ABSTRACT

Monogenic forms of diabetes are responsible for 1-3% of all young-onset diabetes. The multiple genes involved can cause one or both of the main phenotypes- congenital (neonatal) diabetes or MODY (maturity-onset diabetes of the young). The timely and accurate genetic diagnosis of monogenic diabetes provides an opportunity to target therapy to the underlying gene cause, refine management, and identify affected and at-risk relatives. As there is clinical overlap of monogenic diabetes with type 1 and type 2 diabetes, presenting clinical and laboratory features warrant careful attention to aid in diabetes classification and to identify those individuals who warrant genetic testing. These include those negative for islet cell autoantibodies with persistent c-peptide, suggesting a diagnosis other than type 1 diabetes. While obesity does not preclude monogenic diabetes, certainly individuals lacking obesity and other features of metabolic disease should be referred for diagnostic genetic testing. Understanding who and how to refer for genetic testing and how to interpret test results is key to precision medicine in diabetes. The most common forms of monogenic diabetes have specific therapies and management strategies that can optimize glycemic control and minimize complications resulting in improved health outcomes for affected individuals. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

INTRODUCTION

The most common forms of diabetes- type one (T1DM) and type two (T2DM)- are polygenic disorders. There are many identified genes, wherein certain variants cause a genetic predisposition to the development of diabetes. However, they are insufficient to cause disease without additional contributing environmental factors. In contrast, monogenic forms of diabetes are due to highly penetrant variants in single genes or chromosomal abnormalities that are sufficient by themselves to cause diabetes. Phenotypic overlap between monogenic diabetes and polygenic forms means that clinicians must thoughtfully consider diabetes classification in each patient, at diagnosis and thereafter, and order genetic testing to confirm clinically suspected monogenic diabetes.

This chapter will focus on understanding the following important clinical factors for pediatric and adult patients:

• Why test?
• How to test and interpret results.
• Who to test?
• How to treat and manage specific subtypes of monogenic diabetes.

WHY SHOULD YOU DO GENETIC TESTING FOR MONOGENIC DIABETES?

There are two main clinical phenotypes of monogenic diabetes- neonatal diabetes (also called congenital diabetes) and MODY (Maturity-Onset Diabetes of the Young). Neonatal diabetes has a prevalence of 1:90,000 – 1:250,000 and MODY accounts for 1-3% of diabetes diagnosed under 30 years of age (~0.4% of all diabetes) (1-3). Both of these broad phenotypes include syndromic diabetes and there is overlap of causative genes- with MODY, by definition representing autosomal dominant diabetes and neonatal diabetes being caused by a number of overlapping ‘MODY genes’ as well as having several genetic causes unique to congenital forms. There are over 20 known genetic causes of neonatal diabetes mellitus and 14 genes that have been implicated as causes of MODY (Table 1). While monogenic diabetes is uncommon, accurately diagnosing monogenic diabetes through genetic testing has important clinical and economic considerations for the patient, and often for first-degree relatives as well. For the most common subtypes of monogenic diabetes, gene-directed management improves outcomes, alerts the physician of non-pancreatic features that may accompany diabetes, and identifies affected and at-risk family members who may benefit from diagnostic or predictive genetic testing, respectively.

There have now been several economic evaluations of genetic testing for monogenic diabetes. In children, testing for monogenic diabetes has been found to be cost-saving, a rare feat in medicine (4-6). The addition of cascade testing in MODY- that is testing of first-degree relatives of affected individuals- further enhances this cost-effectiveness (6). In adults, routine screening for monogenic diabetes has not yet proven to be cost-effective, which is due to both the absolute number of affected adults and the high percentage of T2DM, where costs of gene-targeted therapy compared to some T2DM regimens, particularly metformin alone, are not substantially different (7,8). However, results strongly suggest that testing only those patients with a high pre-test probability of monogenic diabetes would be cost-effective (7). Thus, genetic testing for adults should still be carried out when careful consideration of the clinical picture is inconsistent with a diagnosis of T1DM or T2DM and is suggestive of MODY or another form of monogenic diabetes.

HOW SHOULD GENETIC TESTING FOR MONOGENIC DIABETES BE CARRIED OUT?

Medical insurance coverage for genetic testing varies not only by insurance company but also by disease. Thus, a prior authorization should be sought before ordering diabetes genetic testing and patients should be instructed to contact their insurance companies to clearly understand any co-pays for which they will be responsible. Some commercial testing companies offer patient protection programs to limit out-of-pockets expenses but typically patients must enroll in such programs prior to ordering genetic testing.

In the past, genetic testing was accomplished through Sanger sequencing, typically of one gene at a time until a causative mutation was determined or all relevant genes were tested without detected abnormality. This process was labor and time intensive and costly. Now, monogenic diabetes panel are frequently used in place of Sanger sequencing of a single gene (5,9,10). There are a number of CLIA-certified commercial labs offering monogenic diabetes panels, including Ambry, Athena Diagnostics, Blueprint Genetics, Prevention Genetics, Invitae, and GeneDx (this list is non-exhaustive and will change over time). Laboratories at some academic institutions also have the capability to provide CLIA-certified genetic testing for monogenic diabetes. The genes carried on panels vary by laboratory and are often divided into a neonatal diabetes panel and a MODY panel. In general, gene panels will be the appropriate test to order because of the overlapping clinical features between various types of monogenic diabetes, but there are cases where the clinical features clearly fit with a distinct gene. Research-based genetic testing for monogenic diabetes is available through a number of different studies. The methodology does not differ from that used in clinical laboratories, but results are not CLIA certified. While it is at a provider’s discretion to act on research findings based on clinical judgment, CLIA confirmation of the finding is advised. In such cases, clinicians must specify that they are confirming a previous research finding so that labs will only sequence the affected gene and look for the specific variant identified. This testing is also appropriate for cascade genetic testing of first-degree relatives. Confirmation of a known genetic finding is relatively inexpensive and typically approved by insurance (authors’ practice experience).

HOW SHOULD GENETIC TESTING RESULTS BE INTERPRETED?

Content of genetic testing reports can vary widely based on the laboratory (11). There is a growing recognition by experts in monogenic diabetes and laboratories themselves that hard-to-interpret genetic testing reports are a disservice to clinicians and patients. It is likely that in the relatively near future, testing reports will be easier to interpret. Until then, recommendations for interpretation include:

• Look at the classification of any variants found as well as any provided references of the published literature relevant to the genetic finding. Terminology used includes pathogenic, likely pathogenic, variant of uncertain significance (VUS), likely benign, and benign.
• Determine if testing includes gene dosage analysis. Sanger sequencing and some panels will not detect partial or whole gene deletions. However, many laboratories will employ additional methods to detects deletions, such as Multiplex Ligation-dependent Probe Amplification (MLPA) or exon-level array comparative genomic hybridization (CGH). If this has not been included, and genetic testing returns negative in a highly suspicious case, additional testing for copy number variation is warranted.
• It is important to understand that due to the redundancy in our genetic code, many gene variants are tolerated with no effect on gene production, transcription, or expression. Thus, a variant in a known monogenic gene in a patient with suspected monogenic diabetes does not mean that the variant is causing their diabetes (12). Additionally, some genes and some variants reported in the published literature that were once thought to cause monogenic diabetes have subsequently proven to be non- causal or have come into question, but they persist in the literature. ClinGen is a NIH-funded resource that defines the clinical relevance of genes and variants (https://www.clinicalgenome.org). There are gene curation expert panels and variant curation expert panels for monogenic diabetes. Currently the work of the gene curation panel is focused on the 14 genes designated as MODY, a number of which have questionable data to support them as legitimate monogenic diabetes genes (BLK, KLF11, PAX4).
• Seek advice from an expert in monogenic diabetes for any level of uncertainty in interpretation of test results before discussing results with the patient and particularly before making changes to diabetes management (ude.ogacihcu@setebaidcinegonom).

WHO SHOULD YOU TEST FOR MONOGENIC DIABETES?

There are many examples of systemic screening for monogenic diabetes in various populations and the result is always the same: if you conduct genetic testing among those diagnosed as T1DM or T2DM, you will find monogenic diabetes cases (2,13-16). While the clinical overlap between different forms of diabetes can make accurate classification challenging, there are several clinical and laboratory features that should prompt consideration of genetic testing for monogenic diabetes (Table 2) (17,18).

All children with diabetes onset before 6 months of age should receive immediate genetic testing for monogenic diabetes as a genetic cause is very likely. Beyond 6 months, T1DM becomes the predominant diagnosis; however, a percentage of infants will still have a monogenic etiology, and many advocate for genetic testing in all cases diagnosed under 12 months of age (19). Another approach is to test these children for pancreatic autoantibodies, which, if positive, would be consistent with autoimmune type 1 diabetes. Those with negative autoantibodies should undergo testing for monogenic diabetes (18). Importantly, there are monogenic causes of early-onset autoimmune diabetes with additional features that suggest a single gene defect (20). A type 1 diabetes genetic risk score along with age can be helpful in discriminating these monogenic autoimmunity cases from polygenic type 1 diabetes (21). While treatment of monogenic autoimmune diabetes will continue to be replacement doses of insulin, accurate genetic diagnosis will help with prognostication and clinical management decisions.

In older children, cost-effectiveness analyses suggest that a reasonable approach to diabetes classification would be to test for pancreatic autoantibodies and endogenous insulin production (as measured by c-peptide) in all pediatric patients, and to test those with negative antibodies and positive c-peptide for monogenic diabetes (5,6). Using this biomarker approach reveals a monogenic diabetes prevalence of 2.5%-6.5%, including a monogenic diabetes prevalence of 4.5% in overweight and obese children, who would fall under the radar of many clinicians for monogenic diabetes consideration (2,3,22). If there are barriers to universal biomarker testing, age at diagnosis in older children may be helpful in considering monogenic diabetes versus T1DM and T2DM. The predominant diagnosis between 1 year of age and puberty will be T1DM. In the peripubertal period both T2DM and monogenic diabetes become higher considerations and T1DM remains a consideration. Additional clinical features of normal weight, lack of acanthosis nigricans or features of metabolic syndrome can identify patients who should undergo genetic testing. Family history is expected to be positive in both monogenic diabetes and type 2 diabetes so asking specific details for each affected family member, including age at diabetes diagnosis, body habitus at the time of diagnosis, and treatment are necessary to make family history useful.

In adults, the substantial burden of type 2 diabetes precludes universal biomarker screening to identify individuals who may have monogenic diabetes (8). However, the same clinical features of body habitus, features of insulin resistance or metabolic syndrome, paired with personal and detailed family history are useful to screen in people for additional evaluation. Age at diabetes onset is also an important consideration, as MODY onset is rarely beyond 35 years of age. There is a prediction model for MODY, known as the MODY calculator, which is available by website and as an app (https://www.diabetesgenes.org/exeter-diabetes-app/). The calculator was developed in an European white population and so must be used with caution for other groups, but on-going work will help to clarify its use in non-white populations (23) (24).

Importantly, until universal genetic testing is available for diabetes classification, some cases will be missed by applying these ‘clinical filters’ for selecting patients for testing, particularly those who have both monogenic diabetes and obesity. Because of the selection bias that results from excluding obese patients from testing, the impact of obesity on management and outcomes of specific subtypes of monogenic diabetes is not well understood.

HOW SHOULD YOU MANAGE SPECIFIC SUBTYPES OF MONOGENIC DIABETES?

Several of the common forms of monogenic diabetes have specific management as discussed below and in Table 3.

ADDITIONAL BENEFITS OF ACCURATE MONOGENIC DIABETES DIAGNOSIS

There are several monogenic diabetes subtypes where insulin is the best or only treatment available. Additionally, for those subtypes with genetically-targeted therapy discussed above, not all affected individuals will respond or be maintained on these therapies and insulin may be necessary. However, genetic testing for accurate diagnosis is still beneficial for multiple reasons. Establishing a molecular diagnosis can often provide a unifying diagnosis for multiple, seemingly unrelated medical conditions, such as in the case of HNF1B-MODY. It also allows for earlier and proactive medical surveillance of extra-pancreatic manifestations, such as early referral to developmental specialists for children with KATP-related neonatal diabetes and neurodevelopmental challenges. Additionally, at-risk and affected family members can be identified and conception counseling can be provided.

CONCLUSIONS

The substantial worldwide burden of diabetes, in terms of sheer numbers and also cost, make it imperative that outcomes are optimized. Early accurate classification to direct management is a crucial step. Since the conception of the Precision Medicine Initiative in 2015, more attention and excitement has been garnered toward tailoring treatment to the individual characteristics of patients. Monogenic diabetes represents an opportunity to use a precision medicine approach to improve therapy selection and management of diabetes to improve glycemic outcomes for affected individuals, often while lowering burden and cost of care (59). The lessons that we learn from the continued investigation into the single gene causes of diabetes will inform our understanding of polygenic diabetes, including how to best subclassify the heterogeneous presentations of type 2 diabetes to guide first-line therapy selection and add-on therapies, expanding the scope of precision medicine in diabetes.

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