Updates - Rare and Inherited Disease Test Directory

Please be aware of several important changes in the Rare and Inherited Disease Genomic Test Directory concerning testing criteria for patients with developmental disorders.

Intellectual Disability

The criteria for intellectual disability testing has been reviewed and updated:

• Patients with unexplained moderate/severe/profound global developmental delay or unexplained moderate/severe/profound intellectual disability are eligible for testing using both microarray (R377) and whole genome sequencing (R29).
• Patients with isolated autism or mild intellectual disability are no longer eligible for genetic testing. This is because the chance of finding an underlying genetic condition in this group is very low.

The criteria for Fragile X testing for intellectual disability has been reviewed and updated:

• Standalone Fragile X testing (R53) should be performed in individuals with a family history of Fragile X.
• Individuals with moderate to severe developmental delay or intellectual disability are eligible for Fragile X testing using whole genome sequencing (R29).
• For females with isolated mild intellectual disability, the diagnostic yield of Fragile X testing is low. We recommend only ordering standalone Fragile X testing in this cohort if there is additional family or personal history consistent with a possible diagnosis of Fragile X syndrome. For example:
• a male family member has moderate or severe intellectual disability
• a family member has premature ovarian failure
• a male relative has symptoms consistent with Fragile X tremor-ataxia syndrome

Congenital Malformation and Dysmorphism Syndromes

As a Genomic Medicine Service, we are working towards providing testing for Congenital Malformation and Dysmorphism Syndromes using whole genome sequencing as a standalone test. In the future, this standalone test will replace the requirement for a separate microarray test in most patients.

Until the introduction of this standalone whole genome sequencing test, testing patients using microarrays, to identify copy number variation, is still indicated.

• Paediatric and adult patients with Congenital Malformation and Dysmorphism Syndromes are eligible for testing using microarray (R28) and whole genome sequencing (R27-Paediatric Disorders).
• Patients with syndromic overgrowth or overgrowth in combination with intellectual disability or developmental delay are also eligible for testing using microarray (R28) and whole genome sequencing (R27).
• In patients where there is a high suspicion of a specific single gene disorder, or where there is likely an autosomal recessive disorder, a genetic diagnosis is more likely to be identified using whole genome sequencing than by microarray. In these patients, we recommend you consider directly ordering whole genome sequencing or referring the patient to your local Clinical Genetics department.

Ordering whole genome sequencing

Instructions for ordering whole genome sequencing can be found on our Rare Disease WGS webpages.

Please use these new testing criteria with immediate effect.

Parallel microarray testing will no longer be performed for WGS test orders. If a microarray is required please clearly indicate this using the appropriate R code.

It is essential that you provide sufficient clinical information, and HPO terms for WGS tests, on the test order form for the GLH team to confirm that a patient meets the testing criteria and to maximise the chance of a diagnosis for your patient.

For test orders received after the 1st November 2024, where a patient does not meet the above testing criteria, or where sufficient information has not been provided, testing will not be initiated. DNA will be stored and a letter sent to the ordering clinician to indicate that testing will not be initiated without additional details.

If you have any queries, please contact your local genomics laboratory at Cambridge, Nottingham or Leicester using the standard contact email addresses.

These changes will be the topic of the September East Genomics Paediatric Forum on the 26 September at 12:30 -13:30. Find out more and register your place here.

The National Genomic Test Directory for Rare and Inherited Disease has been updated.

New tests have been added and tests amended – listed below. Changes have also been made to individual Clinical Indication eligibility criteria. The full change log is provided as a table in the back of the Rare and Inherited Disease eligibility criteria PDF document.

Please review the following information, alongside the published Test Directory documents, to ensure you are aware of any updates that may affect your practice.

The changes to the Rare and Inherited Disease Test Directory will be implemented across the Genomic Medicine Service laboratories over the next 3 months.

The following new clinical indications available for testing were added in February 2024:

The following new clinical indications available for testing, and changes to Clinical Indication names, eligibility criteria and overlapping indications were added in January 2024: