can’t be obtained, though this does significantly reduce the diagnostic yield.

In contrast to the R14 rapid sequencing gene-agnostic approach, R27 is a genome sequencing test focused on genes present on 13 panels (as of January 2025):

• DDG2P (genes highlighted in the Deciphering Developmental Disorders study as contributing to paediatric developmental conditions);
• intellectual disability (R29);
• early onset or syndromic epilepsy (R59);
• likely inborn error of metabolism (R98);
• skeletal dysplasia (R104);
• monogenic hearing loss (R67);
• paediatric conditions – additional genes (new developmental disorder genes);
• clefting (genes associated with cleft lip and palate);
• ophthalmological ciliopathies;
• renal ciliopathies;
• neurological ciliopathies;
• skeletal ciliopathies; and
• limb disorders.

R27 may find the genomic diagnosis that explains the child’s condition. This diagnosis might affect treatment, broader management or surveillance of their condition. It may also provide important information for the wider family. In some cases other family members may be affected, and information about reproductive options may be beneficial.

Alternatively, the test could find a variant of uncertain significance. This means that there is insufficient evidence to determine whether the gene change is causing a specific genetic condition. We all have a lot of variation in our genes and it can be difficult to decide whether a gene change is just part of normal variation or whether it could be the cause of the child’s condition. In this situation, further discussion and (sometimes) extra tests are required to help clinicians decide.

No genomic cause for the child’s health problems may be found. This does not rule out a genetic condition as we have not yet discovered the cause of all genetic conditions, and not all gene changes are detectable, even with this detailed testing. This can be hard for families. Syndromes Without a Name is an invaluable patient-support group.

Very occasionally (fewer than 1 in 100 tests), an unrelated unexpected (often called ‘incidental’) gene change might be discovered. This could be a genomic variant conferring a significant chance of developing a different health problem. Careful consideration is required to decide whether or not it is in the best interests of the patient/family to feedback an incidental finding. Incidental findings should be discussed with the referring clinician before the result is reported.

Note that R27 will show if a parent is not the child’s biological parent (non-paternity or non-maternity) and could also reveal an incestuous relationship between the parents. If this is a concern, please raise it on the test request form. Should it be identified during the test, the result should be discussed with the referring clinician before any report is issued.

Consent for R27 should outline these potential outcomes so that families can decide whether or not they wish to pursue testing. Please see consent conversation for genomic testing for more information on consent.

• Consult the National Genomic Test Directory to determine whether your specialty is eligible to request testing directly.
• It can be useful to discuss options for genomic testing with your local clinical genetics team, particularly if wider panels may be required or prioritised analysis may be indicated.
• Consent needs to be taken:
  • The standard record of discussion form for whole genome sequencing should be used to document consent for the R27 test.
  • Separate forms are required for all participating individuals (for instance the child and both parents in a trio).
  • The forms should be sent to the lab and a copy of the forms should be kept in the patient records.
  • General GeNotes guidance is available on how to complete record of discussion forms.
• A test request form must be completed:
  • Only a single test request form is required for the whole family.
  • You will need to provide details of the requesting clinician, patient identifiers, ethnicity, consanguinity and detailed clinical information that includes the results of any imaging and non-genomic testing.
  • The use of human phenotype ontology (HPO) terms is optional, though recommended.
  • Should any new clinical information become available during the testing process (such as MRI results or evolution of the phenotype), it should be communicated to the laboratory via email as soon as possible because it may aid interpretation of the results.
  • You can find the test order form you require on your local Genomic Laboratory Hub (GLH) website.
• Blood samples are required:
  • EDTA samples (typically a purple-topped tube) are required from the child and both parents (in a trio).

As part of the record of discussion, all families are asked if they agree to their samples being used anonymously in research. This is a personal decision for families, and they do not need to agree in order to access the test. Anonymous data is accessed by approved research groups (public and private) aiming to increase our understanding of the genome. There is a small chance that patients may be contacted by their clinicians in the future with a diagnosis, or information about a trial, due to findings made in the research setting.

• R27 is a multi-panel genome sequencing test.
• R27 no longer requires authorisation by a consultant in clinical genetics, though pre-test discussion may helpful in some instances.
• R27 is useful for individuals with multisystem or syndromic presentations.
• R27 may be prioritised in cases where a diagnosis is likely to have an impact on management but where the patient is not eligible for R14.

For clinicians

• GeneReviews
• Genomics England: PanelApp
• NHS England: National Genomic Test Directory
• Unique: Understanding Rare Chromosome and Gene Disorders

For patients

• Genetic Alliance UK: SWAN UK (Syndromes Without A Name)
• NHS England: Whole genome sequencing patient information leaflets