Reduced penetrance of MODY-associated HNF1A/HNF4A variants but not GCK variants in clinically unselected cohorts

Abstract

The true prevalence and penetrance of monogenic disease variants are often not known because of clinical-referral ascertainment bias. We comprehensively assess the penetrance and prevalence of pathogenic variants in HNF1A, HNF4A, and GCK that account for >80% of monogenic diabetes. We analyzed clinical and genetic data from 1,742 clinically referred probands, 2,194 family members, clinically unselected individuals from a US health system-based cohort (n = 132,194), and a UK population-based cohort (n = 198,748). We show that one in 1,500 individuals harbor a pathogenic variant in one of these genes. The penetrance of diabetes for HNF1A and HNF4A pathogenic variants was substantially lower in the clinically unselected individuals compared to clinically referred probands and was dependent on the setting (32% in the population, 49% in the health system cohort, 86% in a family member, and 98% in probands for HNF1A). The relative risk of diabetes was similar across the clinically unselected cohorts highlighting the role of environment/other genetic factors. Surprisingly, the penetrance of pathogenic GCK variants was similar across all cohorts (89%-97%). We highlight that pathogenic variants in HNF1A, HNF4A, and GCK are not ultra-rare in the population. For HNF1A and HNF4A, we need to tailor genetic interpretation and counseling based on the setting in which a pathogenic monogenic variant was identified. GCK is an exception with near-complete penetrance in all settings. This along with the clinical implication of diagnosis makes it an excellent candidate for the American College of Medical Genetics secondary gene list.

Keywords: ACMG; GCK; HNF1A; HNF4A; MODY; monogenic diabetes; monogenic disease; penetrance; population screening; prevalence; variant curation.

Figure 1

Penetrance of pathogenic HNF1A variants is lower in clinically unselected cohorts compared to a clinically ascertained cohort (A) Kaplan Meier survival curves of diabetes for individuals with (dashed line) and without HNF1A pathogenic variants (solid line) in four study cohorts. Analysis included probands (n = 661), their family members with (n = 622) and without (n = 332) HNF1A variants, individuals with (n = 14) and without (n = 132,180) HNF1A variants from Geisinger health system cohort, and individuals with (n = 22) and without (n = 198,726) HNF1A variants from UK Biobank population cohort. The log rank test p value for penetrance of diabetes for probands versus family member, Geisinger cohort, and UK Biobank cohort was 3 × 10⁻²⁶, 3 × 10⁻⁹, and 5 × 10⁻¹⁶, respectively. (B) Penetrance of diabetes for individuals with pathogenic HNF1A variants in all four cohorts at age 40 years with 95% CI.

Figure 2

Penetrance of pathogenic HNF4A variants is lower in clinically unselected cohorts compared to a clinically ascertained cohort (A) Kaplan Meier survival curves of diabetes for individuals with (dashed line) and without (solid line) HNF4A variants in four study cohorts. Analysis included probands (n = 142), their family members with (n = 169) and without (n = 84) HNF4A variants, individuals with (n = 17) and without (n = 132,177) HNF4A variants from Geisinger health system cohort, and individuals with (n = 29) and without (n = 198,719) HNF4A variants from UK Biobank population cohort. The log rank test p value for penetrance of diabetes for probands versus family member, Geisinger cohort, and UK Biobank cohort was 8 × 10⁻¹¹, 2 × 10⁻¹², and 3 × 10⁻¹⁹, respectively. (B) Penetrance of diabetes for individuals with pathogenic HNF4A variants in all four cohorts at age 50 years with 95%CI.

Figure 3

Cox proportional Hazard ratio for diabetes for individuals with pathogenic HNF1A, HNF4A, and HNF4A c.340C>T (p.Arg114Trp) variants relative to individuals without are largely similar in the clinically unselected cohorts (A) Graph showing the Cox proportional Hazard ratio and 95%CI for diabetes for individuals with relative to individuals without pathogenic HNF1A variants for family members, Geisinger health system cohort, and UK Biobank population cohort. (B) Graph showing the Cox proportional Hazard ratio and 95%CI for diabetes for individuals with relative to individuals without pathogenic HNF4A variants for same three cohorts. (C) Graph showing the Cox proportional Hazard ratio and 95%CI for diabetes for individuals with relative to individuals without pathogenic HNF4A c.340C>T (p.Arg114Trp) variant for same three cohorts.

Figure 4

Penetrance of mild hyperglycemia for pathogenic GCK variants is similar in clinically selected and unselected cohorts (A) Proportion and 95%CI of individuals with mild hyperglycemia (HbA1c ≥ 39 mmol/mol and/or a fasting glucose ≥5.6 mmol/L, definition of prediabetes by American Diabetes Association) for probands of pathogenic GCK variants (n = 939) and individuals with pathogenic GCK variants in their family members (n = 723), Geisinger heath system cohort (n = 32), and UK biobank population cohort (n = 83) as red square. Background rate of mild hyperglycemia and 95%CI in each unselected cohort is also shown as blue circle. (B) Mean HbA1c and 95%CI for GCK-MODY probands and individuals with pathogenic GCK variants in their family members, Geisinger cohort, and UK Biobank as red square. Cohort mean HbA1c and 95%CI for each unselected cohort is shown as blue circle. (C) Mean fasting blood glucose and 95%CI for GCK-MODY probands and individuals with pathogenic GCK variants in their family members, Geisinger cohort, and UK Biobank as red square. Cohort mean fasting blood glucose and 95%CI for each unselected cohort is shown as blue circle.