Improvements in Awareness and Testing Have Led to a Threefold Increase Over 10 Years in the Identification of Monogenic Diabetes in the U.K

Abstract

Objective: Maturity-onset diabetes of the young (MODY) is a rare monogenic form of diabetes. In 2009, >80% of U.K. cases were estimated to be misdiagnosed. Since then, there have been a number of initiatives to improve the awareness and detection of MODY, including education initiatives (Genetic Diabetes Nurse [GDN] project), the MODY probability calculator, and targeted next-generation sequencing (tNGS). We examined how the estimated prevalence of MODY and other forms of monogenic diabetes diagnosed outside the neonatal period has changed over time and how the initiatives have impacted case finding.

Research design and methods: U.K. referrals for genetic testing for monogenic diabetes diagnosed >1 year of age from 1 January 1996 to 31 December 2019 were examined. Positive test rates were compared for referrals reporting GDN involvement/MODY calculator use with those that did not.

Results: A diagnosis of monogenic diabetes was confirmed in 3,860 individuals, more than threefold higher than 2009 (1 January 1996 to 28 February 2009, n = 1,177). Median age at diagnosis in probands was 21 years. GDN involvement was reported in 21% of referrals; these referrals had a higher positive test rate than those without GDN involvement (32% vs. 23%, P < 0.001). MODY calculator usage was indicated in 74% of eligible referrals since 2014; these referrals had a higher positive test rate than those not using the calculator (33% vs. 25%, P = 0.001). Four hundred ten (10.6%) cases were identified through tNGS. Monogenic diabetes prevalence was estimated to be 248 cases/million (double that estimated in 2009 because of increased case finding).

Conclusions: Since 2009, referral rates and case diagnosis have increased threefold. This is likely to be the consequence of tNGS, GDN education, and use of the MODY calculator.

Figure 1

Maps of the U.K. showing regional variations for referrals for MODY testing (per million population) (in green) and cases diagnosed with monogenic diabetes outside the neonatal period (per million population) (in blue) for 1996 to 28 February 2009 (A) and 1 March 2009 to 31 December 2019 (B). Same scale as in original 2010 study (8) used for both.

Figure 2

A: Cumulative frequency of proband referrals (green) and proband cases (blue) of monogenic diabetes from 1996 to 2019 at the Exeter Genomics Laboratory. B: Yearly proband positive test rate of monogenic diabetes. Positive test rate was calculated as the proportion of positive cases of all referrals in that year.

Figure 3

Association between GDN involvement and confirmed cases across the U.K. Each point represents a region of the U.K., with GDN person-time in months on the x-axis against cases diagnosed with confirmed MODY per million population on the y-axis. Association determined using Pearson correlation coefficients (r = 0.86, P < 0.001).