Day Three: Diabetes genetic risk score aids discovery of novel monogenic subtypes

medwireNews: The type 1 diabetes genetic risk score differentiates between patients with monogenic and polygenic autoimmune diabetes and can thus be used to aid the discovery of novel genes associated with the monogenic form.

This can done be through the enrichment of discovery cohorts by removing more common clustering of type 1 diabetes and additional autoimmunity, explained Sarah Flanagan, from The University of Exeter in the UK, at the 58th Annual ESPE Meeting in Vienna, Austria.

Flanagan presented previously published data showing that the risk score, which assigns a score based on the copy number of the top 10 risk regions for type 1 diabetes, including HLA and PTPN22, accurately differentiates between monogenic and polygenic diabetes and is more sensitive than using clinical features or antibodies in children with early-onset diabetes.

Using this method to select patients suitable for full genetic screening helped Flanagan and team to identify STAT3-activating mutations as a cause of autoimmune diabetes with onset in the neonatal period. She said that approximately 30% of patients with this mutation have diabetes.

Another gene discovery case highlighted by Flanagan was that of a homozygous splicing mutation in CD274 in a single family with multiple autoimmunity including diabetes. She said that CD274 knockout mice are more susceptible to autoimmune disorders and it is thought that loss of CD274 results in unchecked immune activation.

However, before causality can be proven multiple mutations in multiple families are needed and recruitment is currently underway to increase the size of the Exeter monogenic autoimmunity cohort studied by Flanagan and team.

Flanagan also talked about how she is using the diabetes genetic risk score to gain new insights into old conditions, specifically trisomy 21.

Flanagan and team found that Down syndrome was seven times more prevalent in the Exeter neonatal diabetes cohort than would be expected in the general population. However, none of the 13 Down syndrome cases identified in this cohort had a mutation in a known neonatal diabetes gene.

After applying the diabetes genetic risk score, these patients were found to have low polygenic risk for type 1 diabetes. This suggests there are two subgroups of diabetes among people with Down syndrome: those with Down syndrome and coexisting type 1 diabetes, who are typically diagnosed around 10 years of age, and those with a diabetes aetiology caused by Down syndrome, who are diagnosed by 1 year of age.

Flanagan concluded: “Identifying novel causes of monogenic autoimmune diabetes can provide key insights into the development of autoimmunity and can provide new targets for therapeutic intervention.”

By Laura Cowen

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