Characterisation of HNF1A variants in paediatric diabetes in Norway using functional and clinical investigations to unmask phenotype and monogenic diabetes.

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.

The use of precision diagnostics for monogenic diabetes: a systematic review and expert opinion.

BACKGROUND: Monogenic diabetes presents opportunities for precision medicine but is underdiagnosed. This review systematically assessed the evidence for (1) clinical criteria and (2) methods for genetic testing for monogenic diabetes, summarized resources for (3) considering a gene or (4) variant as causal for monogenic diabetes, provided expert recommendations for (5) reporting of results; and reviewed (6) next steps after monogenic diabetes diagnosis and (7) challenges in precision medicine field. METHODS: Pubmed and Embase databases were searched (1990-2022) using inclusion/exclusion criteria for studies that sequenced one or more monogenic diabetes genes in at least 100 probands (Question 1), evaluated a non-obsolete genetic testing method to diagnose monogenic diabetes (Question 2). The risk of bias was assessed using the revised QUADAS-2 tool. Existing guidelines were summarized for questions 3-5, and review of studies for questions 6-7, supplemented by expert recommendations. Results were summarized in tables and informed recommendations for clinical practice. RESULTS: There are 100, 32, 36, and 14 studies included for questions 1, 2, 6, and 7 respectively. On this basis, four recommendations for who to test and five on how to test for monogenic diabetes are provided. Existing guidelines for variant curation and gene-disease validity curation are summarized. Reporting by gene names is recommended as an alternative to the term MODY. Key steps after making a genetic diagnosis and major gaps in our current knowledge are highlighted. CONCLUSIONS: We provide a synthesis of current evidence and expert opinion on how to use precision diagnostics to identify individuals with monogenic diabetes.

Some diabetes types, called monogenic diabetes, are caused by changes in a single gene. It is important to know who has this kind of diabetes because treatment can differ from that of other types of diabetes. Some treatments also work better than others for specific types, and some people can for example change from insulin injections to tablets. In addition, relatives can be offered a test to see if they are at risk. Genetic testing is needed to diagnose monogenic diabetes but is expensive, so it's not possible to test every person with diabetes for it. We evaluated published research on who should be tested and what test to use. Based on this, we provide recommendations for doctors and health care providers on how to implement genetic testing for monogenic diabetes.

Second international consensus report on gaps and opportunities for the clinical translation of precision diabetes medicine.

Precision medicine is part of the logical evolution of contemporary evidence-based medicine that seeks to reduce errors and optimize outcomes when making medical decisions and health recommendations. Diabetes affects hundreds of millions of people worldwide, many of whom will develop life-threatening complications and die prematurely. Precision medicine can potentially address this enormous problem by accounting for heterogeneity in the etiology, clinical presentation and pathogenesis of common forms of diabetes and risks of complications. This second international consensus report on precision diabetes medicine summarizes the findings from a systematic evidence review across the key pillars of precision medicine (prevention, diagnosis, treatment, prognosis) in four recognized forms of diabetes (monogenic, gestational, type 1, type 2). These reviews address key questions about the translation of precision medicine research into practice. Although not complete, owing to the vast literature on this topic, they revealed opportunities for the immediate or near-term clinical implementation of precision diabetes medicine; furthermore, we expose important gaps in knowledge, focusing on the need to obtain new clinically relevant evidence. Gaps include the need for common standards for clinical readiness, including consideration of cost-effectiveness, health equity, predictive accuracy, liability and accessibility. Key milestones are outlined for the broad clinical implementation of precision diabetes medicine.

Potassium channels in behavioral brain disorders. Molecular mechanisms and therapeutic potential: A narrative review.

Potassium channels (K+-channels) selectively control the passive flow of potassium ions across biological membranes and thereby also regulate membrane excitability. Genetic variants affecting many of the human K+-channels are well known causes of Mendelian disorders within cardiology, neurology, and endocrinology. K+-channels are also primary targets of many natural toxins from poisonous organisms and drugs used within cardiology and metabolism. As genetic tools are improving and larger clinical samples are being investigated, the spectrum of clinical phenotypes implicated in K+-channels dysfunction is rapidly expanding, notably within immunology, neurosciences, and metabolism. K+-channels that previously were considered to be expressed in only a few organs and to have discrete physiological functions, have recently been found in multiple tissues and with new, unexpected functions. The pleiotropic functions and patterns of expression of K+-channels may provide additional therapeutic opportunities, along with new emerging challenges from off-target effects. Here we review the functions and therapeutic potential of K+-channels, with an emphasis on the nervous system, roles in neuropsychiatric disorders and their involvement in other organ systems and diseases.

A Systematic Review of the use of Precision Diagnostics in Monogenic Diabetes.

Monogenic forms of diabetes present opportunities for precision medicine as identification of the underlying genetic cause has implications for treatment and prognosis. However, genetic testing remains inconsistent across countries and health providers, often resulting in both missed diagnosis and misclassification of diabetes type. One of the barriers to deploying genetic testing is uncertainty over whom to test as the clinical features for monogenic diabetes overlap with those for both type 1 and type 2 diabetes. In this review, we perform a systematic evaluation of the evidence for the clinical and biochemical criteria used to guide selection of individuals with diabetes for genetic testing and review the evidence for the optimal methods for variant detection in genes involved in monogenic diabetes. In parallel we revisit the current clinical guidelines for genetic testing for monogenic diabetes and provide expert opinion on the interpretation and reporting of genetic tests. We provide a series of recommendations for the field informed by our systematic review, synthesizing evidence, and expert opinion. Finally, we identify major challenges for the field and highlight areas for future research and investment to support wider implementation of precision diagnostics for monogenic diabetes.

Intellectual Disability in KATP Channel Neonatal Diabetes.

OBJECTIVE: Neonatal diabetes has been shown to be associated with high neuropsychiatric morbidity in a genotype-phenotype-dependent manner. However, the specific impact of different mutations on intellectual functioning is still insufficiently characterized. Specifically, only a small number of subjects with developmental delay have been comprehensively assessed, creating a knowledge gap about patients carrying the heaviest burden. RESEARCH DESIGN AND METHODS: We assessed the intellectual functioning and mental health of the complete Norwegian population with KATP channel neonatal diabetes. Eight sulfonylurea-treated children (five with the p.V59M genotype [KCNJ11]) were assessed using age-matched control subjects with type 1 diabetes. The investigations included a physical and motor developmental examination, cerebral MRI, psychometrical examination, and questionnaires assessing intellectual capabilities and psychiatric morbidity. RESULTS: A strong genotype-phenotype correlation was found, revealing the p.V59M genotype as highly associated with substantial intellectual disability, with no significant correlation with the time of sulfonylurea initiation. Consistent with previous studies, other genotypes were associated with minor cognitive impairment. Cerebral MRI verified normal brain anatomy in all but one child. CONCLUSIONS: We here presented a comprehensive assessment of intellectual functioning in the largest cohort of p.V59M subjects to date. The level of intellectual disability revealed not only changes the interpretation of other psychological measures but downplays a strong protective effect of sulfonylurea. Within the scope of this study, we could not find evidence supporting an early treatment start to be beneficial, although a weaker effect cannot be ruled out.

Effectiveness and safety of long-term treatment with sulfonylureas in patients with neonatal diabetes due to KCNJ11 mutations: an international cohort study.

BACKGROUND: KCNJ11 mutations cause permanent neonatal diabetes through pancreatic ATP-sensitive potassium channel activation. 90% of patients successfully transfer from insulin to oral sulfonylureas with excellent initial glycaemic control; however, whether this control is maintained in the long term is unclear. Sulfonylurea failure is seen in about 44% of people with type 2 diabetes after 5 years of treatment. Therefore, we did a 10-year multicentre follow-up study of a large international cohort of patients with KCNJ11 permanent neonatal diabetes to address the key questions relating to long-term efficacy and safety of sulfonylureas in these patients. METHODS: In this multicentre, international cohort study, all patients diagnosed with KCNJ11 permanent neonatal diabetes at five laboratories in Exeter (UK), Rome (Italy), Bergen (Norway), Paris (France), and Krakow (Poland), who transferred from insulin to oral sulfonylureas before Nov 30, 2006, were eligible for inclusion. Clinicians collected clinical characteristics and annual data relating to glycaemic control, sulfonylurea dose, severe hypoglycaemia, side-effects, diabetes complications, and growth. The main outcomes of interest were sulfonylurea failure, defined as permanent reintroduction of daily insulin, and metabolic control, specifically HbA1c and sulfonylurea dose. Neurological features associated with KCNJ11 permanent neonatal diabetes were also assessed. This study is registered with ClinicalTrials.gov, number NCT02624817. FINDINGS: 90 patients were identified as being eligible for inclusion and 81 were enrolled in the study and provided long-term (>5·5 years cut-off) outcome data. Median follow-up duration for the whole cohort was 10·2 years (IQR 9·3-10·8). At most recent follow-up (between Dec 1, 2012, and Oct 4, 2016), 75 (93%) of 81 participants remained on sulfonylurea therapy alone. Excellent glycaemic control was maintained for patients for whom we had paired data on HbA1c and sulfonylurea at all time points (ie, pre-transfer [for HbA1c], year 1, and most recent follow-up; n=64)-median HbA1c was 8·1% (IQR 7·2-9·2; 65·0 mmol/mol [55·2-77·1]) before transfer to sulfonylureas, 5·9% (5·4-6·5; 41·0 mmol/mol [35·5-47·5]; p<0·0001 vs pre-transfer) at 1 year, and 6·4% (5·9-7·3; 46·4 mmol/mol [41·0-56·3]; p<0·0001 vs year 1) at most recent follow-up (median 10·3 years [IQR 9·2-10·9]). In the same patients, median sulfonylurea dose at 1 year was 0·30 mg/kg per day (0·14-0·53) and at most recent follow-up visit was 0·23 mg/kg per day (0·12-0·41; p=0·03). No reports of severe hypoglycaemia were recorded in 809 patient-years of follow-up for the whole cohort (n=81). 11 (14%) patients reported mild, transient side-effects, but did not need to stop sulfonylurea therapy. Seven (9%) patients had microvascular complications; these patients had been taking insulin longer than those without complications (median age at transfer to sulfonylureas 20·5 years [IQR 10·5-24·0] vs 4·1 years [1·3-10·2]; p=0·0005). Initial improvement was noted following transfer to sulfonylureas in 18 (47%) of 38 patients with CNS features. After long-term therapy with sulfonylureas, CNS features were seen in 52 (64%) of 81 patients. INTERPRETATION: High-dose sulfonylurea therapy is an appropriate treatment for patients with KCNJ11 permanent neonatal diabetes from diagnosis. This therapy is safe and highly effective, maintaining excellent glycaemic control for at least 10 years. FUNDING: Wellcome Trust, Diabetes UK, Royal Society, European Research Council, Norwegian Research Council, Kristian Gerhard Jebsen Foundation, Western Norway Regional Health Authority, Southern and Eastern Norway Regional Health Authority, Italian Ministry of Health, Aide aux Jeunes Diabetiques, Societe Francophone du Diabete, Ipsen, Slovak Research and Development Agency, and Research and Development Operational Programme funded by the European Regional Development Fund.