Genetics Of Monogenic Diabetes Present Clinical Challenges-Books Pdf

Genetics of Monogenic Diabetes Present Clinical Challenges
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141 Page 2 of 11 Curr Diab Rep 2018 18 141, Table 1 Genes implicated in monogenic diabetes MODY and neonatal diabetes. Gene Protein Function Inheritance, Maturity onset diabetes of the young. Common causes of MODY with well established evidence base. HNF1A Hepatocyte nuclear factor 1 Beta cell transcription factor Autosomal dominant. HNF4A Hepatocyte nuclear factor 4 Beta cell transcription factor Autosomal dominant. GCK Glucokinase Glucose sensor first rate limiting Autosomal dominant. enzyme in glycolysis, HNF1B Hepatocyte nuclear factor 1 Beta cell transcription factor Autosomal dominant. ABCC8 Sulphonylurea receptor subunit of cell K ATP Closure of the ATP sensitive Autosomal dominant. channel potassium channel leads to, KCNJ11 Potassium channel subunit of cell K ATP channel beta cell membrane depolarisation Autosomal dominant. calcium influx and fusion of, insulin secretory granules with.
beta cell membrane, INS Insulin Production of insulin or Autosomal dominant. insulin action, Rare causes of MODY with reasonable evidence supporting. NEUROD1 Neurogenic differentiation factor 1 Beta cell transcription factor Autosomal dominant. IPF1 Insulin promotor factor 1 Beta cell transcription factor Recessive. CEL Carboxyl ester lipase Exocrine pancreas function Deletion of variable number. tandem repeat, WSF1 Wolframin Function of the endoplasmic Recessive. RFX6 Regulatory factor X 6 Beta cell transcription factor Dominant protein. truncating variant, APPL1 Adaptor protein phosphotyrosine interaction Protein that bind to AKT in the Autosomal dominant. PH domain and leucine zipper containing 1 insulin signalling pathway. Neonatal diabetes, Causes of neonatal diabetes accounting for 2 5 of cases.
ABCC8 Sulphonylurea receptor subunit of cell Closure of the ATP sensitive Dominant often de novo. K ATP channel potassium channel leads to or recessive. KCNJ11 Potassium channel subunit of cell K ATP channel beta cell membrane depolarisation Dominant often de novo. calcium influx and fusion of insulin, secretory granules with. beta cell membrane, GCK Glucokinase Glucose sensor first rate limiting Autosomal recessive. enzyme in glycolysis, GATA6 GATA binding factor 6 Transcription factor Dominant often de novo. INS Insulin Production of insulin or insulin action Dominant often de novo or. PTF1A Pancreatic associate transcription factor 1 A Transcription factor involved in Recessive. pancreatic development, EIF2AK3 Eukaryotic translation initiation factor Kinase enzyme in endoplasmic Recessive. 2 alpha kinase 3 reticulum, RFX6 Regulatory factor X 6 Beta cell transcription factor Recessive.
Some of the information in Table 1 came from https www diabetesgenes org tests for diabetes subtypes targeted next generation sequencing analysis. of 45 monogenic diabetes genes 5, Though the clinical benefits of a diagnosis are increasingly to obscure detection Closely related to this is the need to. clear significant challenges still remain The first of these is to improve accessibility of sequencing technologies and devel. improve the identification of misdiagnosed cases as evidence oping a standardised approach to select or stratify appropriate. suggests many are still misclassified 9 In particular a shift individuals for genetic testing with consensus criteria that. in focus towards the identification of MODY across all ethnic have transethnic applicability Perhaps most importantly. groups is warranted as in certain ethnicities the overlapping though is the need to ensure quality interpretation of genetic. features of young onset type 2 diabetes and MODY are likely sequencing data that is clinically translatable and meaningful. Curr Diab Rep 2018 18 141 Page 3 of 11 141, along with the need for consistency in classifying a gene as information to predict the probability of testing positive for. potentially causing monogenic diabetes MODY When compared to traditional criteria the prediction. In this review we outline advances in the field of mono model improved the sensitivity and specificity for identifying. genic diabetes and discuss the remaining clinical challenges MODY However the model was developed and validated in. the same cohort of white individuals of European descent. There is a need for validation in other cohorts and some early. Identifying Cases of Monogenic Diabetes studies in east Asians have shown good sensitivity but re. duced specificity 16, The biggest barrier to making a diagnosis of monogenic dia. betes is lack of clinical suspicion or awareness A UK study in Biomarker Approach. 2012 demonstrated a marked geographical variation in referral. to a centralised genetic testing laboratory 9 Raising aware With non specific clinical criteria attention has turned to the. ness of genetic forms of diabetes and recognising atypical use of biomarkers that assist the selection of individuals for. features in people diagnosed with type 1 or type 2 diabetes genetic testing C peptide pancreatic auto antibodies lipid. is therefore key Though the cost of genetic testing continues profiles and high sensitivity C reactive protein CRP have. to fall it is still relatively expensive and testing is recommend variable discriminatory value but also have several limitations. ed in those individuals with a moderate to high possibility of a 17 22 Pancreatic autoantibodies are positive close to diag. positive finding Worldwide access to quality genetic testing nosis in 80 of people with type 1 diabetes if glutamic acid. services remains problematic decarboxylase GAD and insulinoma antigen 2 IA2 anti. bodies are measured 19 although titres may decrease with. Clinical Approach duration of diabetes and a negative result does not therefore. exclude type 1 diabetes People from some ethnic groups with. The original clinical criteria to define MODY included an age type 1 diabetes have been shown not to have detectable auto. of onset below 25 years not requiring insulin treatment and antibodies at diagnosis and so again the absence of pancreatic. having a generational family history of diabetes 10 Since auto antibody positivity does not preclude a diagnosis of type. this first description however the criteria have proven to be 1 diabetes. insensitive in many confirmed cases 2 as well as increas C peptide levels a marker of endogenous insulin produc. ingly non specific This is unsurprising with the rising preva tion have also been used to help segregate people with type 1. lence of young onset type 2 diabetes that is at diagnosis non diabetes where C peptide is low or undetectable from those. insulin requiring like MODY and typically occurs in the set with MODY However this is not useful at diagnosis of dia. ting of a strong family history Indeed in some cases of adult betes where C peptide may be detectable in early type 1 dia. onset type 1 diabetes the slow progression to beta cell failure betes and even in long duration type 1 diabetes approximately. may not require insulin treatment immediately 11 thus the 8 of people have stimulated C peptide levels well above. lack of a need for insulin is not particularly discriminatory for thresholds considered typical for type 1 diabetes 23. monogenic diabetes Additionally a family history of diabetes Similarly individuals with severe hyperglycaemia due to ei. is often encountered in many people with any type of diabetes ther monogenic or type 2 diabetes may have undetectable C. again due to the rising prevalence of type 2 diabetes In addi peptide levels due to transient beta cell glucotoxicity. tion it is recognised that 20 of children with confirmed Practically a combination of clinical and biomarker ap. type 1 diabetes have an affected first degree relative after de proaches is likely to yield the highest sensitivity In the US. cades of follow up 12 Age at onset below 25 years is also an SEARCH study youths diagnosed with diabetes below the. arbitrary cut off and although commoner in younger adults age of 30 years were selected for genetic testing if pancreatic. confirmed MODY mutations can present into the 5th decade auto antibody testing was negative and fasting C peptide. of life 13 0 8 ng ml and yielded a detection rate of 8 in those tested. In ethnic groups with a higher prevalence of young onset In the Young Diabetes in Oxford study a pick up rate for. type 2 diabetes the discriminatory value of these criteria are MODY of 15 was observed in those with type 2 diabetes. even poorer Indeed in one study of UK south Asian individ diagnosed before 45 years without features of insulin resis. uals referred for genetic testing although the south Asian re tance or 10 of those with type 1 diabetes from individuals. ferrals were more likely to meet the clinical referral criteria selected on the basis of antibody negativity and preserved C. than white individuals the detection rate of MODY in those peptide 24 The UK UNITED study demonstrated a MODY. genetically tested was less than half of the white group 14 prevalence of 3 6 using a biomarker approach in those di. The MODY probability calculator offers a more agnosed 30 years with diabetes a detectable urine C peptide. standardised approach to select individuals for genetic testing and negative antibodies In this study the MODY probability. 15 The online calculator combines broad clinical calculator also missed 55 of cases identified using the. 141 Page 4 of 11 Curr Diab Rep 2018 18 141, biomarker approach 25 Recently the Norwegian childhood including south Asian and African Caribbean though the de. diabetes registry was used to estimate MODY prevalence in tection rate was lower in these groups compared to white. all the antibody negative children in the registry which has a 14 Interestingly south Asian people referred for testing. high case ascertainment A total of 4 1 of individuals had were more likely to meet clinical referral criteria. likely pathogenic or pathogenic variants in the commonest The SEARCH study identified MODY mutations in. MODY genes HNF1A HNF4A HNF1B GCK or INS 3 African American and Pacific Islander youths 34 HNF1A. The biomarker approach is likely to result in more individuals HNF4A and GCK mutations had been detected in various. being selected for testing However since the cases identified reported studies from India although the assessment of what. in those tested appear to be less likely to meet clinical criteria constitutes a pathogenic mutation versus a benign nucleotide. or are missed by the MODY probability calculator testing change remains challenging 35 38 Monogenic diabetes has. more individuals may be warranted 2 also been detected in many east Asian populations including. China 39 and Japan 40, Genetic Risk Scores Lessons can be learnt from a study of comprehensive test.
ing for neonatal diabetes in 79 countries which demonstrated. When antibodies are negative and C peptide levels are pre variability in mutation frequency and inheritance patterns de. served the clinical picture could be consistent with type 1 pending on the population studied 1 For example recessive. type 2 or monogenic diabetes In these cases assessing prob E1F2AK3 mutations were most common in countries with. ability of type 1 or type 2 diabetes on the basis of polygenic higher prevalence of consanguineous unions 1 whereas mu. risk so called genetic risk scores may have some additional tations in KCNJ11 and ABCC8 predominate elsewhere A. discriminatory value A genetic risk score for type 1 diabetes recent study in Oman demonstrates a higher frequency of. that incorporates key human leukocyte antigen HLA suscep recessive GCK mutations 41. tibility loci 26 has been shown to facilitate discrimination of It is likely that the lower reported number of cases of. type 1 from monogenic diabetes 27 and type 2 diabetes 28 MODY in non white ethnic groups reflects a more challeng. However as with other approaches this was validated in ing clinical separation from those with young onset type 2. white European populations and evidence suggests ethnic diabetes For example type 2 diabetes in south Asians is as. specific variations will be required 29 sociated with a leaner body mass index BMI and stronger. family history 42 and proportions of antibody positive indi. In practice misclassification of all diabetes types may oc viduals in non white ethnicities with type 1 diabetes appear to. cur and healthcare practitioners need be alert to this possibility be lower in native countries 43 although systematic assess. 30 31 The application of a systematic approach to individ ment is lacking. uals who are newly diagnosed particularly young adults and In preliminary data from the MY DIABETES study the. in those from non white ethnic groups could assist classifica biomarker approach found similar detection rates of MODY. tion of common forms of diabetes and identify those in whom across UK south Asian African Caribbean and white ethnic. molecular investigation would be beneficial Using bio groups 44 As the number of cases of young onset type 2. markers in this strategy is worthwhile as long as the limita diabetes continues to rise and because obesity can co present. tions of these specialist tests are appreciated with any form of diabetes including MODY clinicians may. have to expect to test more individuals to identify hidden cases. of MODY especially in ethnic groups with a high prevalence. Identifying Monogenic Diabetes Across Ethnic of younger onset type 2 diabetes. To date monogenic diabetes has predominantly been studied Testing Individual Genes Versus a Panel

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