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Abstract Purpose Congenital hyperinsulinism (CHI) is a rare, monogenic disease characterized by excessive insulin secretion. We aimed to evaluate all probands with suspected CHI in Norway registered over the past 2 decades. Methods The study included 98 probands. Clinical data were cumulated from medical records. All probands were screened for variants in the genes ABCC8 and KCNJ11. Other CHI-related genes were Sanger-sequenced as indicated by the patients’ phenotype (n = 75) or analyzed by next-generation sequencing employing a panel of 30 CHI-related genes (n = 23). Results Twenty-one probands (21%) received a diagnosis other than CHI, the most common being idiopathic ketotic hypoglycemia (9%) or syndromic hyperinsulinism (4%). In the final cohort of 77 CHI probands, genetic findings were revealed in 46 (60%). ABCC8 variants were most common (n= 40), and 5 novel variants were identified. One proband harbored both the pathogenic GCK variant p.(Ala456Val) and the ABCC8 variant p.(Gly505Cys). Although most ABCC8 variants caused immediate disease onset with severe hypoglycemia and were diazoxide-unresponsive, 8 probands had a heterozygous, apparently dominant variant with milder phenotype. Two probands had pathogenic variants in GLUD1, whereas variants in HADH, HNF4A, KCNJ11, and HK1 were identified in 1 proband each, the latter being noncoding. Neurologic sequelae were reported in 53% of the CHI probands. Of nonsurgically treated probands, 43% had spontaneous resolution. The minimum birth prevalence of CHI in Norway is 1:19,400 live births. Main Conclusion Individuals with disease-causing ABCC8 variants dominated our cohort. Patients with known genetic etiology had earlier and more severe disease onset than genetically unsolved patients.

Aims/hypothesis MODY can be wrongly diagnosed as type 1 diabetes in children. We aimed to find the prevalence of MODY in a nationwide population-based registry of childhood diabetes. Methods Using next-generation sequencing, we screened the HNF1A , HNF4A , HNF1B , GCK and INS genes in all 469 children (12.1%) negative for both GAD and IA-2 autoantibodies and 469 antibody-positive matched controls selected from the Norwegian Childhood Diabetes Registry (3882 children). Variants were classified using clinical diagnostic criteria for pathogenicity ranging from class 1 (neutral) to class 5 (pathogenic). Results We identified 58 rare exonic and splice variants in cases and controls. Among antibody-negative patients, 6.5% had genetic variants of classes 3–5 (vs 2.4% in controls; p  = 0.002). For the stricter classification (classes 4 and 5), the corresponding number was 4.1% (vs 0.2% in controls; p  = 1.6 × 10 −5 ). HNF1A showed the strongest enrichment of class 3–5 variants, with 3.9% among antibody-negative patients (vs 0.4% in controls; p  = 0.0002). Antibody-negative carriers of variants in class 3 had a similar phenotype to those carrying variants in classes 4 and 5. Conclusions/interpretation This is the first study screening for MODY in all antibody-negative children in a nationwide population-based registry. Our results suggest that the prevalence of MODY in antibody-negative childhood diabetes may reach 6.5%. One-third of these MODY cases had not been recognised by clinicians. Since a precise diagnosis is important for treatment and genetic counselling, molecular screening of all antibody-negative children should be considered in routine diagnostics.

Monogenic diabetes is characterized as a group of diseases caused by rare variants in single genes. Like for other rare diseases, multiple genes have been linked to monogenic diabetes with different measures of pathogenicity, but the information on the genes and variants is not unified among different resources, making it challenging to process them informatically. We have developed an automated pipeline for collecting and harmonizing data on genetic variants linked to monogenic diabetes. Furthermore, we have translated variant genetic sequences into protein sequences accounting for all protein isoforms and their variants. This allows researchers to consolidate information on variant genes and proteins linked to monogenic diabetes and facilitates their study using proteomics or structural biology. Our open and flexible implementation using Jupyter notebooks enables tailoring and modifying the pipeline and its application to other rare diseases.

Interpreting variants is challenging in clinical practice. We aimed to integrate functional, clinical, and family data to improve variant classification, describe clinical features of carriers and report registry-level prevalence of alterations. Clinical, genetic, and family data were analyzed from the Norwegian MODY Registry (NMR) and the Norwegian Childhood Diabetes Registry (NCDR). Clinical features of sequence variant and 17q12 deletion (17q12del) carriers were summarized, and variants were classified using ACMG-AMP-ClinGen criteria. Registry-level prevalence was reported with 95% confidence intervals. sequence variants were functionally assessed, showing that lower transactivation (TA) was associated with higher clinical severity. Eleven variants demonstrated impaired functional activity, with TA inversely correlated with clinical burden (ρ = -0.701, = 0.002). We identified 28 individuals with 17q12del (21 in NMR, seven in NCDR) and 15 individuals carrying 14 unique pathogenic/likely pathogenic (P/LP) sequence variants, all detected in the NMR. Overall, 36/486 probands (7.4%) with genetically confirmed monogenic diabetes in the NMR carried a P/LP sequence variant or 17q12del. In the NCDR, ~0.2% carried 17q12del (7/3583; 3/7 GADA/IA-2A-positive). Functional data enabled reclassification of three variants. Since many pediatric 17q12del carriers in the NMR were referred for testing due to structural renal anomalies without diabetes, screening should be considered in children with renal/extra-renal features, irrespective of diabetes or autoantibody status.

David Altshuler and colleagues sequenced seven genes for maturity-onset diabetes of the young (MODY), a dominant Mendelian disorder, in 4,003 individuals drawn from three population-based cohorts. They find ~2% of individuals unselected for phenotype carry low frequency variants in one of these MODY genes, predicted as likely to be pathogenic; however most of these individuals remain asymptomatic through middle age. Genome sequencing can identify individuals in the general population who harbor rare coding variants in genes for Mendelian disorders 1 , 2 , 3 , 4 , 5 , 6 , 7 and who may consequently have increased disease risk. Previous studies of rare variants in phenotypically extreme individuals display ascertainment bias and may demonstrate inflated effect-size estimates 8 , 9 , 10 , 11 , 12 . We sequenced seven genes for maturity-onset diabetes of the young (MODY) 13 in well-phenotyped population samples 14 , 15 ( n = 4,003). We filtered rare variants according to two prediction criteria for disease-causing mutations: reported previously in MODY or satisfying stringent de novo thresholds (rare, conserved and protein damaging). Approximately 1.5% and 0.5% of randomly selected individuals from the Framingham and Jackson Heart Studies, respectively, carry variants from these two classes. However, the vast majority of carriers remain euglycemic through middle age. Accurate estimates of variant effect sizes from population-based sequencing are needed to avoid falsely predicting a substantial fraction of individuals as being at risk for MODY or other Mendelian diseases.

Monogenic diabetes is a gateway to precision medicine through molecular mechanistic insight. Hepatocyte nuclear factor 1A (HNF-1A) and HNF-4A are transcription factors that engage in crossregulatory gene transcription networks to maintain glucose-stimulated insulin secretion in pancreatic β cells. Variants in the HNF1A and HNF4A genes are associated with maturity-onset diabetes of the young (MODY). Here, we explored 4 variants in the P2- HNF4A promoter region: 3 in the HNF-1A binding site and 1 close to the site, which were identified in 63 individuals from 21 families of different MODY disease registries across Europe. Our goal was to study the disease causality for these variants and to investigate diabetes mechanisms on the molecular level. We solved a crystal structure of HNF-1A bound to the P2- HNF4A promoter and established a set of techniques to probe HNF-1A binding and transcriptional activity toward different promoter variants. We used isothermal titration calorimetry, biolayer interferometry, x-ray crystallography, and transactivation assays, which revealed changes in HNF-1A binding or transcriptional activities for all 4 P2- HNF4A variants. Our results suggest distinct disease mechanisms of the promoter variants, which can be correlated with clinical phenotype, such as age of diagnosis of diabetes, and be important tools for clinical utility in precision medicine.

Genetic testing for monogenic diabetes is important for patient care. Given the extensive genetic and clinical heterogeneity of diabetes, exome sequencing might provide additional diagnostic potential when standard Sanger sequencing-based diagnostics is inconclusive. The aim of the study was to examine the performance of exome sequencing for a molecular diagnosis of MODY in patients who have undergone conventional diagnostic sequencing of candidate genes with negative results. We performed exome enrichment followed by high-throughput sequencing in nine patients with suspected MODY. They were Sanger sequencing-negative for mutations in the HNF1A, HNF4A, GCK, HNF1B and INS genes. We excluded common, non-coding and synonymous gene variants, and performed in-depth analysis on filtered sequence variants in a pre-defined set of 111 genes implicated in glucose metabolism. On average, we obtained 45 X median coverage of the entire targeted exome and found 199 rare coding variants per individual. We identified 0-4 rare non-synonymous and nonsense variants per individual in our a priori list of 111 candidate genes. Three of the variants were considered pathogenic (in ABCC8, HNF4A and PPARG, respectively), thus exome sequencing led to a genetic diagnosis in at least three of the nine patients. Approximately 91% of known heterozygous SNPs in the target exomes were detected, but we also found low coverage in some key diabetes genes using our current exome sequencing approach. Novel variants in the genes ARAP1, GLIS3, MADD, NOTCH2 and WFS1 need further investigation to reveal their possible role in diabetes. Our results demonstrate that exome sequencing can improve molecular diagnostics of MODY when used as a complement to Sanger sequencing. However, improvements will be needed, especially concerning coverage, before the full potential of exome sequencing can be realized.

Aims/hypothesis Correctly diagnosing MODY is important, as individuals with this diagnosis can discontinue insulin injections; however, many people are misdiagnosed. We aimed to develop a robust approach for determining the pathogenicity of variants of uncertain significance in hepatocyte nuclear factor-1 alpha (HNF1A) - MODY and to obtain an accurate estimate of the prevalence of HNF1A-MODY in paediatric cases of diabetes. Methods We extended our previous screening of the Norwegian Childhood Diabetes Registry by 830 additional samples and comprehensively genotyped HNF1A variants in autoantibody-negative participants using next-generation sequencing. Carriers of pathogenic variants were treated by local healthcare providers, and participants with novel likely pathogenic variants and variants of uncertain significance were enrolled in an investigator-initiated, non-randomised, open-label pilot study (ClinicalTrials.gov registration no. NCT04239586). To identify variants associated with HNF1A-MODY, we functionally characterised their pathogenicity and assessed the carriers’ phenotype and treatment response to sulfonylurea. Results In total, 615 autoantibody-negative participants among 4712 cases of paediatric diabetes underwent genetic sequencing , revealing 19 with HNF1A variants. We identified nine carriers with novel variants classified as variants of uncertain significance or likely to be pathogenic, while the remaining ten participants carried five pathogenic variants previously reported. Of the nine carriers with novel variants, six responded favourably to sulfonylurea. Functional investigations revealed their variants to be dysfunctional and demonstrated a correlation with the resulting phenotype, providing evidence for reclassifying these variants as pathogenic. Conclusions/interpretation Based on this robust classification, we estimate that the prevalence of HNF1A-MODY is 0.3% in paediatric diabetes. Clinical phenotyping is challenging and functional investigations provide a strong complementary line of evidence. We demonstrate here that combining clinical phenotyping with functional protein studies provides a powerful tool to obtain a precise diagnosis of HNF1A-MODY. Graphical Abstract

This study shows that some patients with permanent neonatal diabetes have an activating mutation in the gene encoding Kir6.2, a subunit of the ATP-sensitive potassium (K ATP ) channel. Such mutations are predicted to reduce membrane depolarization in response to ATP and thereby insulin secretion from pancreatic beta cells. Three patients with mutant Kir6.2 secreted insulin in response to a sulfonylurea, which stimulates insulin secretion independently of ATP, suggesting a strategy for treatment. An activating mutation, a subunit of the ATP-sensitive potassium channel, and a possible strategy for treatment. Neonatal diabetes may be defined as insulin-requiring hyperglycemia that is diagnosed within the first three months of life. It may be either transient, resolving within a median of three months, or permanent, in which case insulin treatment is required for life. 1 Substantial progress has been made in our understanding of transient neonatal diabetes, with the majority of cases being attributable to an abnormality in an imprinted region of chromosome 6. 2 In most patients, the cause of permanent neonatal diabetes is unknown; homozygous and compound heterozygous mutations in the gene encoding glucokinase account for a minority of cases, 3 – 6 and the . . .

Permanent neonatal diabetes (PND) can be caused by mutations in the transcription factors insulin promoter factor (IPF)-1, eukaryotic translation initiation factor-2alpha kinase 3 (EIF2AK3), and forkhead box-P3 and in key components of insulin secretion: glucokinase (GCK) and the ATP-sensitive K(+) channel subunit Kir6.2. We sequenced the gene encoding Kir6.2 (KCNJ11) in 11 probands with GCK-negative PND. Heterozygous mutations were identified in seven probands, causing three novel (F35V, Y330C, and F333I) and two known (V59M and R201H) Kir6.2 amino acid substitutions. Only two probands had a family history of diabetes. Subjects with the V59M mutation had neurological features including motor delay. Three mutation carriers tested had an insulin secretory response to tolbutamide, but not to glucose or glucagon. Glibenclamide was introduced in increasing doses to investigate whether sulfonylurea could replace insulin. At a glibenclamide dose of 0.3-0.4 mg. kg(-1). day(-1), insulin was discontinued. Blood glucose did not deteriorate, and HbA(1c) was stable or fell during 2-6 months of follow-up. An oral glucose tolerance test performed in one subject revealed that glucose-stimulated insulin release was restored. Mutations in Kir6.2 were the most frequent cause of PND in our cohort. Apparently insulin-dependent patients with mutations in Kir6.2 may be managed on an oral sulfonylurea with sustained metabolic control rather than insulin injections, illustrating the principle of pharmacogenetics applied in diabetes treatment.