EASD 2022 | Support for tailored genetic counseling in people with incidentally discovered MODY mutations


medwire news: mutations in HNF1A and HNF4A are less likely to be associated with a diagnosis of adult-onset diabetes (MODY) when discovered incidentally than in a clinically selected cohort, the research says.

Mutations in glucokinase (GCK) have a similar impact on the likelihood of MODY, regardless of the environment in which they are detected, reported Kashyap Patel (University of Exeter, UK) at the 58th EASD Annual Meeting in Stockholm, Sweden.

In support of the study, Patel explained that “next-generation sequencing has transformed the way we do genetic testing,” allowing for a shift from “single-gene testing in clinical contexts” to multi-gene testing both in and out of the clinic.

Along with the increase in direct-to-consumer testing, “we are now finding mutations in monogenic diseases [such as MODY] long before the onset of the disease,” and it’s not clear what to do in such situations, he added.

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Patel gave the example of a clinically unselected person (with no family members with diabetes) who was determined to have diabetes HNF1A Mutation by commercial testing where the risk of developing diabetes is currently unknown.

To fill this knowledge gap, the team compared genetic penetrance – defined as the proportion of people with a particular genetic variant who develop the associated disease phenotype – with HNF1A, HNF4Aand GCK Mutations in clinically selected versus clinically unselected cohorts.

The clinically selected cohorts included 1742 UK individuals with MODY and 2194 of their family members (53% with diabetes), while the clinically unselected group included 132,194 individuals from a US hospital cohort (24% with diabetes) and 198,748 individuals from the UK Biobank (6% with diabetes).

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In the unselected cohorts, the prevalence of HNF1A and HNF4A Variants ranged from approximately one case in 10,000 to one in 7,000, while the prevalence of GCK Mutations ranged from about 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 by age 40 developing diabetes, 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 features.

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On the other hand z GCK Variants were of similarly high penetrance whether discovered incidentally or not, with 89-97% of subjects in all cohorts presenting with mild hyperglycemia.

Taken together, these results indicate that “we cannot use family-based risk information to counsel those individuals who are incidentally found to be infected HNF1A and HNF4A mutations, but we can use that for glucokinase MODY,” the moderator concluded.

medwireNews is an independent medical news service from Springer Healthcare Ltd. © 2022 Springer Healthcare Ltd, part of the Springer Nature Group

EASD Annual Meeting; Stockholm, Sweden: June 19-23 Sept 2022



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