Maturity-onset Diabetes Of The Young Cases Research Articles

Focusing on Rare Variants Related to Maturity‐Onset Diabetes of the Young in Children

Background: In this study, we analysed the clinical and genetic characteristics and follow‐up data of patients with maturity‐onset diabetes of the young (MODY).Methods: From January 2015 to December 2022, patients with persistent hyperglycaemia suspected of having monogenic diabetes or diabetes syndrome were recruited, and next‐generation sequencing (NGS) was performed at the Shanghai Children’s Medical Center. Patients’ clinical and laboratory findings were recorded preceding follow‐ups. Candidate variants were verified using Sanger sequencing. Variant pathogenicity was evaluated according to the American College of Medical Genetics and Genomics (ACMG) guidelines.Results: Genetic testing was performed in 175 children. MODY‐related pathogenic or likely pathogenic gene variants were identified in 30 patients from different families. Of these, 11 were diagnosed with GCK‐MODY (36.7%), six with INS‐MODY (20%), five with HNF1A‐MODY (16.7%), five with ABCC8‐MODY (16.7%), two with HNF1B‐MODY (6.7%) and one with HNF4A‐MODY (3.3%). There was one shift variant and seven splice‐site variants, and the rest were missense variants. We discovered six novel variants. Of the 30 patients, 63.3% had a family history of diabetes, 13.3% had diabetic ketoacidosis (DKA), and 16.7% had positive diabetes‐associated autoantibodies. The diabetes phenotype of patients with the INS variant was similar to that of patients with type 1 diabetes. All patients, including those having positive autoantibodies, required long‐term insulin therapy during follow‐ups. Four patients with the ABCC8 variant were unable to switch to oral sulfonylurea therapy and continued insulin therapy.Conclusion: Genetic testing is helpful for the precise diagnosis and treatment of patients with MODY, including those with DKA history and positive diabetes autoantibody. GCK‐MODY is the most common type of MODY, and patients with INS variant account for a relatively large proportion of MODY cases in our cohort.

Monogenic Defects of Beta Cell Function: From Clinical Suspicion to Genetic Diagnosis and Management of Rare Types of Diabetes

Monogenic defects of beta cell function refer to a group of rare disorders that are characterized by early-onset diabetes mellitus due to a single gene mutation affecting insulin secretion. It accounts for up to 5% of all pediatric diabetes cases and includes transient or permanent neonatal diabetes, maturity-onset diabetes of the young (MODY), and various syndromes associated with diabetes. Causative mutations have been identified in genes regulating the development or function of the pancreatic beta cells responsible for normal insulin production and/or release. To date, more than 40 monogenic diabetes subtypes have been described, with those caused by mutations in HNF1A and GCK genes being the most prevalent. Despite being caused by a single gene mutation, each type of monogenic diabetes, especially MODY, can appear with various clinical phenotypes, even among members of the same family. This clinical heterogeneity, its rarity, and the fact that it shares some features with more common types of diabetes, can make the clinical diagnosis of monogenic diabetes rather challenging. Indeed, several cases of MODY or syndromic diabetes are accurately diagnosed in adulthood, after having been mislabeled as type 1 or type 2 diabetes. The recent widespread use of more reliable sequencing techniques has improved monogenic diabetes diagnosis, which is important to guide appropriate treatment and genetic counselling. The current review aims to summarize the latest knowledge on the clinical presentation, genetic confirmation, and therapeutic approach of the various forms of monogenic defects of beta cell function, using three imaginary clinical scenarios and highlighting clinical and laboratory features that can guide the clinician in reaching the correct diagnosis.

Coinheritance of HNF1A and glucokinase variants in maturity-onset diabetes of the young.

Maturity-onset diabetes of the young (MODY) is a group of monogenic forms of diabetes mellitus characterized by early-onset diabetes with dominant inheritance of beta-cell dysfunction. There are few reports of the coinheritance of glucokinase (GCK) and hepatocyte nuclear factor 1 alpha gene (HNF1A) variants underlying MODY in patients. Herein, we describe a case involving combinations of monoallelic GCK and HNF1A variants associated with MODY. A 10-year-old Japanese girl with a three-generation family history of diabetes without obesity showed high levels of urinary glucose during a school screening test. Her glucose metabolism profile revealed 124 mg/dL of fasting glucose, 6.9% glycated hemoglobin (HbA1c), and 2.78 ng/mL of C-peptide immunoreactivity levels. In a 75-g oral glucose tolerance test, her base glucose, peak glucose, insulin resistance, and homeostasis model assessment of beta cell function levels were 124 mg/dL, 210 mg/dL (120 min), 1.71, and 33%, respectively. Based on the clinical phenotype of GCK-MODY, alimentary and exercise therapy without oral hypoglycemic agents were used to maintain her fasting glucose and HbA1c levels. We explored the coinheritance of MODY with GCK and HNF1A variants in this and past cases and found that careful clinical follow-up is required to firmly establish phenotypic features. Moreover, the accumulation of data on genetically confirmed MODY associated with the coinheritance of GCK and HNF1A variants will be useful for understanding genotype-phenotype correlations. MODY is a group of monogenic forms of diabetes mellitus characterized by early-onset diabetes with the dominant inheritance of beta-cell dysfunction. MODY2 and MODY3 caused by heterozygous loss-of-function variants in the glucokinase (GCK) and hepatocyte nuclear factor 1 alpha (HNF1A) genes, respectively, are the most common forms of the disease. Few cases of MODY have previously been reported as being associated with the coinheritance of GCK and HNF1A variants. Careful clinical follow-up is required to firmly establish phenotypic features in the coinheritance of MODY with GCK and HNF1A variants. The accumulation of data on genetically confirmed MODY associated with the coinheritance of GCK and HNF1A variants will be useful for understanding genotype-phenotype correlations.

High prevalence of copy number variations in the Japanese participants with suspected MODY.

Maturity-Onset Diabetes of the Young (MODY) is a diabetes mellitus subtype caused by a single gene. The detection rate of the responsible gene is 27% in the United Kingdom, indicating that the causative gene remains unknown in the majority of clinically diagnosed MODY cases. To improve the detection rate, we applied comprehensive genetic testing using whole exome sequencing (WES) followed by Multiplex Ligation-dependent Probe Amplification (MLPA) and functional analyses. Twenty-one unrelated Japanese participants with MODY were enrolled in the study. To detect copy number variations (CNVs), WES was performed first, followed by MLPA analysis for participants who were negative on the basis of WES. Undetermined variants were analyzed according to their functional properties. WES identified 7 pathogenic and 3 novel likely pathogenic variants in the 21 participants. Functional analyses revealed that 1 in 3 variants was pathogenic. MLPA analysis applied to the remaining 13 undetermined samples identified 4 cases with pathogenic CNVs: 3 in HNF4A and 1 in HNF1B. Pathogenic variants were identified in 12 participants (12/21, 57.1%) - relatively high rate reported to date. Notably, one-third of the participants had CNVs in HNF4A or HNF1B, indicating a limitation of WES-only screening.

Development of a clinical calculator to aid the identification of MODY in pediatric patients at the time of diabetes diagnosis

Maturity Onset Diabetes of the Young (MODY) is a young-onset, monogenic form of diabetes without needing insulin treatment. Diagnostic testing is expensive. To aid decisions on who to test, we aimed to develop a MODY probability calculator for paediatric cases at the time of diabetes diagnosis, when the existing “MODY calculator” cannot be used. Firth logistic regression models were developed on data from 3541 paediatric patients from the Swedish ‘Better Diabetes Diagnosis’ (BDD) population study (n = 46 (1.3%) MODY (HNF1A, HNF4A, GCK)). Model performance was compared to using islet autoantibody testing. HbA1c, parent with diabetes, and absence of polyuria were significant independent predictors of MODY. The model showed excellent discrimination (c-statistic = 0.963) and calibrated well (Brier score = 0.01). MODY probability > 1.3% (ie. above background prevalence) had similar performance to being negative for all 3 antibodies (positive predictive value (PPV) = 10% v 11% respectively i.e. ~ 1 in 10 positive test rate). Probability > 1.3% and negative for 3 islet autoantibodies narrowed down to 4% of the cohort, and detected 96% of MODY cases (PPV = 31%). This MODY calculator for paediatric patients at time of diabetes diagnosis will help target genetic testing to those most likely to benefit, to get the right diagnosis.

Double whammy: Coexistence of Mature onset diabetes of the young and autoimmune diabetes: A case report

Maturity-Onset Diabetes of the Young (MODY)encompasses genetic disorders caused by mutations in single genes associated with beta cell dysfunction, constituting 1-6% of all diabetes cases. Mutations in ATP binding cassette transporter subfamily C member 8 (ABCC8) causes MODY 12 which accounts for 1% among MODY cases. It can present in childhood, adolescence or adulthood. Despite growing awareness, accurate MODY diagnosis remains challenging, often leading to misclassification as type 1 or type 2 diabetes. Correct identification is crucial for tailored treatment and implications for family members. The coexistence of MODY and autoimmune related diabetes is a very rare phenomenon with only a handful of cases reported. We describe a unique case where the index patient was initially diagnosed with type 1 diabetes at age 8 due to antibody positivity, leading to insulin treatment. After 15 years, he presented with evidence of all microvascular complications. Interestingly, his brother also developed diabetes at age of 14 years but with out antibody positivity. Due to a strong family history, both siblings underwent genetic testing, revealing a heterozygous mutation in the ABCC8 gene (C.4799630 G>A; P-Arg 1600His).

SAT092 A Case Of Mature Onset Diabetes Of The Young

Abstract Disclosure: L. Beshay: None. A. Thakkar: None. Background: Maturity onset diabetes of the young (MODY) is a disorder characterized by noninsulin-dependent diabetes diagnosed at a young age (<25 years) with autosomal dominant inheritance and lack of autoantibodies. It accounts for 2 to 5 percent of diabetes cases. Several different genetic abnormalities have been identified causing disruption in pancreatic beta cells development and function leading to impaired insulin secretion. Mutations in hepatocyte nuclear factor-1-alpha (HNF1A) is the most commonly identified mutation occurring in 52 to 65 of MODY cases. Case Description: A 21 year old female with a history of diabetes and recurrent skin abscesses presented to the emergency room with right lower quadrant epidermal abscess. Endocrinology was consulted for evaluation of her diabetes. She was diagnosed at age 14 when she presented with weight loss, polyuria, polydipsia, BG 406 without diabetic ketoacidosis. She reported a history of type 2 diabetes in mother. Her medications included metformin, lantus and humalog. It was noted that her diabetes was never controlled with an A1c persistently >10%. Patient reported skin swelling with insulin injections and working two jobs which limited her ability to take more than one injection per day. Her BMI is 23 kg/m2. Labs this admission showed HbA1c 13.7%, GAD 65 Ab and IA-2 Ab negative, c-peptide 1.1 ng/ml, with a glucose of 209 mg/dl. MODY was suspected due to her age, intact c-peptide, and lack of DM1 antibodies. The patient was discharged on Trulicity 0.75 mg weekly, Lantus 12U nightly, Glipizide 2.5mg daily. On follow up, a MODY genetic panel confirmed a HNF1A missense variant with AD inheritance. Since initiation of sulfonylurea, she has had improved control of diabetes. Glipizide dose is being titrated up with concomitant decrease in insulin dose with plan to discontinue basal insulin once her blood sugars are at goal. Conclusion: The HNF1A gene on chromosome 12 is a weak transactivator of the insulin gene in beta cells. Mutations of HNF1A can lead to abnormal insulin secretion and a low renal threshold for glucose. These patients are at risk for micro- and macrovascular complications of diabetes. In terms of treatment, they exhibit increased insulin sensitivity and marked sensitivity to the hypoglycemic effects of sulfonylureas compared with patients with type 2 diabetes. Thus, patients can be successfully treated with sulfonylurea monotherapy, and in one clinical study, approximately 70 percent of patients previously treated with insulin successfully switched to sulfonylureas. Thus, it is important to evaluate etiology of diabetes, as detection of MODY variants in which sulfonylureas are used for treatment simplifies management and improves outcomes as demonstrated in this case. Presentation: Saturday, June 17, 2023

SAT078 A Case Of MODY Due To A Rare Activating Variant In The ABCC8 Gene

Abstract Disclosure: J. Milosavljevic: None. J.M. Greally: None. S. Milman: None. Background: ATP-binding cassette transporter subfamily C member 8 (ABCC8) gene encodes the sulfonylurea receptor 1 (SUR1) regulatory subunit of the beta cell ATP-sensitive K+ channel (KATP). Activating mutations in the ABCC8 cause both neonatal and maturity-onset diabetes of the young (MODY). The majority of patients (85%) with diabetes due to ABCC8 gene mutations could be successfully treated with oral sulfonylureas. A substitution c.2473C>T in the ABCC8 gene results in R825W change in the nucleotide-binding domain 1 of SUR1 and in activation of the KATP channel. We report a case of MODY with an activating mutation of ABCC8 gene (R825W). Clinical Case: A 23-year old woman with a history of ventricular septal defect was diagnosed with diabetes mellitus after she presented with a 2-month history of polyuria and polydipsia. At the time of diagnosis, random serum glucose level was 242 mg/dL, Hemoglobin A1c 7.6%, and BMI was 18 kg/m2. There was absence of acanthosis nigricans on exam or a family history of diabetes, although paternal medical history was unknown. A history of low birth weight was reported, but no developmental delays, neonatal diabetes or history of hypoglycemia. A history of seizure during childhood was also noted but was not associated with hypoglycemia. Additional work-up revealed absence of glutamic acid decarboxylase, islet cell, and insulin autoantibodies. C-peptide level was 2.0 ng/mL with blood glucose 113 mg/dL. The patient did not experience microvascular complications of diabetes. Genetic testing was negative for known mutations in HNF1A, HNF1B, HNF4A, GCK, and PPX1 genes. The patient was initially treated with metformin, but never achieved adequate glycemic control and experienced side effects. She was subsequently treated with sitagliptin and ertugliflozin, however, glycemic control remained inadequate (HbA1C 8.1%). At the age of 33 she was referred for clinical exome sequencing. This detected heterozygous ABCC8 variant c.2473 C>T; p.(R825W). Glucose control improved once therapy was switched to glipizide, resulting in the most recent HbA1C of 6.0%. Conclusion: Activating mutations of ABCC8 gene are infrequent genetic causes of diabetes in adults. Sequencing of the ABCC8 gene should be considered in select adult patients, as diagnosis can guide management decisions. Presentation: Saturday, June 17, 2023

An Italian MODY family with proband and son carrying variants in GCK and HFN1A: is it a true case of digenic MODY?

Maturity Onset Diabetes of the Young (MODY) is a monogenic autosomal dominant disorder affecting 1-5 % of all patients with diabetes mellitus. In Caucasians, GCK and HNF1A mutations are the most common cause of MODY. Here, we report two family members carrying a genetic variant of both GCK and HNF1A gene and their nine year clinical follow-up. Our report urges physicians to be cautious when variants in two genes are found in a single patient and suggests that collaboration with MODY genetics experts is necessary for correct diagnosis and treatment.

A Novel Variant in the PAX4 Gene Causes Maturity-Onset Diabetes of the Young (MODY), Type IX with Neurodevelopmental Disorder

A genetically diverse condition, maturity-onset diabetes of the young (MODY), frequently develops before the age of 25. MODY is caused by disease-causing sequence variations in the PAX4 gene, which is found on chromosome 7q32.1. Additionally, it has also been observed that variants in PAX4 have also been associated with neurodevelopmental disability. Whole exome sequencing (WES) followed by Sanger sequencing was performed for all the available affected and unaffected members of the family. Data analysis revealed a novel heterozygous nonsense variant (c.61C>T; p.Gln21*) in the PAX4 gene in the affected individuals, which segregated perfectly with the disease phenotype. The present study adds to the PAX4 mutation spectrum and reports on the first case of MODY associated with neurodevelopmental disorders in humans.

Precision diabetes: Lessons learned from maturity-onset diabetes of the young (MODY).

Maturity‐onset of diabetes of the young (MODY) are monogenic forms of diabetes characterized by early onset diabetes with autosomal dominant inheritance. Since its first description about six decades ago, there have been significant advancements in our understanding of MODY from clinical presentations to molecular diagnostics and therapeutic responses. The prevalence of MODY is estimated as at least 1.1–6.5% of the pediatric diabetes population with a high degree of geographic variability that might arise from several factors in the criteria used to ascertain cases. GCK‐MODY, HNF1A‐MODY, and HNF4A‐MODY account for >90% of MODY cases. While some MODY forms do not require treatment (i.e., GCK‐MODY), some others are highly responsive to oral agents (i.e., HNF1A‐MODY). The risk of micro‐ and macro‐vascular complications of diabetes also differ significantly between MODY forms. Despite its high clinical impact, 50–90% of MODY cases are estimated to be misdiagnosed as type 1 or type 2 diabetes. Although there are many clinical features suggestive of MODY diagnosis, there is no single clinical criterion. An online MODY Risk Calculator can be a useful tool for clinicians in the decision‐making process for MODY genetic testing in some situations. Molecular genetic tests with a commercial gene panel should be performed in cases with a suspicion of MODY. Unresolved atypical cases can be further studied by exome or genome sequencing in a clinical or research setting, as available.

IDF21-0348 Incidence and risk of diabetic retinopathy in Emirati patients with maturity onset diabetes of the young (MODY)

Background: Diabetic retinopathy (DR) is a potentially sight-threatening complication of diabetes mellitus. The incidence and associated risk factors of DR has been studied in primary forms of diabetes but little is known with regards to maturity onset diabetes of the young (MODY), particularly in Middle Eastern populations Aim: We aimed to study the incidence of DR in Emirati patients with MODY and to identify clinical and biochemical risk factors associated with its occurrence. Method: Patients with diabetes mellitus underwent digital retinal photography at Imperial College London Diabetes Centre, United Arab Emirates (UAE). Retinal photographs were graded according to the NHS Diabetic Eye Screening Programme for severity of DR and presence or absence of maculopathy. Forty-eight patients highly suspected to have MODY were tested for mutations in all known monogenic diabetes genes using targeted next generation sequencing. Clinical and biochemical parameters were reviewed. Results: Pathogenic MODY mutations were identified in a total of 30 cases, with HNF1A, GCK, HNF4A, HNF1B, and CEL in 50%, 26.7%, 16.7%, 3.3% and 3.3%, respectively. Retinal disease of any grade was found in 26.7% (n=8) of individuals with a genetic diagnosis of MODY, with 75% (n=6) of HNF1A-MODY patients having background (n=4), proliferative (n=1), or stable-proliferative DR (n=1), and 25% (n=2) of HNF4A-MODY patients having background (n=1) or stable-proliferative (n=1) retinopathy. Maculopathy occurred in half (50%) of the HNF1A-MODY cases and all (100%) with HNF4A-MODY. Overall, the incidence rate of any degree of DR in patients with MODY was 880 (270-1490) cases per 10,000 person-years. Significant differences were found in univariate analysis in mean duration of diabetes (14.2±5.3 vs 5.4±6.3years, p=0.002), HbA1c (9.5±1.8% vs 7.1±1.3%, p=<0.001), total cholesterol (TC) (5.3±1.7 vs 4.1±1.0mmol/L, p=0.030), and triglycerides (1.8±1.1 vs 1.0±0.6mmol/L, p=0.018) between individuals with any degree of retinopathy and those without retinal disease. Treatment modality was significantly different in cases with and without any retinopathy (p=0.001), with 50% vs 9.1% receiving insulin. No significant difference in age at onset of diabetes (p=0.640), LDL (p=0.225), albumin-creatinine ratio (p=0.208) were observed. Mean age at examination, blood pressure (BP), estimated glomerular filtration rate, and BMI in individuals with or without retinopathy were 32.2±9.9 vs 19.9±10.9years, 114.5±9.8/69.4±7.4 vs 112.9±12.1/67.1±10.5mmHg, 122±31.6 vs 120.3±25mL/min/1.73m2, 24.1±2.4 vs 22.5±5.3kg/m2, respectively. In multivariate Cox regression incorporating TC:HDL ratio, systolic BP and HbA1c, increased TC:HDL was independently associated with significantly increased hazard of any degree of retinopathy (HR 3.96 (1.08-14.5)). Discussion: The incidence rate of any degree of retinopathy in Emirati patients with primarily HNF1A and HNF4A MODY appears increased in comparison to recently published incidence rates for Type 2 Diabetes (200 to 300 per 10,000 person-years) and comparable with rates reported in Type 1 Diabetes (500 to 660 cases per 10,000 person-years). The high incidence of retinal disease in HNF1A MODY highlights the importance of retinal screening from the time of diagnosis, along with early identification of potential MODY cases in order to optimise blood glucose quickly and effectively.

Clinical and genetic features of maturity-onset diabetes of the young in pediatric patients: a 12-year monocentric experience

BackgroundA retrospective observational study was conducted to assess the prevalence of maturity onset diabetes of the young (MODY) in a large paediatric population of Southern Italy newly diagnosed with diabetes. Clinical and genetic features of the identified MODY patients were also described.MethodsGenetic testing was performed in children and adolescents newly diagnosed with diabetes who presented autoantibody negativity and fasting C-peptide levels ≥ 0.8 ng/mL. Patients with a low insulin daily dose and optimal glycaemic control after two years from diabetes onset were also investigated for monogenic diabetes, regardless of their autoimmunity status and/or C-peptide levels.ResultsA prevalence of 6.5% of MODY was found. In particular, glucokinase-MODY was the most common type of MODY. The mean age at diagnosis was 9.1 years. Clinical presentation and biochemical data were heterogeneous also among patients belonging to the same MODY group.ConclusionsWe found a relatively high prevalence of MODY among paediatric patients with a new diagnosis of diabetes in comparison to literature data. Our findings highlight that a more detailed clinical evaluation along with easier and less expensive approachability to genetic testing may allow diagnosing an increasing number of MODY cases. A correct, prompt diagnosis is crucial to choose the most appropriate treatment and offer adequate genetic counselling.

Maturity Onset Diabetes of the Young Masquerading as New Onset Diabetes Mellitus Type 1

Introduction:/background: Maturity-onset diabetes of the young (MODY) is a heterogeneous group of monogenic disorders with autosomal dominant mode of inheritance. Mutation in hepatocyte nuclear factor-1β (HNF-1β) gene results in an error of embryonic development of pancreas and nephron, leading to MODY type 5. MODY 5 accounts for 1% of maturity-onset diabetes of the young. It has peak incidence in adolescence/early adulthood, and is associated with renal pathology. Clinical Case: A 15-year boy with history of hypertension and Hashimoto thyroiditis with normal thyroid function was referred for Hb A1C of 6.7% (< 6.4%). Physical exam was remarkable for normal weight at 64%, normal BMI at 83%, absence of thyromegaly or acanthosis nigricans. Diabetes was confirmed by 2 hour Oral Glucose Tolerance Test study (baseline glucose 154 mg/dL (<126 mg/dL), 2 hour glucose 384 mg/dL (<140 mg/dL)). Small doses of insulin (total daily dose 0.1 units/kg/day) resulted in good glucose control. Further labs were significant for weakly positive TTG and GAD antibodies (tTG Ab IgA 55.5 U/mL (<4.0 U/mL), GAD-65 Ab 0.05 nmol/L (< 0.02 nmol/L)), positive TPO (0.0 - 34.9 IU/mL) and detectable ATA antibodies 45.8 IU/mL (0.0 - 40.0 IU/mL), C-peptide 2.9 ng/mL (0.9–7.1 ng/mL). Islet cell, Insulin and Zinc transporter 8 antibodies were negative. Over the next few months he was weaned off insulin and subsequently he had a high insulin of 29.43 uU/mL (3.0 - 17.0 uU/mL) with glucose level of 169 mg/dL. Renal US was performed as part of the work up for hypertension and revealed a small right calculus with no hydronephrosis and a small 8-mm cortical cyst in the right kidney. Urinalysis showed microalbuminuria. Upper GI endoscopy and colonoscopy with biopsy ruled out celiac disease. Presumptive diagnosis of MODY was entertained despite positive TPO, ATA, TTG and GAD antibodies suggesting autoimmune endocrinopathies. His Hb A1C levels were in the range of 5.7 to 6 % during the 15 months of follow up. Genetic testing for MODY resulted in heterozygous deletion of exons 1–9 of the HNF1B gene consistent with MODY5. Conclusion: This is a case of MODY 5 with weakly positive GAD 65 antibodies that was initially misdiagnosed as type 1 diabetes. The presence of weakly positive antibodies should not preclude a work up for MODY in a patient who does not have the clinical features of classic type 1 DM.

Prenatal diagnosis of HNF1b mutation allows recognition of neonatal dysglycemia

Maturity onset diabetes of the young (MODY) is the most common form of monogenic diabetes in Europe, affecting between 1 and 6% of diabetic patients. It comprises a group of heterogeneous genetic disorders characterized by early onset of diabetes (commonly before age 25), absence of autoimmunity, and beta-cell dysfunction. So far, mutations in 14 different genes involved in glucose homeostasis and pancreatic development [1] have been associated with this disease. Although it is an autosomal dominant disorder, de novo mutations should be taken into consideration in patients without a family history of diabetes. Most cases of MODY are due to mutations in GCK, HNF1a, HNF4a and HNF1b, previously known as MODY2, MODY3, MODY1, and MODY5, respectively. Among these, HNF1b is an active transcription factor that forms homodimers or heterodimers with HNF1a and plays a fundamental role in kidney development, nephron differentiation, and pancreatic growth and differentiation. Mutations in this gene lead to congenital anomalies of the kidney and urinary tract, genital malformations, pancreatic atrophy with endocrine and exocrine deficiency [2]. Diabetes usually onsets in early adulthood and frequently requires insulin treatment. We present an unusual case of a prenatal diagnosis that revealed a mutation in the HNF1b gene responsible for neonatal hyperglycemia in a pregnant woman affected by X-linked ectodermal dysplasia.

A new screening strategy and whole-exome sequencing for the early diagnosis of maturity-onset diabetes of the young.

This study aimed to establish a systematic screening strategy to select candidates for genetic testing among patients with maturity-onset diabetes of the young (MODY) and to accomplish early diagnosis of MODY. We enrolled 1478 sporadic patients from the outpatient department of endocrinology. Out of the1478 patients, 1279 participants were successfully screened according to the "AACM" strategy, which includes the age of onset, autoantibody to islet antigen, C-peptide and metabolic syndrome. Another six probands and their families who fulfilled the common clinical criteria for MODY were also examined for causative gene mutations. Whole-exome sequencing (WES) was performed to examine the mutations. A total of 24 out of 1279 sporadic patients with newly diagnosed diabetes were eligible for genetic testing. Mutations were found in 4/24 participants in the cohort, as well as in 2/6 pedigrees. A likely pathogenic alteration, a likely benign alteration and three alterations with uncertain significance were identified with WES. Most of the mutant genes recognised in our trial were not the most common causative genes of MODY, and all of the mutations were specifically reported in Asian patients only, suggesting a unique genetic background of MODY in different ethnicities. In this systematic study of MODY in a new-onset diabetes cohort, MODY cases were incorrectly diagnosed as type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM), suggesting that an observant clinician is necessary for early and correct MODY diagnosis. This systematic approach to screening is practical and specific enough to identify patients who are most appropriate for genetic testing.

Treatment Options for MODY Patients: A Systematic Review of Literature.

Maturity-onset diabetes of the young (MODY) is an unusual form of diabetes with specific features that distinguish it from type 1 and type 2 diabetes. There are 14 known subtypes of MODY, and mutations in three genes (HNF1A, HNF4A, GCK) account for about 95% of all MODY cases. Diagnosis usually occurs before the age of 25 years, although less frequent forms may occur more often—but not necessarily—later in life. The molecular diagnosis may tailor the choice of the most appropriate treatment, with the aim to optimize blood glucose control, reduce the risk of hypoglycemic events and long-term complications, and enable proper genetic counseling. Treatment is usually unnecessary for patients with mutations in the GCK gene, while oral hypoglycemic agents (generally sulphonylureas) are recommended for patients with mutations in the HNF4A and HNF1A genes. More recent data show that other glucose-lowering agents can be effective in the latter patients, and additional and alternative therapies have been proposed. Proper management guidelines during pregnancy have been developed for carriers of GCK gene mutations, but such guidelines are still a subject of debate in other cases, although some recommendations are available. The other subtypes of MODY are even more rare, and very little data are available in the literature. In this review we summarize the most pertinent findings and recommendations on the treatment of patients with the different subtypes of MODY. Our aim is to provide the reader with an easy-to-read update that can be used to drive the clinician’s therapeutical approach to these patients after the molecular diagnosis.

1551-P: Optimizing MODY Detection in a Pediatric Diabetes Population

Maturity-onset diabetes of the young (MODY) is under-diagnosed or misdiagnosed as type 1 diabetes (T1D) or type 2 diabetes (T2D), in part due to lack of systematic genetic testing. We aimed to define patient characteristics that could guide the decision to conduct genetic testing for MODY diagnosis in racially/ethnically diverse youth with diabetes. In our electronic health record-based Diabetes Registry, we found 4,752 cases carrying a diagnosis of T1D (78.3%), T2D (20.4%) or MODY (1.3%) seen within the past 3 years. We then screened the Diabetes Registry in an agnostic manner for likely MODY cases (“Study Cohort”) based on: (1) diagnosis of diabetes at age &amp;lt;25 y, (2) family history of diabetes in 3-consecutive generations, (3) absent islet autoantibodies (Ab) except GAD65 Ab. We collected data on their clinical and biochemical characteristics, and results of MODY testing if available. In the Study Cohort (n=350, 7.4% of the Diabetes Registry), 62.3% were female; 57% Hispanic, 13.8% non-Hispanic white, 26.4% non-Hispanic black and 2.9% other. 4.6% had previously received a diagnosis of MODY, 16.6% T1D and 78.8% T2D. Frequency of MODY diagnosis was 3.5 times higher in the Study Cohort than in the Diabetes Registry (p&amp;lt;0.001). At diabetes diagnosis, mean age was 13 y (± 3.2) and HbA1c 9.8% (± 2.6). To further refine characteristics of potential MODY, we performed cluster analysis on the Study Cohort using variables commonly used to establish diabetes type at diagnosis: age, BMI-z score, glucose, C-peptide, HbA1c and islet Ab. The cluster with the highest rate of prior MODY diagnosis (25%) had the lowest age at onset (10.9 ± 2.5 y), BMI-z (0.5 ± 0.9), C-peptide (1.5 ± 1.2 ng/mL) and acanthosis nigricans frequency (12.5%) (all p&amp;lt;0.05). Furthermore, in this cluster, molecular confirmation rate was 75% in those patients who had undergone genetic testing (1/3 of the cluster). The patient characteristics defined by this stepwise approach expands and enhances accurate MODY diagnosis and improves the yield of genetic testing for MODY. Disclosure M. Tosur: None. A.K. Refaey: None. D. Guffey: None. A. Balasubramanyam: None. M.J. Redondo: None. Funding Mike Hogg Fund

1550-P: Whole-Exome Sequencing in Children with Suspected Maturity-Onset Diabetes of the Young (MODY)

The yield of commercial gene panels for MODY has been reported as low as 27% suggesting the role of un-identified gene variants in MODY. We aimed to study novel genetic factors of MODY. We identified 10 probands who had clinical characteristics suggestive of MODY (i.e., positive family history of diabetes, negative islet autoantibodies, and diagnosis of diabetes at &amp;lt;25 y/o) but negative genetic test results on a commercial MODY gene panel. We performed whole-exome sequencing (WES) in probands and their parents. In each trio, we prioritized rare protein-altering variants (stop-gain, frameshift indels, splicing and missense variants) in 70 neonatal diabetes and MODY candidate genes. Mean age at diabetes diagnosis was 10 (± 3.8) years. Six were females; 4 were non-Hispanic white, 5 Hispanic, and 1 Asian. Previously assigned diabetes types were type 1 diabetes (T1D) (n=7), unknown (n=2) and ketosis-prone diabetes (n=1). We found a likely pathogenic, de novo variant in INS gene (c.94G&amp;gt;A, p.Gly32Ser), confirmed by Sanger sequencing, in a proband who was previously diagnosed with T1D at 3 y/o. This very rare variant, absent in the general population (gnomAD database), has been reported previously in multiple individuals with neonatal diabetes. We also identified a frameshift deletion (c.2650delC, p.Gln884AsnfsTer57) in RFX6 gene in a child with a previous diagnosis of T1D at 12 y/o. The variant was inherited from the mother, who was diagnosed with diabetes of unknown etiology at 25 y/o. Heterozygous protein-truncating variants in RFX6 gene have been recently reported in individuals with MODY. In conclusion, we identified two new MODY cases, with a novel variant not previously associated with MODY in one of them, using WES in children who were initially diagnosed with T1D. Our study demonstrates clinical utility of exome sequencing in atypical cases of diabetes suspected of MODY. Disclosure M. Tosur: None. A. Sabo: None. M.M. Khayat: None. S.N. Jhangiani: None. A.K. Refaey: None. D. Muzny: None. R.A. Gibbs: None. A. Balasubramanyam: None. M.J. Redondo: None. Funding Mike Hogg Fund

1454-P: Identifying Maturity-Onset Diabetes of the Young in Electronic Health Records

Maturity onset diabetes of the young (MODY) is a rare cause of diabetes. Most clinical information required to diagnose MODY is difficult to extract from Electronic Health Records (EHR) due to the lack of specific billing code and diagnoses found only in clinical notes. Natural language processing (NLP) can be used to extract information from clinical text and assign labels. In this study, we designed NLP algorithms to scan clinical notes, characterize structured information, and confirmed classification with chart review to develop a reusable process to identify MODY patients in EHR.A de-identified version of the EHR from a large academic medical center was used. We built NLP algorithms to identify notes that mention MODY or MODY 14 genes. We further characterized the relevant mention with context labels), then reviewed charts to confirm MODY cases. We implemented published electronic phenotype algorithms for type 1 diabetes (T1D) and type 2 diabetes (T2D) to identify alternative diagnoses and characterize overlap. Finally, we extracted structured clinical features related to diabetes including frequency of billing codes, outpatient diabetes prescriptions, and laboratory values (A1C, c-peptide, antibody).The total number of notes identified with NLP was 6240 belonging to 959 unique subjects. The notes including negation, affirmation, possible, and family FH were 799, 3407, 1408, and 372 and subjects were 122, 354, and 181, respectively. The MODY count confirmed with review was 354.In MODY cohort, 66% of MODY subjects had T1D codes, 59% had T2D codes, 45% had both T1D and T2D codes, and 20% had no diabetes codes. The number of subjects identified using published algorithms that overlapped the MODY cohort was 26 subjects for T2D and 6 subjects for T1D. On average, MODY subjects had more T1D codes compared to T2D diabetes (59.8 vs. 35.3). The mean A1C of MODY subjects was 7.7 which was lower than for algorithm defined T1D, 8.2. They received lower insulin treatment compared to non-insulin treatment, on average. Disclosure L. Sulieman: None. A. Ramirez: None.