Rare Disease Genetic Testing

Advances in genomic technologies coupled with national strategic transformation, means an increasing number of patients and families with rare diseases are receiving a ‘genomic’ diagnosis.

Consequently GPs will see an increasing number of patients seeking advice regarding either their own or a family member’s result. The National Genomic Test Directory has standardised genomic testing detailing which tests are commissioned by the NHS in England, and includes when they should be performed and by whom.

Such tests may include:

• Chromosome analysis (microarray).

Microarray, sometimes referred to as an array CGH (comparative genomic hybridisation), is now widely used by a range of clinicians, including paediatricians as the first tier genetic test for patients with congenital anomalies, developmental delay, intellectual disability and dysmorphism. It can identify chromosomal abnormalities, copy number variants (CNV) (missing or duplicated segments of chromosomes), a frequent cause of these clinical problems.

• Single gene testing (e.g. in cystic fibrosis, fragile X).

Single gene tests are still widely used when there is a specific disease query, possibly due to a family history, strong clinical suspicion or for confirmatory testing of those with an existing biochemical diagnosis ( e.g. inherited metabolic diseases)

• Next generation sequencing tests such as gene panels.

An increasing number of clinical presentations have a gene panel. (e.g. Intellectual disability (ID), liver diseases, cardiac presentations, congenital malformations and seizure disorders). In addition to when and by whom a gene panel should be performed, the genes and pathogenic variants included on the panels have been defined in the national genomic test directory and the associated PanelApp

• Whole exome or genome sequencing (WES/WGS).

Rare diseases have been at the vanguard of sequencing technologies. Genomics England’s 100,000 Genome project sequenced 100,000 genomes taken from patients affected with either a rare disease or cancer. 190 rare diseases were included. The diagnostic yield of the rare disease cohort was 26% and of those with intellectual disability 37%.

Watch this video from Health Education England, covering the role of GPs in rare disease and an introduction to the 100,000 Genomes project: Rare disease video

The UK-wide Deciphering Developmental Disorders project (DDD) utilised WES to improve the diagnosis of previously undiagnosed children with development delay (87% of whom had ID). Trio based WES (both parents and child) achieved a diagnostic yield of 27%, in what is a previously extensively investigated cohort. In the next step we will be looking at an example of how a child with a developmental disorder might present in primary care.

Follow this link to the RCGP Genomics toolkit with further information about the different types of genomic testing.