Pre-conception Expanded Carrier Screening is a technology that uses whole genome sequencing to screen prospective parents as potential carriers of a broad range of recessive diseases. Genomic technologies have enabled major developments in the understanding and treatment of genetic disorders. We now have access to a large body of genomic data, a range of diagnostic tests for different genetic diseases and we are continually developing targeted therapies to treat them.
However, the majority of data utilised during Expanded Carrier Screening is derived from people of European ancestry. Whereas, the genetic composition of pathogenic variants differs greatly among different populations. Thus, this data is often not representative of those with non-European ancestry.
A recent paper by Professor Simon Easteal at al. considers Expanded Carrier Screening in Australia. The paper suggests that in order to ensure that access to this technology is truly equitable, there must be meaningful inclusion, analysis and translation of genetic information for all Australians. This is particularly true for Aboriginal and Torres Strait Islander Australians, who already face significant health disparities.
Pathogenic variants are rare and specific:
Monogenic diseases are rare and are often attributable to many different DNA variants in one or more specific genes. Almost all of these genetic variants are rare and often occur only in people from a specific geographical region, or sometimes even from a single family. As a result, carrier screening panels designed for ancestrally European populations often fail to detect rare variants from other populations. The geographical restriction and rarity of pathogenic variants have two main consequences:
Firstly, the genetic makeup of pathogenic variants which exist in Indigenous populations are likely to be unique. Therefore, it is probable that a multitude of variants exist which have not been previously identified by European-based data sets. These variants may produce more serious forms of the disease or differential responses to treatments which are currently available. This may remain true even if they possess similar molecular properties to known variants. Thus, clinical investigation into the pathogenicity and phenotypes of these variants is essential.
Secondly, genomic background is also likely to influence the phenotypic manifestation of monogenic diseases. Aboriginal populations or individuals with mixed ancestry may exhibit more severe disease profiles than those predicted by European ancestral-based data. This unpredictability may be amplified by differences in environment and lifestyle, as these factors impact disease manifestation. This is especially true following changes in diet, economic or social circumstances, displacement or migration.
How different are the variants in Aboriginal and Torres Strait Islander communities?
Global prevalence estimates (1),(2), predict that >30,000 Aboriginal and Torres Strait Islander people may be affected by monogenic diseases. An even greater number may be carriers of pathogenic variants different to those already identified.
Unpublished data from the National Centre for Indigenous Genomics, estimates that:
- 25% of all DNA variants in the genome of an Aboriginal person are unknown in people outside of Australia. (This excludes those inherited from non-Aboriginal ancestors). These are also not represented in International or Australian genomic databases or in current screening panels.
- Of these Aboriginal-specific variants, ~40% are likely only found in a single region or community. To put it another way: using data from the Northern Territory as a basis for treatment in the Southern Territory is comparable to treating people of British ancestry based on clinical data from the population of Cambodia.
This gap in the database means that Expanded Carrier Screening will frequently produce results with less certainty, such as ‘likely pathogenic variants’ or ‘variants of unknown significance’. This also risks the incorrect reporting of benign variants as pathogenic or vice-versa and makes the overall test less sensitive. Thus, more couples may have a child affected by a disease which Expanded Carrier Screening failed to predict.
How do we tackle the current disparity in access to Expanded Carrier Screening?
The validity of the Expanded Carrier Screening is wholly dependent on the available population reference data. The existing database was developed largely through direct clinical interventions of patients and linking DNA variants to their clinical phenotypes. For minority groups to share the benefits of Expanded Carrier Screening, a similar level of evidence is required.
Easteal et al. stress that achieving this scale of data collection, requires a well-designed and sufficiently resourced program. Pre-existing programs which were not designed to suit indigenous communities will likely be ineffective. Instead, at all levels of development, Indigenous community leadership, co-design and data governance is essential. Prioritisation of research involving underrepresented groups must be made a priority.
Expanded Carrier Screening is just one of many genomic technologies that has the potential to transform healthcare for the better. However, equitable access to this technology requires universal coverage of all populations.