Genetics and neonatal diabetes: towards precision medicine

Diabetes is a lifelong chronic disease. During the past 100 years, its diagnosis has been based on measurements of raised blood glucose concentrations. In the 1960s, diabetes was subclassified based on age at onset and need for insulin treatment (ie, juvenile or maturity onset; insulin or non-insulin-requiring diabetes). Because diabetes was believed to be an inherited disease, much hope was placed on the identification of genetic markers that would help to diagnose diabetic subgroups. Although investigators in the 1970s noted that type 1 diabetes was strongly associated with the HLA locus on chromosome 6, determination of HLA genotypes did not add substantial diagnostic value because of their high prevalence.1Christy M Nerup J Bottazzo GF et al.Association between HLA-B8 and autoimmunity in juvenile diabetes mellitus.Lancet. 1976; 2: 142-143Abstract PubMed Scopus (23) Google Scholar The discovery of autoantibodies to different islet antigens in the 1980s2Christgau S Schierbeck H Aanstoot HJ et al.Pancreatic beta cells express two autoantigenic forms of glutamic acid decarboxylase, a 65-kDa hydrophilic form and a 64-kDa amphiphilic form which can be both membrane-bound and soluble.J Biol Chem. 1991; 266: 21257-21264Summary Full Text PDF PubMed Google Scholar added strong discriminatory power to the diagnosis of autoimmune type 1 diabetes, and this knowledge was later applied to a late-onset autoimmune form of diabetes in adults.3Tuomi T Groop LC Zimmet PZ Rowley MJ Knowles W Mackay IR Antibodies to glutamic acid decarboxylase reveal latent autoimmune diabetes mellitus in adults with a non-insulin-dependent onset of disease.Diabetes. 1992; 42: 359-362Crossref Scopus (542) Google Scholar The first real genetic breakthroughs in diabetes classification came with the discovery that mutations in the genes encoding glucokinase, HNF1A, and HNF4A were associated with different forms of maturity-onset diabetes of the young.4Froguel P Vaxillaire M Sun F et al.Close linkage of glucokinase locus on chromosome 7p to early-onset non-insulin-dependent diabetes mellitus.Nature. 1992; 356: 162-164Crossref PubMed Scopus (566) Google Scholar, 5Yamagata K Oda N Kaisaki PJ et al.Mutations in the hepatocyte nuclear factor-1α gene in maturity-onset diabetes of the young (MODY3).Nature. 1996; 384: 455-458Crossref PubMed Scopus (1045) Google Scholar, 6Yamagata K Furuta H Oda N et al.Mutations in the hepatocyte nuclear factor-4α gene in maturity-onset diabetes of the young (MODY1).Nature. 1996; 384: 458-460Crossref PubMed Scopus (1051) Google Scholar Whereas maturity-onset diabetes of the young can show varying penetrance and severity, neonatal diabetes, a rare (1:100 000 births) severe form of diabetes, is diagnosed in infants younger than 6 months. The group in Exeter, UK, pioneered the genetic dissection of neonatal diabetes, and noted that one form could be linked to mutations in the KCNJ11 gene encoding the Kir6.2 subunit of the ATP-dependent potassium channel in pancreatic islets, and could be treated with sulfonylureas.7Gloyn AL Pearson ER Antcliff JF et al.Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes.N Engl J Med. 2004; 350: 1838-1849Crossref PubMed Scopus (981) Google Scholar, 8Pearson ER Flechtner I Njølstad PR et al.Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations.N Engl J Med. 2006; 355: 467-477Crossref PubMed Scopus (794) Google Scholar During the past 20 years, more than 20 genes have been identified as causing neonatal diabetes, as discussed by Elisa De Franco and colleagues in their accompanying study in The Lancet.9De Franco E Flanagan SE Houghton JA et al.The effect of early, comprehensive genomic testing on clinical care in neonatal diabetes: an international cohort study.Lancet. 2015; (published online July 29.)http://dx.doi.org/10.1016/S0140-6736(15)60098-8PubMed Google Scholar In many of these monogenic diseases, a causal diagnosis has had an important effect on choice of treatment and disease outcome. In one striking case,10Slingerland AS Nuboer R Hadders-Algra M et al.Improved motor development and good long-term glycaemic control with sulfonylurea treatment in a patient with the syndrome of intermediate developmental delay, early-onset generalised epilepsy and neonatal diabetes associated with the V59M mutation in the KCNJ11 gene.Diabetologia. 2006; 49: 2559-2563Crossref PubMed Scopus (108) Google Scholar after identification of a mutation in the KCNJ11 gene in a poorly developing child with neonatal diabetes and switching from insulin to large doses of sulfonylurea, the child's diabetes could not only be well controlled, but development, walking, and talking became possible. Kir6.2 is also expressed in the brain, and this combination of diabetes, developmental brain defects, and sometimes epilepsy has been called developmental delay-epilepsy-neonatal diabetes. Clear evidence exists of a genetic diagnosis improving treatment.7Gloyn AL Pearson ER Antcliff JF et al.Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes.N Engl J Med. 2004; 350: 1838-1849Crossref PubMed Scopus (981) Google Scholar, 8Pearson ER Flechtner I Njølstad PR et al.Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations.N Engl J Med. 2006; 355: 467-477Crossref PubMed Scopus (794) Google Scholar In patients diagnosed with maturity-onset diabetes of the young, those with mutations in the glucokinase gene do not need any treatment because the mutation only modestly raises the threshold for the phosphorylating capacity of the enzyme, but the slight increase in glucose can fully overcome this defect. Therefore, maturity-onset diabetes of the young 2 caused by glucokinase mutations is not really a disease, but a compensated metabolic disorder.11Spégel P Ekholm E Tuomi T et al.Metabolite profiling reveals normal metabolic control in carriers of mutations in the glucokinase gene (MODY2).Diabetes. 2013; 62: 653-661Crossref PubMed Scopus (34) Google Scholar One of my patients received a diagnosis of diabetes as a child, but, after many years and about 19 000 insulin injections, received a precise genetic diagnosis that her diabetes was caused by a mutation in the glucokinase gene. Now, she needs no treatment. The Exeter group has not only pioneered research in this specialty, but also removed barriers by providing genetic tests to patients from many different countries for free covered by research grants.8Pearson ER Flechtner I Njølstad PR et al.Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations.N Engl J Med. 2006; 355: 467-477Crossref PubMed Scopus (794) Google Scholar In the early days of the study in 2000, genetic testing was expensive and time consuming, and the investigators used Sanger sequencing of genes that were selected on the basis of previous clinical information. The addition of targeted next-generation sequencing to Sanger sequencing in 2012 reduced the cost and time required, and also broadened the range of variants that could be tested without clinical data. This change resulted in the identification of a genetic diagnosis in 82% (840/1020) of tested patients in De Franco and colleagues' study.9De Franco E Flanagan SE Houghton JA et al.The effect of early, comprehensive genomic testing on clinical care in neonatal diabetes: an international cohort study.Lancet. 2015; (published online July 29.)http://dx.doi.org/10.1016/S0140-6736(15)60098-8PubMed Google Scholar Because most patients are now referred within weeks of being diagnosed with diabetes, physicians can achieve an early genetic diagnosis and predict the development of associated clinical features. Indeed, De Franco and colleagues document the clinical benefit of early diagnosis and treatment in certain subgroups of patients with neonatal diabetes.9De Franco E Flanagan SE Houghton JA et al.The effect of early, comprehensive genomic testing on clinical care in neonatal diabetes: an international cohort study.Lancet. 2015; (published online July 29.)http://dx.doi.org/10.1016/S0140-6736(15)60098-8PubMed Google Scholar This approach still requires a prediction of the genes to sequence, which is reasonable in neonatal diabetes (ie, with a clear phenotype of diagnosis of diabetes <6 months of age), but not all cases of monogenic diabetes are this clear cut. The next step in less clear clinical situations will be whole-genome sequencing without any assumptions about what genes might be involved. Although cost is a restriction in this situation, this whole-genome sequencing approach can already work for recessive mutations, which are rare. We recently identified three recessive mutations in BBS10 causing the Bardet-Bield syndrome in an analysis of next-generation sequence data from Finland.12Lim ET Liu YP Chan Y et al.A novel test for recessive contributions to complex diseases implicates Bardet-Biedl syndrome gene BBS10 in idiopathic type 2 diabetes and obesity.Am J Hum Genet. 2014; 95: 509-520Summary Full Text Full Text PDF PubMed Scopus (24) Google Scholar The three adult carriers had not been diagnosed with the syndrome, even though clinical features meant that Bardet-Bield syndrome could not be excluded. However, many challenges will need to be overcome before whole-genome sequencing becomes part of routine clinical work-up in different specialties. Hopefully the UK Government's 100 000 Genome Project and the US$215 million promised by President Obama to create a Precision Medicine Initiative in the USA will provide impetus towards this goal. Such projects should not only lead to more precise diagnosis informing treatment in different genetically-determined diseases, but also increase the number of affected individuals who will benefit from diagnosis and treatment. I declare no competing interests. The effect of early, comprehensive genomic testing on clinical care in neonatal diabetes: an international cohort studyPatients are now referred for genetic testing closer to their presentation with neonatal diabetes. Comprehensive testing of all causes identified causal mutations in more than 80% of cases. The genetic result predicts the best diabetes treatment and development of related features. This model represents a new framework for clinical care with genetic diagnosis preceding development of clinical features and guiding clinical management. Full-Text PDF Open Access