Monogenic diabetes in a Chinese population with young-onset diabetes: A 17-year prospective follow-up study in Hong Kong.

AIMS: Asians have a high prevalence of young-onset diabetes, but the pattern of monogenic diabetes is unknown. We aimed to determine the prevalence of monogenic diabetes in Chinese patients with young-onset diabetes and compare the clinical characteristics and outcome between patients with and without monogenic diabetes. MATERIALS AND METHODS: We sequenced a targeted panel of 33 genes related to monogenic diabetes in 1021 Chinese patients with non-type 1 diabetes diagnosed at age ≤40 years. Incident complications including cardiovascular disease (CVD), end-stage kidney disease (ESKD) and all-cause death were captured since enrolment (1995-2012) until 2019. RESULTS: In this cohort (mean ± SD age at diagnosis: 33.0 ± 6.0 years, median[IQR] diabetes duration 7.0[1.0-15.0] years at baseline, 44.9% men), 22(2.2%, 95% confidence interval[CI] 1.4%-3.2%) had monogenic diabetes. Pathogenic (P) or likely pathogenic (LP) variants were detected in GCK (n = 6), HNF1A (n = 9), HNF4A (n = 1), PLIN1 (n = 1) and PPARG (n = 2), together with copy number variations in HNF1B (n = 3). Over a median follow-up of 17.1 years, 5(22.7%) patients with monogenic diabetes (incidence rate 12.3[95% CI 5.1-29.4] per 1000 person-years) versus 254(25.4%) without monogenic diabetes (incidence rate 16.7[95% CI 14.8-18.9] per 1000 person-years) developed the composite outcome of CVD, ESKD and/or death (p = 0.490). The multivariable Cox model did not show any difference in hazards for composite events between groups. CONCLUSIONS: In Chinese with young-onset non-type 1 diabetes, at least 2% of cases were contributed by monogenic diabetes, over 80% of which were accounted for by P/LP variants in common MODY genes. The incidence of diabetes complications was similar between patients with and without monogenic diabetes.

Diabetic Nephropathy, Retinopathy, and Functional Hypogonadism in a Patient with MODY10: A Case Report.

(1) Background and objectives: Maturity-onset diabetes of the young (MODY) is a group of diabetes caused by gene defects related to insulin secretion. MODY1, MODY2, and MODY3 are the most common and account for approximately 80% of all cases. Other types are relatively rare. This study describes the clinical, analytical, and genetic characteristics of a patient with MODY10, and diabetic nephropathy, retinopathy, and functional hypogonadism diagnosis. (2) Materials and methods: A clinical case was analyzed and whole exome generation sequencing (WES) was used to detect mutations related to a monogenic variant. (3) Results: A seventeen-year-old male patient, who was diagnosed with apparent type 1 diabetes at the age of eight was started with insulin therapy. He came to the emergency room with glycemic decompensation, facial, and lower limb edema. During his evaluation, he had near-nephrotic range proteinuria of 2902 mg/24 h, a kidney ultrasound showing mild pyelocalyceal dilation, proliferative diabetic retinopathy, and was also diagnosed with functional hypogonadotropic hypogonadism. These comorbidities improved with adequate glycemic control. WES showed missense variant c.94G>A (p.Gly32Ser) in the INS gene, according to Clinvar corresponding to MODY10. It was a "de novo" variant not reported in his parents. (4) Conclusions: Monogenic diabetes (MD) is rare and MODY10 is among the less frequent types. MODY should be suspected in patients with type 1 phenotype with negative autoimmunity even in the absence of a family history of diabetes. To the best of our knowledge, we present here the first patient with these phenotypic traits of MODY10 reported in Latin America.

A multigenerational study on phenotypic consequences of the most common causal variant of HNF1A-MODY.

AIMS/HYPOTHESIS: Systematic studies on the phenotypic consequences of variants causal of HNF1A-MODY are rare. Our aim was to assess the phenotype of carriers of a single HNF1A variant and genetic and clinical factors affecting the clinical spectrum. METHODS: We conducted a family-based multigenerational study by comparing heterozygous carriers of the HNF1A p.(Gly292fs) variant with the non-carrier relatives irrespective of diabetes status. During more than two decades, 145 carriers and 131 non-carriers from 12 families participated in the study, and 208 underwent an OGTT at least once. We assessed the polygenic risk score for type 2 diabetes, age at onset of diabetes and measures of body composition, as well as plasma glucose, serum insulin, proinsulin, C-peptide, glucagon and NEFA response during the OGTT. RESULTS: Half of the carriers remained free of diabetes at 23 years, one-third at 33 years and 13% even at 50 years. The median age at diagnosis was 21 years (IQR 17-35). We could not identify clinical factors affecting the age at conversion; sex, BMI, insulin sensitivity or parental carrier status had no significant effect. However, for 1 SD unit increase of a polygenic risk score for type 2 diabetes, the predicted age at diagnosis decreased by 3.2 years. During the OGTT, the carriers had higher levels of plasma glucose and lower levels of serum insulin and C-peptide than the non-carriers. The carriers were also leaner than the non-carriers (by 5.0 kg, p=0.012, and by 2.1 kg/m2 units of BMI, p=2.2 × 10-4, using the first adult measurements) and, possibly as a result of insulin deficiency, demonstrated higher lipolytic activity (with medians of NEFA at fasting 621 vs 441 µmol/l, p=0.0039; at 120 min during an OGTT 117 vs 64 µmol/l, p=3.1 × 10-5). CONCLUSIONS/INTERPRETATION: The most common causal variant of HNF1A-MODY, p.(Gly292fs), presents not only with hyperglycaemia and insulin deficiency, but also with increased lipolysis and markedly lower adult BMI. Serum insulin was more discriminative than C-peptide between carriers and non-carriers. A considerable proportion of carriers develop diabetes after young adulthood. Even among individuals with a monogenic form of diabetes, polygenic risk of diabetes modifies the age at onset of diabetes.

Insights into the etiology and physiopathology of MODY5/HNF1B pancreatic phenotype with a mouse model of the human disease.

Maturity-onset diabetes of the young type 5 (MODY5) is due to heterozygous mutations or deletion of HNF1B. No mouse models are currently available to recapitulate the human MODY5 disease. Here, we investigate the pancreatic phenotype of a unique MODY5 mouse model generated by heterozygous insertion of a human HNF1B splicing mutation at the intron-2 splice donor site in the mouse genome. This Hnf1bsp2/+ model generated with targeted mutation of Hnf1b mimicking the c.544+1G>T (T) mutation identified in humans, results in alternative transcripts and a 38% decrease of native Hnf1b transcript levels. As a clinical feature of MODY5 patients, the hypomorphic mouse model Hnf1bsp2/+ displays glucose intolerance. Whereas Hnf1bsp2/+ isolated islets showed no altered insulin secretion, we found a 65% decrease in pancreatic insulin content associated with a 30% decrease in total large islet volume and a 20% decrease in total ß-cell volume. These defects were associated with a 30% decrease in expression of the pro-endocrine gene Neurog3 that we previously identified as a direct target of Hnf1b, showing a developmental etiology. As another clinical feature of MODY5 patients, the Hnf1bsp2/+ pancreases display exocrine dysfunction with hypoplasia. We observed chronic pancreatitis with loss of acinar cells, acinar-to-ductal metaplasia, and lipomatosis, with upregulation of signaling pathways and impaired acinar cell regeneration. This was associated with ductal cell deficiency characterized by shortened primary cilia. Importantly, the Hnf1bsp2/+ mouse model reproduces the pancreatic features of the human MODY5/HNF1B disease, providing a unique in vivo tool for molecular studies of the endocrine and exocrine defects and to advance basic and translational research. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Low genetic confirmation rate in South Indian subjects with a clinical diagnosis of maturity-onset diabetes of the young (MODY) who underwent targeted next-generation sequencing for 13 genes.

PURPOSE: To screen for maturity-onset diabetes of the young (MODY) variants in subjects with an early age of onset and positive family history of diabetes mellitus. METHODS: 60 subjects with onset of diabetes between 3 and 30 years of age and parental history (onset < 35 years) of diabetes were recruited after excluding autoimmune, pancreatic and syndromic forms of diabetes. Detailed pedigree chart and clinical data were recorded. MODY genetic testing (MODY 1-13) was performed and variant classification was done adhering to the ACMG guidelines. RESULTS: Baseline characteristics of subjects were as follows: mean age of onset of diabetes 19.9 ± 7 years, mean duration of diabetes 6.3 ± 6.8 years, BMI 23.3 ± 3 kg/m2 and C-peptide 1.56 ± 1.06 nmol/l. Four out of sixty (6.6%) were positive for variants classifiable as pathogenic/likely pathogenic: one patient with HNF4Ac.691C > T, (p.Arg231Trp), two with HNF 1A c.746C > A(p.Ser249Ter) and c.1340C > T(p.Pro447Leu), and one with ABCC8 c.4544C > T (p.Thr1515Met). MODY 1 and MODY 3 variants were documented in the paediatric age group (< 18 years). CONCLUSION: A genetic diagnosis of MODY could be confirmed in only 6.6% (4/60) of patients clinically classifiable as MODY. This is less than that reported in clinically diagnosed MODY subjects of European descent. Newly published population data and more stringent criteria for assessment of pathogenicity and younger age of onset of type 2 diabetes in Indians could have contributed to the lower genetic confirmation rate. Apart from variants in the classical genes (HNF1A, HNF4A), a likely pathogenic variant in a non-classical gene (ABCC8) was noted in this study.

Heterozygous recurrent HNF4A variant p.Arg85Trp causes Fanconi renotubular syndrome 4 with maturity onset diabetes of the young, an autosomal dominant phenocopy of Fanconi Bickel syndrome with colobomas.

Heterozygous pathogenic variants in HNF4A cause hyperinsulinism, maturity onset diabetes of the young type 1, and more rarely Fanconi renotubular syndrome. Specifically, the recurrent missense pathogenic variant c.253C>T (p.Arg85Trp) has been associated with a syndromic form of hyperinsulinism with additional features of macrosomia, renal tubular nephropathy, hypophosphatemic rickets, and liver involvement. We present an affected mother, who had been previously diagnosed clinically with the autosomal recessive Fanconi Bickel Syndrome, and her affected son. The son's presentation expands the clinical phenotype to include multiple congenital anomalies, including penile chordee with hypospadias and coloboma. This specific pathogenic variant should be considered in the differential diagnosis of Fanconi Bickel Syndrome when genetics are negative or the family history is suggestive of autosomal dominant inheritance. The inclusion of hyperinsulinism and maturity onset of the diabetes of the young changes the management of this syndrome and the recurrence risk is distinct. Additionally, this family also emphasizes the importance of genetic confirmation of clinical diagnoses, especially in adults who grew up in the premolecular era that are now coming to childbearing age. Finally, the expansion of the phenotype to include multiple congenital anomalies suggests that the full spectrum of HNF4A is likely unknown.

Analysis of the promoter regions of disease-causing genes in maturity-onset diabetes of the young patients.

Maturity-onset diabetes of the young (MODY) is a form of monogenic diabetes caused by the variants in MODY-related genes. In addition to coding variants, variants in the promoter region of MODY-related genes can cause the disease as well. In this study, we screened the promoter regions of the most common MODY-related genes GCK, HNF1A, HNF4A and HNF1B in our cohort of 29 MODY patients. We identified one genetic variant in the HNF1A gene, a 7 bp insertion c.-154-160insTGGGGGT, and three variants in the GCK gene, -282C>T; -194A>G; 402C>G appearing as set. Chloramphenicol acetyltransferase (CAT) assay was performed to test the effect of the 7 bp insertion and the variant set on the activity of the reporter gene in HepG2 and RIN-5F cell, respectively, where a decreasing trend was observed for both variants. In silico analysis and electrophoretic mobility shift assay showed that the 7 bp insertion did not create the binding site for new transcriptional factors, but gave rise to additional binding sites for the existing ones. Results from our study indicated that the 7 bp insertion in the HNF1A gene could be associated with the patient's diabetes. As for the GCK variant set, it is probably not associated with diabetes in patients, but it may modify the fasting glucose level by causing small elevation in variant set carriers. We have presented two promoter variants in MODY-related genes. Variant in the HNF1A gene is presumed to be disease-causing and the GCK promoter variant set could be a phenotype modifier.

Clinical manifestations of a sporadic maturity-onset diabetes of the young (MODY) 5 with a whole deletion of HNF1B based on 17q12 microdeletion.

We report a sporadic case of maturity-onset diabetes of the young type 5 (MODY5) with a whole-gene deletion of the hepatocyte nuclear factor-1beta (HNF1B) gene. A 44-year-old Japanese man who had been diagnosed with early-onset non-autoimmune diabetes mellitus at the age of 23 was examined. He showed multi-systemic symptoms, including a solitary congenital kidney, pancreatic hypoplasia, pancreatic exocrine dysfunction, elevation of the serum levels of liver enzymes, hypomagnesemia, and hyperuricemia. These clinical characteristics, in spite of the absence of a family history of diabetes, prompted us to make the diagnosis of maturity-onset diabetes of the young 5 (MODY 5). One allele deletion of the entire HNF1B gene revealed by multiplex ligation-dependent probe amplification (MLPA) led us to the diagnoses of 17q12 microdeletion syndrome even though there were negative chromosomal analyses with array comparative genomic hybridization (CGH). 17q12 microdeletion syndrome, which is not rare especially in sporadic cases since 17q12 is a typical hot spot for chromosomal deletion, could have complicated the clinical heterogeneity of MODY5.

Not quite type 1 or type 2, what now? Review of monogenic, mitochondrial, and syndromic diabetes.

Diabetes mellitus is a heterogeneous group of conditions defined by resultant chronic hyperglycemia. Given the increasing prevalence of diabetes mellitus and the increasing understanding of genetic etiologies, we present a broad review of rare genetic forms of diabetes that have differing diagnostic and/or treatment implications from type 1 and type 2 diabetes. Advances in understanding the genotype-phenotype associations in these rare forms of diabetes offer clinically available examples of evolving precision medicine where defining the correct genetic etiology can radically alter treatment approaches. In this review, we focus on forms of monogenic diabetes, mitochondrial diabetes, and syndromic diabetes.

[Molecular genetics of maturity-onset diabetes of the young]. / Molekuliarnaia genetika MODY.

To verify the type of diabetes mellitus (DM) remains an extremely important problem in endocrinology, as along with types 1 and 2 DM there are rarer hereditary types of DM, including maturity-onset diabetes of the young (MODY). The latter is a genetic type of DM, which is characterized by an autosomal dominant inheritance. Eleven types of MODY (MODY 1 to MODY13) are identified; each is associated with mutations in the certain gene: HNF4A, GCK, HNF1A, PDX1, HNF1B, NEUROD1, KLF11, CEL, PAX4, INS, BLK, KCNJ11 and ABCC8. A molecular genetic testing for suspected MODY is conducted to verify the diagnosis and to define a subtype of MODY, patient management tactics, to predict the outcome of the disease and its complications in relation to the found subtype of MODY. It is also important to seek mutation causing MODY in terms of the early detection of MODY in the first-degree relatives of a proband, appropriate therapy of the disease, and prevention of its complications.

Ten years of the national genetic diabetes nurse network: a model for the translation of genetic information into clinical care.

Increasing technological advances have resulted in the recognition of a range of genetic conditions not traditionally seen by clinical genetics teams. This has implications for the education of other healthcare professionals who may have insufficient knowledge to identify or support families with these conditions. The national genetic diabetes nurse (GDN) project, which trains diabetes specialist nurses (DSNs), was started in 2002 to increase awareness of monogenic diabetes among healthcare professionals across the UK. This paper describes the development and evaluation of the first 10 years of this project, indicating that GDNs have increased diagnostic referral rates and supported local families through diagnosis and treatment changes across the UK. The GDN project has proved an effective, innovative means of disseminating new genetic information from a centre of excellence and is suggested as a model for the successful and rapid dissemination of genetic information into routine clinical care in other conditions.

A Japanese school urine screening program led to the diagnosis of KCNJ11-MODY: A case report.

Although KCNJ11 mutation is the main cause of neonatal diabetes mellitus, reports of maturity-onset diabetes in the young (MODY) related to KCNJ11 are rare. Here, we report a case of KCNJ11-MODY in a 12-yr-old Japanese female. Hyperglycemia was initially detected during a school urine screening program. Subsequent laboratory examinations revealed impaired insulin secretion; however, no islet autoantibodies were detected. Genetic testing of KCNJ11 revealed a novel heterozygous variant, c.153G>C, p.Glu51Asp. The patient's father had the same mutation and was diagnosed with diabetes at 46 yr of age. KCNJ11-MODY was suspected, and sulfonylurea administration resulted in adequate glycemic control in the patient. The American College of Medical Genetics and Genomics guidelines classify this variant as likely pathogenic, and the effectiveness of sulfonylureas supports its pathogenicity. The patient could be treated with 0.02-0.03 mg/kg/d of glibenclamide, as this mutation may be responsive to only a small amount of sulfonylurea. A detailed family history and sequencing of causative genes, including KCNJ11, may help diagnose diabetes in school-aged patients.

A novel mutation in the ABCC8 gene causing maturity-onset diabetes of the young: A case report.

A 34-year-old woman was diagnosed with type 1 diabetes mellitus and treated with insulin for 24 years. The patient has a family history of diabetes in three consecutive generations. Her Whole exon sequencing showed a heterozygous mutation in the ABCC8 gene, and it also found some of her relatives to carry this mutation. She was diagnosed with MODY12 and received glimepiride therapy with the achievement of good glycaemic control.

[Striking manifestation and unexpected therapeutic course of diabetes mellitus in a 22-year-old male patient]. / Eindrucksvolle Manifestation und unerwarteter Therapieverlauf eines Diabetes mellitus bei einem 22-jährigen Patienten.

The case of a 22-year-old male patient who presented with acute on chronic hyperglycemia in known MODY ("maturity onset diabetes of the young") 12 (ABCC8 gene) after 11 months of treatment cessation is reported. To emphasize the importance of the awareness of this therapeutically important entity of diabetes, the essential facts of this inherited disease are summarized.

Less common forms of diabetes in young population.

Types diabetes other than type 1 are generally considered rare in children and adolescents. The incidence of type 2 diabetes has increased dramatically over the past decade in some ethnic groups. The increased incidence of this type of diabetes mellitus has corresponded tem-porally to unprecedented increases in body weight and obesity prevalence in adolescents in various ethnic populations. Early treatment of insulin resistance is important to prevent the development of diabetes. In therapy, lifestyle modification is essential for weight loss, and if this is not enough, pharmacotherapy is required. Maturity-onset diabetes of the young (MODY), another type of insulin-dependent diabetes, is characterised by early onset and autosomal dominant inheritance. MODY is mainly caused by ß-cell defects, resulting in insufficient insulin secretion for a given blood glucose level. Unlike non-insulin-dependent diabetes in youth (NIDDM-Y), there is no significant increase in insulin resistance. The purpose of this article is to characterise and present types of diabetes other than type 1 found in the young population.

Japanese 17q12 Deletion Syndrome with Complex Clinical Manifestations.

17q12 deletion syndrome is a rare chromosomal anomaly with variable phenotypes, caused by the heterozygous deletion of chromosome 17q12. We herein report a 35-year-old Japanese patient with chromosomal 17q12 deletion syndrome identified by de novo deletion of the 1.46 Mb segment at the 17q12 band by genetic analyses. He exhibited a wide range of phenotypes, such as maturity-onset diabetes of the young (MODY) type 5, structural or functional abnormalities of the kidney, liver, and pancreas; facial dysmorphic features, electrolyte disorders; keratoconus, and acquired perforating dermatosis. This case report provides valuable resources concerning the clinical spectrum of rare 17q12 deletion syndrome.

Monogenic diabetes: old and new approaches to diagnosis.

Up to 5% of young adults diagnosed with diabetes have a monogenic aetiology, the most common of which is maturity-onset diabetes of the young (MODY). A definitive molecular diagnosis is important, as this affects treatment, prognosis and family screening. Currently, however, rates of diagnosis are low due to a combination of lack of awareness of the benefits of making the diagnosis and the challenges of differentiating patients with MODY from those with common forms of diabetes. This article aims to introduce general physicians to the characteristics of monogenic diabetes and the clinical features that can be used to diagnose patients. Recently, genomewide association studies have resulted in the identification of C-reactive protein and glycan profile as specific biomarkers for the most common MODY subtype due to HNF1A mutations, and the potential translation of these findings are discussed.

ABCC8-related maturity-onset diabetes of the young: switching from insulin to sulphonylurea therapy: how long do we need for a good metabolic control?

OBJECTIVES: Activating variants of the ABCC8 gene cause neonatal diabetes or maturity-onset diabetes of the young (MODY). We report three cases of MODY type 12 caused by variants in the ABCC8 encoding sulphonylurea receptor 1, and the experience of switching from insulin therapy to sulphonylurea therapy. CASE PRESENTATIONS: We describe a 12.5-year-old girl with permanent neonatal diabetes mellitus, and two diabetes mellitus cases with variants in the ABCC8 gene. Two of these cases were successfully switched from subcutaneous insulin to oral glibenclamide, with a marked improvement in glycemic control. In permanent neonatal diabetes case, glibenclamide dose was progressively increased to achieve a full dose (2 mg/kg/day) in 9 days. Nine months after starting oral sulphonylurea therapy, her blood glucose control dramatically improved and insulin therapy was discontinued. CONCLUSIONS: We conclude that patients with ABCC8 gene variants can successfully switch from insulin to sulphonylureas.

Genetic testing for misclassified monogenic diabetes in Maori and Pacific peoples in Aotearoa New Zealand with early-onset type 2 diabetes.

Aims: Monogenic diabetes accounts for 1-2% of diabetes cases yet is often misdiagnosed as type 2 diabetes. The aim of this study was to examine in Maori and Pacific adults clinically diagnosed with type 2 diabetes within 40 years of age, (a) the prevalence of monogenic diabetes in this population (b) the prevalence of beta-cell autoantibodies and (c) the pre-test probability of monogenic diabetes. Methods: Targeted sequencing data of 38 known monogenic diabetes genes was analyzed in 199 Maori and Pacific peoples with BMI of 37.9 ± 8.6 kg/m2 who had been diagnosed with type 2 diabetes between 3 and 40 years of age. A triple-screen combined autoantibody assay was used to test for GAD, IA-2, and ZnT8. MODY probability calculator score was generated in those with sufficient clinical information (55/199). Results: No genetic variants curated as likely pathogenic or pathogenic were found. One individual (1/199) tested positive for GAD/IA-2/ZnT8 antibodies. The pre-test probability of monogenic diabetes was calculated in 55 individuals with 17/55 (31%) scoring above the 20% threshold considered for diagnostic testing referral. Discussion: Our findings suggest that monogenic diabetes is rare in Maori and Pacific people with clinical age, and the MODY probability calculator likely overestimates the likelihood of a monogenic cause for diabetes in this population.