medwireNews: Mutations in HNF1A and HNF4A are less likely to be associated with a diagnosis of maturity-onset diabetes of the young (MODY) when discovered incidentally versus in a clinically selected cohort, research suggests.
However, mutations in glucokinase (GCK) have a similar impact on the likelihood of MODY irrespective of the setting in which they are discovered, reported Kashyap Patel (University of Exeter, UK) at the 58th EASD Annual Meeting in Stockholm, Sweden.
Discussing the rationale for the study, Patel explained that “next-generation sequencing has transformed the way we do genetic testing,” allowing a move from “single-gene testing in clinical contexts” to multi-gene testing both inside and outside the clinic.
Taken together with the rise in direct-to-consumer testing, “we are now finding mutations in monogenic disorders [such as MODY] well before disease onset,” and it is not clear what to do in these situations, he added.
Patel gave the example of a clinically unselected individual (with no family members having diabetes) who was found to have an HNF1A mutation through commercial testing, in whom the risk for developing diabetes is currently unknown.
To address this gap in knowledge, the team compared genetic penetrance – defined as the proportion of people with a particular genetic variant who develop the associated disease phenotype – of HNF1A, HNF4A, and GCK mutations in clinically selected versus clinically unselected cohorts.
The clinically selected cohorts comprised 1742 people from the UK with MODY and 2194 of their family members (53% with diabetes), while the clinically unselected group comprised 132,194 individuals from a US hospital-based cohort (24% with diabetes) and 198,748 people from the UK Biobank (6% with diabetes).
In the unselected cohorts, the prevalence of the HNF1A and HNF4A variants ranged from approximately one case in 10,000 to one in 7000, while the prevalence of GCK mutations ranged from around one in 4000 to one in 2000.
Patel reported that the penetrance of HNF1A variants was “substantially lower” in the clinically unselected cohorts, with 30–50% of people having diabetes by 40 years of age, compared with 86% in the family members of people with MODY. A similar pattern of results was seen for HNF4A mutations, and these findings remained consistent after accounting for clinical characteristics.
On the other hand, for GCK variants, the penetrance was similarly high irrespective of whether they were detected incidentally or not, with 89–97% of individuals having mild hyperglycemia across the cohorts.
Together, these findings indicate that “we cannot use family-based risk information to counsel the people who are incidentally found to have HNF1A and HNF4A mutations, but we can use that for glucokinase MODY,” concluded the presenter.
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EASD Annual Meeting; Stockholm, Sweden: Sept 19–23, 2022