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 homo-zygous GCK mutation causing PNDM at birth. This study demonstrates the effectiveness of multi-gene panel anal ysis in uncovering molecular diagnoses in patients with monogenic forms of diabetes.
Aims GCK-MODY leads to mildly elevated blood glucose typically not requiring therapy. It has been described in all ethnicities, but mainly in Caucasian Europeans. Here we describe our United States cohort of GCK-MODY. Methods We examined the rates of detection of heterozygous mutations in the GCK gene in individuals referred to the US Monogenic Diabetes Registry with a phenotype consistent with GCK-MODY. We also assessed referral patterns, treatment, and demography, including ethnicity, of the cohort. Results Deleterious heterozygous GCK mutations were found in 54.7% of Registry probands selected for GCK sequencing for this study. Forty-nine percent were previously unnecessarily treated with glucose-lowering agents, causing hypoglycemia and other adverse effects in some of the subjects. The proportion of probands found to have a GCK mutation through research based testing was similar across each ethnic group. However, together African American, Latino and Asian subjects represented only 20.5% of screened probands and 17.2% of those with GCK-MODY, despite higher overall diabetes prevalence in these groups. Conclusions Our data show a high detection rate of GCK-MODY is possible based on clinical phenotype, and that prior to genetic diagnosis, a large percentage are inappropriately treated with glucose-lowering therapies. We also find low minority representation in our Registry, which may be due to disparities in diagnostic diabetes genetic testing, and is an area needing further investigation.
Aims 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 subjects with KCNJ11 mutations and their sibling controls. Methods Through our Monogenic Diabetes Registry (http://monogenicdiabetes.uchicago.edu/), we evaluated 23 subjects with KCNJ11 mutations with (n=9) and without (n=14) global developmental delay successfully treated with sulfonylurea and 20 healthy sibling controls, using a battery of targeted neuropsychological and behavioural assessments with scaled scores that are comparable across a wide range of ages. Results Subjects with KCNJ11-related diabetes without global developmental delay had significant differences compared to sibling controls on a range of assessments including IQ, measures of academic achievement and executive function. KCNJ11 subjects with global delay exhibited significant differences in behavioural symptoms with a tendency to avoid social contact and displayed a reduced ability to adapt to new circumstances. Parents reported more immature behaviour, gross mood swings, bizarre thoughts, other unusual and severe behaviours and there were also significant deficits in all subdomains of daily living skills. Conclusions This series represents the largest and most comprehensive study of neuropsychological and behavioural dysfunction of individuals with KCNJ11-diabetes and is the first to compare outcome with sibling controls. Our data demonstrates the variety of neurodevelopmental problems seen in those with KCNJ11 mutations, even in those without recognized global developmental delays. These data can be used to counsel families and guide structured neurodevelopmental assessments and treatments based on the initial genetic diagnosis in patients with neonatal diabetes.
<b>Objective </b><br><p> <i>ABCC8</i> mutations cause neonatal diabetes that can be transient (TNDM) or less commonly permanent (PNDM); ~90% individuals can be treated with oral sulfonylureas instead of insulin. Previous studies suggested that people with <i>ABCC8-</i>PNDM require lower sulfonylurea doses and have milder neurological features than those with <i>KCNJ11-</i>PNDM. However, these studies were short-term and included combinations of permanent and transient forms of <i>ABCC8</i>-NDM. We aimed to assess the long-term glycemic and neurological outcomes in sulfonylurea-treated <i>ABCC8</i>-PNDM. <b><br> Research Design and Methods </b><br> We studied all 24 individuals with <i>ABCC8-</i>PNDM diagnosed in the UK, Italy, France or USA known to transfer from insulin to sulfonylureas before May 2010. Data on glycemic control, sulfonylurea dose, adverse effects including hypoglycemia, and neurological features were analysed using non-parametric statistical methods. <b><br> Results </b><br> Long-term data were obtained for 21/24 individuals (median follow-up 10.0 (4.1-13.2) years). 18/21 remained on sulfonylureas without insulin at most recent follow-up. Glycemic control improved on sulfonylureas (pre-sulfonylurea vs 1-year post-transfer HbA1c 7.2% vs 5.7%, p=0.0004) and remained excellent long-term (1-year vs. 10-year HbA1c 5.7% vs. 6.5%, p=0.04), n=16. Relatively high doses were used (1-year vs 10-year dose 0.37 vs 0.25mg/kg/day glyburide, p=0.50), without any severe hypoglycemia. Neurological features were reported in 13/21 individuals: these improved following sulfonylurea transfer in 7/13. The commonest features were learning difficulties (52%), developmental delay (48%), and ADHD (38%).<b><br> Conclusions </b><br> Sulfonylurea treatment of <i>ABCC8</i>-PNDM results in excellent long-term glycemic control. Overt neurological features frequently occur and may improve with sulfonylureas, supporting early, rapid genetic testing to guide appropriate treatment and neurodevelopmental assessment. </p>
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