David Carmody

Cost-Effectiveness of MODY Genetic Testing: Translating Genomic Advances Into Practical Health Applications

OBJECTIVE To evaluate the cost-effectiveness of a genetic testing policy for HNF1A-, HNF4A-, and GCK-MODY in a hypothetical cohort of type 2 diabetic patients 25–40 years old with a MODY prevalence of 2%. RESEARCH DESIGN AND METHODS We used a simulation model of type 2 diabetes complications based on UK Prospective Diabetes Study data, modified to account for the natural history of disease by genetic subtype to compare a policy of genetic testing at diabetes diagnosis versus a policy of no testing. Under the screening policy, successful sulfonylurea treatment of HNF1A-MODY and HNF4A-MODY was modeled to produce a glycosylated hemoglobin reduction of −1.5% compared with usual care. GCK-MODY received no therapy. Main outcome measures were costs and quality-adjusted life years (QALYs) based on lifetime risk of complications and treatments, expressed as the incremental cost-effectiveness ratio (ICER) (USD/QALY). RESULTS The testing policy yielded an average gain of 0.012 QALYs and resulted in an ICER of 205,000 USD. Sensitivity analysis showed that if the MODY prevalence was 6%, the ICER would be ∼50,000 USD. If MODY prevalence was >30%, the testing policy was cost saving. Reducing genetic testing costs to 700 USD also resulted in an ICER of ∼50,000 USD. CONCLUSIONS Our simulated model suggests that a policy of testing for MODY in selected populations is cost-effective for the U.S. based on contemporary ICER thresholds. Higher prevalence of MODY in the tested population or decreased testing costs would enhance cost-effectiveness. Our results make a compelling argument for routine coverage of genetic testing in patients with high clinical suspicion of MODY.

Phenotypic heterogeneity in monogenic diabetes: The clinical and diagnostic utility of a gene panel-based next-generation sequencing approach

Single gene mutations that primarily affect pancreatic β-cell function account for approximately 1-2% of all cases of diabetes. Overlapping clinical features with common forms of diabetes makes diagnosis of monogenic diabetes challenging. A genetic diagnosis often leads to significant alterations in treatment, allows better prediction of disease prognosis and progression, and has implications for family members. Currently, genetic testing for monogenic diabetes relies on selection of appropriate individual genes for analysis based on the availability of often-limited phenotypic information, decreasing the likelihood of making a genetic diagnosis. We thus developed a targeted next-generation sequencing (NGS) assay for the detection of mutations in 36 genes known to cause monogenic forms of diabetes, including transient or permanent neonatal diabetes mellitus (TNDM or PNDM), maturity-onset diabetes of the young (MODY) and rare syndromic forms of diabetes. A total of 95 patient samples were analyzed: 19 with known causal mutations and 76 with a clinically suggestive phenotype but lacking a genetic diagnosis. All previously identified mutations were detected, validating our assay. Pathogenic sequence changes were identified in 19 out of 76 (25%) patients: 7 of 32 (22%) NDM cases, and 12 of 44 (27%) MODY cases. In 2 NDM patients the causal mutation was not expected as consanguinity was not reported and there were no clinical features aside from diabetes. A 3 year old patient with NDM diagnosed at 3 months of age, who previously tested negative for INS, KCNJ11 and ABCC8 mutations, was found to carry a novel homozygous mutation in EIF2AK3 (associated with Wolcott-Rallison syndrome), a gene not previously suspected because consanguinity, delayed growth, abnormal bone development and hepatic complications had not been reported. Similarly, another infant without a history of consanguinity was found to have a homozygous GCK mutation causing PNDM at birth. This study demonstrates the effectiveness of multi-gene panel analysis in uncovering molecular diagnoses in patients with monogenic forms of diabetes.

Sulfonylurea Treatment Before Genetic Testing in Neonatal Diabetes: Pros and Cons

CONTEXT Diabetes in neonates nearly always has a monogenic etiology. Earlier sulfonylurea therapy can improve glycemic control and potential neurodevelopmental outcomes in children with KCNJ11 or ABCC8 mutations, the most common gene causes. OBJECTIVE Assess the risks and benefits of initiating sulfonylurea therapy before genetic testing results become available. DESIGN, SETTING, AND PATIENTS Observational retrospective study of subjects with neonatal diabetes within the University of Chicago Monogenic Diabetes Registry. MAIN OUTCOME MEASURES Response to sulfonylurea (determined by whether insulin could be discontinued) and treatment side effects in those treated empirically. RESULTS A total of 154 subjects were diagnosed with diabetes before 6 months of age. A genetic diagnosis had been determined in 118 (77%), with 73 (47%) having a mutation in KCNJ11 or ABCC8. The median time from clinical diagnosis to genetic diagnosis was 10.4 weeks (range, 1.6 to 58.2 wk). In nine probands, an empiric sulfonylurea trial was initiated within 28 days of diabetes diagnosis. A genetic cause was subsequently found in eight cases, and insulin was discontinued within 14 days of sulfonylurea initiation in all of these cases. CONCLUSIONS Sulfonylurea therapy appears to be safe and often successful in neonatal diabetes patients before genetic testing results are available; however, larger numbers of cases must be studied. Given the potential beneficial effect on neurodevelopmental outcome, glycemic control, and the current barriers to expeditious acquisition of genetic testing, an empiric inpatient trial of sulfonylurea can be considered. However, obtaining a genetic diagnosis remains imperative to inform long-term management and prognosis.

Case Report: Preservation of Reduced Numbers of Insulin-Positive Cells in Sulfonylurea-Unresponsive KCNJ11-related Diabetes

Context The most common genetic cause of permanent neonatal diabetes mellitus is activating mutations in KCNJ11, which can usually be treated using oral sulfonylureas (SUs) instead of insulin injections, although some mutations are SU unresponsive. In this work, we provide a report of the pancreatic islet endocrine cell composition and area in a patient with an SU-unresponsive KCNJ11 mutation (p.G334D), in comparison with age-matched controls. Case Description Pancreatic autopsy tissue sections from a 2-year-old female child diagnosed with KCNJ11-related diabetes at 4 days of age and 13 age-matched controls were stained with insulin, glucagon, somatostatin, pancreatic polypeptide, and Ki67 antibodies to determine islet endocrine cell composition and area. β-cell ultrastructure was assessed by electron microscopic (EM) analysis. The patients pancreas (sampling from head to tail) revealed insulin-positive cells in all regions. The pancreatic β-cell (insulin) area was significantly reduced compared with controls: 0.50% ± 0.04% versus 1.67% ± 0.20%, respectively (P < 0.00001). There were no significant differences in α-cell (glucagon) or δ-cell (somatostatin) area. EM analysis revealed secretory granules with a dense core typical of mature β-cells as well as granules with a lighter core characteristic of immature granules. Conclusions Our results suggest that mechanisms exist that allow preservation of β-cells in the absence of insulin secretion. It remains to be determined to what extent this reduction in β-cells may be reversible.

ADHD, learning difficulties and sleep disturbances associated with KCNJ11-related neonatal diabetes.

Mutations in KCNJ11 are the most common cause of permanent neonatal diabetes mellitus (NDM). Approximately 25% of patients have obvious neurological dysfunction, but whether milder related problems might be more common has been unclear. We sought to assess the prevalence of parental concerns about learning, behavior, attention deficit hyperactivity disorder (ADHD), social competency, and sleep in subjects with KCNJ11‐related NDM compared to unaffected sibling controls.

Diabetes Presentation in Infancy: High Risk of Diabetic Ketoacidosis

Diabetes in childhood has been associated with increased morbidity and mortality, but the risks for diabetes in infancy remain unclear. Cases with onset of hyperglycemia in the first 6 months of life consist predominantly of monogenic diabetes, whereas type 1 autoimmune diabetes accounts for the majority of cases beyond this threshold. Regardless of etiology, diabetes symptoms tend to be difficult to recognize in an infant, putting patients at increased risk for delays in diagnosis, which may lead to higher blood glucose levels and diabetic ketoacidosis (DKA) at presentation. Here, we report a high degree of morbidity among a cohort of subjects with infancy-onset diabetes. We examined diagnosis records from 88 cases with diabetes onset ≤13 months of age collected through the University of Chicago Monogenic Diabetes Registry (1). We assessed laboratory values and sign/symptoms, and if a causal mutation for diabetes was detected, participants were subdivided by similar mutation subtypes. Data were managed using REDCap electronic data capture tools and analyzed using Stata version 14 (StataCorp, 2015). The majority of participants were male ( n = 46, …

Continued lessons from the INS gene: an intronic mutation causing diabetes through a novel mechanism

Background Diabetes in neonates usually has a monogenic aetiology; however, the cause remains unknown in 20–30%. Heterozygous INS mutations represent one of the most common gene causes of neonatal diabetes mellitus. Methods Clinical and functional characterisation of a novel homozygous intronic mutation (c.187+241G>A) in the insulin gene in a child identified through the Monogenic Diabetes Registry (http://monogenicdiabetes.uchicago.edu). Results The proband had insulin-requiring diabetes from birth. Ultrasonography revealed a structurally normal pancreas and C-peptide was undetectable despite readily detectable amylin, suggesting the presence of dysfunctional β cells. Whole-exome sequencing revealed the novel mutation. In silico analysis predicted a mutant mRNA product resulting from preferential recognition of a newly created splice site. Wild-type and mutant human insulin gene constructs were derived and transiently expressed in INS-1 cells. We confirmed the predicted transcript and found an additional transcript created via an ectopic splice acceptor site. Conclusions Dominant INS mutations cause diabetes via a mutated translational product causing endoplasmic reticulum stress. We describe a novel mechanism of diabetes, without β cell death, due to creation of two unstable mutant transcripts predicted to undergo nonsense and non-stop-mediated decay, respectively. Our discovery may have broader implications for those with insulin deficiency later in life.

Role of Noninsulin Therapies Alone or in Combination in Chromosome 6q24-Related Transient Neonatal Diabetes: Sulfonylurea Improves but Does Not Always Normalize Insulin Secretion

Chromosome 6q24-related transient neonatal diabetes (6q24-TND) is a rare form of diabetes caused by an overexpression of PLAGL1 and HYMAI (1). After remitting in infancy, diabetes recurs in most patients later in life. While the best treatment remains unknown, many patients are managed with insulin (1). We sought to characterize β-cell function and glucose homeostasis in patients with 6q24-TND and assess their response to sulfonylurea (SU) therapy. Adults with 6q24-TND and recurrence of hyperglycemia requiring insulin therapy later in life were identified through The University of Chicago Monogenic Diabetes Registry (http://monogenicdiabetes.uchicago.edu/registry) and invited to participate in a trial of SU therapy. Four patients with insulin doses of 0.41–0.76 units/kg/day attempted the trial. Three were available for a mixed-meal test (MMT) and arginine stimulation test (AST) on day one and day five of SU treatment. All insulin products were withheld on the morning of day one. Subjects ingested 7 mL/kg (maximal 360 mL) of BOOST High Protein (http://www.boost.com) within 5 …

Microcephaly, epilepsy, and neonatal diabetes due to compound heterozygous mutations in IER3IP1: insights into the natural history of a rare disorder

Neonatal diabetes mellitus is known to have over 20 different monogenic causes. A syndrome of permanent neonatal diabetes along with primary microcephaly with simplified gyral pattern associated with severe infantile epileptic encephalopathy was recently described in two independent reports in which disease‐causing homozygous mutations were identified in the immediate early response‐3 interacting protein‐1 (IER3IP1) gene. We report here an affected male born to a non‐consanguineous couple who was noted to have insulin‐requiring permanent neonatal diabetes, microcephaly, and generalized seizures. He was also found to have cortical blindness, severe developmental delay and numerous dysmorphic features. He experienced a slow improvement but not abrogation of seizure frequency and severity on numerous anti‐epileptic agents. His clinical course was further complicated by recurrent respiratory tract infections and he died at 8 years of age.

Patients with KCNJ11-related diabetes frequently have neuropsychological impairments compared with sibling controls.

KCNJ11‐related diabetes is the most common form of permanent neonatal diabetes and has been associated with a spectrum of neurodevelopmental problems. We compared neurodevelopmental outcomes in patients with KCNJ11 mutations and their sibling controls.