Genomic Diagnosis and Individualized Therapy of Monogenic Diabetes

The most common and well-known causes of diabetes are type 1 and type 2 diabetes; however, there are many other etiologies of diabetes. At least 1-2% of diabetes cases result from high penetrance single gene defects, most commonly in a gene encoding either a transcription factor involved in beta cell development and function or the enzyme glucokinase (GCK). Others have mutations in transcription factors necessary for beta cell development and function. This subset of monogenic diabetes cases is autosomal dominant and is known as "Maturity-Onset Diabetes of the Young" (MODY). Patients with type 1 diabetes are insulin dependent, meaning they lack insulin production and therefore require multiple daily injections of insulin, as well as multiple times a day blood glucose monitoring. This can be quite burdensome. Type 2 diabetes is predominantly an insulin resistance problem and can often be managed with pills initially, but there are many who also require insulin either at diagnosis or later on in their disease course. Usually, monogenic diabetes is misdiagnosed as type 1 or type 2 diabetes and thus treated suboptimally. Those with monogenic diabetes, due to a defect in a gene encoding a transcription factor, respond extremely well to a class of oral diabetes medications called sulfonylureas. Those with GCK-MODY often have a mild, stable, fasting, nonprogressive hyperglycemia for which pharmacological treatment is often not necessary. It is important to accurately diagnose our patients with the correct etiology to their diabetes for a multitude of reasons. Accurately diagnosing a patient with MODY, for example, can predict their clinical course and we can tailor treatment accordingly. If diagnosed with a transcription factor MODY, we can try switching the patient from insulin to an oral sulfonylurea, and if diagnosed with a GCK-MODY, we can consider discontinuing pharmacological treatment altogether. With specific tailoring of treatment, we would hope to improve quality of life by discontinuing perhaps multiple daily injections of insulin and glucose checking as these may not be necessary. In addition, we would hope to improve glycemic control with an eventual decreased cost to society by decreasing the complication rate of diabetes, resulting in less specialty referrals, lab tests, supplies and procedures. Further, given MODY is an autosomal dominant condition with a 50% chance of inheritance to first-degree family members, we could offer testing to asymptomatic family members which could lead to prevention and/or early diagnosis and treatment. Overall, testing for monogenic diabetes is underutilized clinically. Testing is being done in the U.K., but in the U.S. we are lagging behind. This is most predominantly due to lack of knowledge and concern over cost. In addition, it is difficult to differentiate the relatively small number of monogenic diabetes cases from the larger number with type 1 and type 2 diabetes as each of these etiologies have overlapping characteristics. In fact, many patients with monogenic diabetes are being misdiagnosed with type 1 and type 2 diabetes. There are recommendations set forth by different societies on who to consider screening for monogenic diabetes. However, these recommendations are difficult to employ clinically as they are general recommendations, there is no specific algorithm, and they are based on varying levels of evidence. The purpose of this study is to implement a personalized diabetes medicine program to enhance the identification of individuals and families affected by highly penetrant diabetes gene mutations through a combination of systematic screening and genetic testing at the University of Maryland Center for Diabetes and Endocrinology, the Baltimore VA Medical Center and additional partner centers at Geisinger Health System and Bay West Endocrinology Associates, and other UM outpatient clinics. Our hope is to develop an approach that can be eventually implemented across the United States so that we can more often uncover the correct etiology to diabetes, tailor treatment accordingly, and test asymptomatic family members.]]> RESEARCH ASSENT FORMRESEARCH CONSENT FORMClinical Selection Criteria Monogenic DiabetesCriteria for Genetic TestingIntake Questionnaire Version 2Intake Questionnaire Version 3Intake Questionnaire Version 4Intake Questionnaire Version 5Intake Questionnaire Version 6PDMP HEALTH HISTORY QUESTIONNAIREStudy ProtocolOriginal criteria - Inclusion criteria - has at least one of the following characteristics suggesting high likelihood of monogenic diabetes: Diagnosed with diabetes < 1 year of age, or Diagnosed with type 1 diabetes and has a parent with type 1 diabetes, or Diagnosed with type 2 diabetes at < 30 years old and not obese at diagnosis, or Diagnosed with type 2 diabetes at < 45 years old and not obese at diagnosis and two or more relatives with diabetes diagnosed < 50 years old Presence in patient of diabetes plus extrapancreatic features fulfilling diagnostic criteria for a genetic diabetes syndrome (e.g. urological abnormalities, optic atrophy, deafness), or High suspicion of highly penetrant genetic form of diabetes Exclusion criteria: Non-English speaking Subject or Legally Authorized Representative unable to provide informed consent. Revised criteria, started 3/13/17 - Inclusion criteria - meets at least one of the following criteria: Diagnosed with diabetes mellitus (any type), or History of persistent mild hyperglycemia, or Fasting glucose greater than or equal to 100 mg/dl during a current or past pregnancy without pre-existing diabetes together with a pre-pregnancy BMI < 25, or Clinical suspicion of highly penetrant genetic form of diabetes based on clinician referral or review of available lab results. Exclusion criteria: Subject or Legally Authorized Representative unable to provide informed consent. Subject recruited from the VAMHCS less than 18 years of age. ]]> The study was designed to implement, evaluate, and disseminate a process for identifying, genomically diagnosing, and promoting individualized therapy for individuals with highly penetrant/monogenic forms of diabetes. As such, we originally restricted recruitment into the study to individuals suspicious for having monogenic diabetes based on features identified from a screening questionnaire or clinical suspicion of monogenic diabetes by a provider or patient. The screening questions were based on evidence-based published criteria identifying individuals likely to have monogenic diabetes (e.g., non-type 1 diabetes by age 30). We were aware that some cases are not picked up by screening criteria, and further evidence of this emerged from both the literature and our evaluation of individuals referred for clinical suspicion. Furthermore, universal testing of diabetic individuals for monogenic diabetes may become feasible in the future. Thus, we modified the study design in 2017 to enable anyone with diabetes to enroll in the study to evaluate this approach. We maintained the ability to evaluate the efficacy of our screening approach by classifying patients entering the study as meeting criteria vs. not meeting criteria for suspicion of monogenic diabetes.]]>糖尿病最常见且广为人知的致病类型为1型与2型糖尿病，但糖尿病的病因实则存在诸多其他类型。至少1%~2%的糖尿病病例由高外显率单基因缺陷所致，其中最常见的突变基因分别为参与β细胞发育与功能调控的转录因子编码基因，以及葡萄糖激酶（glucokinase, GCK）编码基因。另有部分病例的突变位点位于调控β细胞发育与功能的转录因子编码基因上。这类单基因糖尿病病例呈常染色体显性遗传，被称为青少年起病的成人型糖尿病（Maturity-Onset Diabetes of the Young, MODY）。 1型糖尿病患者需依赖胰岛素治疗：由于自身无法合成胰岛素，他们需要每日多次注射胰岛素，且每日需多次监测血糖，这会给患者带来沉重的生活负担。2型糖尿病的核心病理机制为胰岛素抵抗，初期通常可通过口服药物控制病情，但仍有不少患者在确诊时或病程后期需要接受胰岛素治疗。 临床中，单基因糖尿病常被误诊为1型或2型糖尿病，因此治疗方案并不优化。因转录因子编码基因缺陷导致的单基因糖尿病患者，对磺脲类（sulfonylureas）口服降糖药有着极佳的治疗响应。而葡萄糖激酶型青少年起病的成人型糖尿病（GCK-MODY）患者通常表现为轻度、稳定的空腹高血糖，且病情无进展，一般无需药物治疗。 精准明确糖尿病患者的病因分型具有多重重要意义。以MODY患者为例，精准确诊可预判其临床病程，从而实现个体化治疗。若确诊为转录因子缺陷型MODY，可将患者的胰岛素治疗调整为磺脲类口服药物；若为GCK-MODY，则可考虑完全停用药物治疗。通过个体化精准治疗，可停用每日多次的胰岛素注射与血糖监测（此类操作往往并非必需），从而提升患者的生活质量。此外，优化治疗可改善患者的血糖控制，降低糖尿病并发症发生率，减少专科转诊、实验室检测、耗材使用与侵入性操作，最终降低社会医疗成本。此外，由于MODY呈常染色体显性遗传，一级亲属的遗传概率高达50%，因此可为无症状的家族成员提供基因检测，以实现疾病的早预防、早诊断与早治疗。 总体而言，单基因糖尿病的基因检测在临床中并未得到充分应用。英国已开展此类检测，但美国的临床应用仍相对滞后。这一现状主要源于临床认知不足以及对检测成本的顾虑。此外，由于单基因糖尿病与1型、2型糖尿病的临床特征存在诸多重叠，难以从大量的1型/2型糖尿病患者中甄别出相对少见的单基因糖尿病病例。事实上，不少单基因糖尿病患者均被误诊为1型或2型糖尿病。 不同医学学会已发布针对单基因糖尿病筛查人群的推荐标准，但此类推荐因仅为通用指南、缺乏标准化的筛查流程，且证据等级参差不齐，故而难以在临床中落地实施。 本研究旨在推行一项糖尿病个体化诊疗项目，通过联合系统筛查与基因检测，提升对携带高外显率糖尿病致病基因突变的个体及家族的识别能力。项目实施地点包括马里兰大学糖尿病与内分泌中心、巴尔的摩退伍军人医疗中心，以及合作机构盖辛格健康系统（Geisinger Health System）、西湾内分泌医师协会（Bay West Endocrinology Associates）与马里兰大学（UM）其他门诊诊所。本研究期望开发一套可在全美范围内推广的筛查方案，以更精准地明确糖尿病的病因分型、实施个体化治疗，并为无症状家族成员提供基因检测。 ### 研究知情同意书 #### 单基因糖尿病临床筛选标准与基因检测指征 入组问卷版本2至版本6、PDMP健康史问卷 #### 研究方案 ##### 原始入排标准（2017年3月13日前） - **纳入标准**：满足以下任意一项提示单基因糖尿病高风险的特征： 1. 发病年龄<1岁即确诊糖尿病； 2. 确诊为1型糖尿病，且父母一方亦为1型糖尿病患者； 3. 30岁前确诊2型糖尿病，且确诊时无肥胖； 4. 45岁前确诊2型糖尿病，确诊时无肥胖，且至少2名亲属在50岁前确诊糖尿病； 5. 患者同时罹患糖尿病与胰腺外特征，符合遗传性糖尿病综合征的诊断标准（如泌尿系统异常、视神经萎缩、耳聋等）； 6. 临床高度怀疑为高外显率遗传性糖尿病。 - **排除标准**：受试者或其法定代理人无法提供知情同意，且受试者母语非英语。 ##### 修订后入排标准（2017年3月13日起实施） - **纳入标准**：满足以下任意一项： 1. 确诊任何类型的糖尿病； 2. 存在持续性轻度高血糖病史； 3. 妊娠期间（无论当前或既往）空腹血糖≥100mg/dl，且孕前无糖尿病史、孕前BMI<25； 4. 经临床医师转诊或结合现有实验室检查结果，临床高度怀疑为高外显率遗传性糖尿病。 - **排除标准**： 1. 受试者或其法定代理人无法提供知情同意； 2. 从退伍军人医疗保健系统（VAMHCS）招募的受试者年龄<18岁。 本研究旨在建立、评估并推广一套针对高外显率/单基因糖尿病患者的识别、基因组诊断及个体化治疗流程。研究初期，仅纳入通过筛查问卷提示单基因糖尿病疑似病例，或由临床医师、患者自身怀疑为单基因糖尿病的受试者。本研究的筛查问题基于已发表的循证标准，用于甄别疑似单基因糖尿病的个体（例如30岁前确诊非1型糖尿病）。研究团队意识到部分单基因糖尿病病例无法被现有筛查标准识别，这一结论已得到文献及临床疑似病例评估结果的佐证。此外，未来对所有糖尿病患者开展单基因糖尿病通用检测或将成为可能。因此，研究团队于2017年修订了研究方案，允许所有糖尿病患者入组，以评估该筛查策略的有效性。同时，本研究仍保留了通过将入组受试者分为“符合单基因糖尿病疑似标准”与“不符合”两类，以评估初始筛查方案效能的研究设计。