Monogenic Forms of Diabetes

Summary

Monogenic diabetes is a term used to describe a group of single-gene causes of diabetes. Traditional nomenclature has focused on the types of diabetes known as MODY, defined as maturity-onset diabetes of the young; infantile (or perinatal) onset diabetes, including permanent and transient neonatal diabetes mellitus; and syndromic types. These syndromes include genes associated with insulin resistance, such as the insulin receptor itself. A growing field is also focused on single gene variants that are responsible for multi-autoimmune syndromes that include type 1 diabetes. Altogether, monogenic diabetes may account for up to 3% of all diabetes diagnosed before age 35 years, amounting to an estimated 300,000 cases in the United States. However, a systematic study of incidence and prevalence in the United States has not been done.

Introduction

The term “monogenic diabetes” includes “maturity-onset diabetes of the young (MODY),” a term coined by Fajans and Tattersall only a few decades ago to describe a presentation of non-insulin-dependent diabetes that occurs in young people with a strong autosomal dominant inheritance (1,2). The initial case reports and, then, meticulous studies of several families by Fajans and colleagues (1) led to the identification of the first MODY genes by international teams, including those of Bell, Hattersley, Froguel, Njølstad, and others. Fajans suggested identification of these forms could be aided by using simple criteria: appearance of diabetes in adolescents and young adults age <30 years; a strong family history affecting two to three linear generations in an autosomal dominant pattern; usually not obese; and in some cases, high sensitivity to sulfonylureas (2).

To date, over 20 genes have been labeled as “monogenic diabetes genes.” Previously, many of these genes (particularly those linked to MODY) were numbered based on their order of discovery and frequently described using uninformative numbers rather than gene names. As the list of MODY genes grew and the designation of some MODY genes was refuted (3), it became more appropriate to refer to these entities by the gene name, such as GCK-MODY (rather than MODY 2) or HNF1B-MODY (rather than MODY 5), to avoid confusion. Accordingly, these gene names are used throughout the text, but both gene names and the older MODY number designations are utilized in the tables. This approach is particularly important as some of the more recent putative “MODY” genes were given the same numerical designation by different authors, and several “MODY” genes listed in the tables are either not causal for diabetes at all or are very rare. Establishing an accessible nomenclature is an important part of efforts to make recognition and diagnosis of these entities commonplace.

Monogenic diabetes-related genes constitute about 1.2%–2.5% of all new-onset childhood diabetes (4), amounting to an estimated 300,000 cases in the United States (5). The glucokinase gene, GCK, is the most common, followed by HNF1A (at least in several reports). Individuals with monogenic diabetes may come to attention when they have a urinalysis showing glucosuria (see the HNF1A-MODY section) but still have normal blood glucose and glycated hemoglobin (A1c) tests.

This article focuses on common issues in the presentation and treatment of monogenic diabetes and updates Chapter 7: Monogenic Forms of Diabetes, published in Diabetes in America, 3rd edition (6). For forms that appear to be most common, the incidence, prevalence, clinical features, and approaches to treatment are reviewed. Very uncommon monogenic diabetes forms are listed in the tables, and the reader is referred to focused reviews for more information.

Monogenic Diabetes

Epidemiology

Overall, monogenic diabetes accounts for approximately 2%–3% of all patients diagnosed with diabetes before age 35 years, based on data from the University of Exeter group; in the United Kingdom, the minimum prevalence of MODY was estimated to be 108 cases per million (4,7). Monogenic diabetes has been studied in registries across Europe and to a lesser extent in Asian, African, Latino, and Middle Eastern populations, with variations in prevalence and relative prevalence of subtypes (8). In European countries (United Kingdom, Germany, The Netherlands, Norway, Poland), the most common subtype is HNF1A-MODY, followed by GCK-, HNF4A-, and HNF1B-MODY (8,9,10). In 2020, the first MODY cases were reported in patients from Africa, where the predominant subtype, HNF1A-MODY, represented 5.9% of the study population (11).

The Exeter group showed that mutations in recessive genes are major contributors to childhood-onset monogenic diabetes in a population with a high rate of consanguinity (12). In addition to true differences in prevalence, geographic variations in prevalence also likely result from differences in ascertainment (e.g., more GCK-MODY cases where asymptomatic glucose screening is standard of care), genotyping/sequencing methodology, and reduced ability to classify genetic variants in non-White populations due to limited available data (8).

In the U.S. SEARCH for Diabetes in Youth Study (5), of approximately 5,000 newly diagnosed children with diabetes (diagnosed age <20 years), 730 youth (14.5%) were autoantibody-negative and fasting C-peptide-positive (also termed A-B+). Of these children, 586 underwent sequencing of GCK, HNF1A, and HNF4A, and 48 (8.2%) were positive for a likely pathogenic mutation in one of these three genes. Thus, about 1.2% of the original cohort of children had genetically confirmed monogenic diabetes. Non-Hispanic White (35%), African American (24%), Hispanic (26%), and Asian and Pacific Islander (13%) individuals were all found in the monogenic diabetes group. Almost all were previously considered to have type 1 diabetes or type 2 diabetes and treated with insulin or metformin and other oral hypoglycemic medications, respectively.

The U.S. Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) Study enrolled 699 racially and ethnically diverse individuals who were diagnosed with type 2 diabetes, overweight or obese (body mass index [BMI] ≥85th percentile), and A-B+ in a metformin +/- rosiglitazone or lifestyle intervention clinical trial. From this cohort, 488 individuals with available DNA samples underwent targeted sequencing for 40 genes implicated in monogenic diabetes or related disorders (13). Of these individuals, 22 (4.5%) were found to have variants classified as pathogenic or likely pathogenic for monogenic diabetes (seven HNF4A, seven GCK, five HNF1A, two insulin gene [INS], and one KLF11) based on the 2015 American College of Medical Genetics and Genomics/Association of Molecular Pathology (ACMG/AMP) guidelines. Only one of these cases was in a gene (KLF11) now refuted as a monogenic diabetes gene by the Clinical Genomic Resource (ClinGen) Monogenic Diabetes Expert Panel Gene Curation Expert Panel (MDEP GCEP), bringing the total to 4.3%. There may have been more individuals with monogenic diabetes in the cohort given that 30 variants of uncertain significance (VUS) were identified in the common and rare MODY genes described in Table 1 (14). These data provided evidence that monogenic diabetes should be considered in the differential diagnosis for diabetes in children and adolescents, regardless of adiposity. Importantly, the adverse impact of a missed monogenic diabetes diagnosis on treatment response was demonstrated in the TODAY study. The seven individuals with HNF4A-MODY were significantly more likely to fail to respond to the insulin-sensitizing treatments used in the study as measured by the primary outcome of reaching an A1c level >8% (>64 mmol/mol) in 6 months or the inability to wean the participant off insulin within 3 months after treatment initiation (hazard ratio [HR] 5.03, 95% confidence interval 2.18–11.58, p=0.0002) (13). This is expected given that HNF4A-MODY represents an insulin secretory rather than sensitivity defect. Conversely, none of the seven individuals with GCK-MODY failed treatment (HR undefined due to no events), which is expected given that A1c in individuals with GCK-MODY is rarely, if ever, >7.6% (>60 mmol/mol) regardless of treatment (15).

TABLE 1.

Classification of Maturity-Onset Diabetes of the Young, U.S., 2022

A larger, overlapping sample comprising 492 SEARCH participants with clinician diagnosed-diabetes before age 20 years, a slightly larger sample from TODAY (n=511), and a cross-sectional sample of 2,330 additional U.S. pediatric type 2 diabetes cases (diagnosed before age 18 years with BMI ≥85th percentile) underwent exome sequencing as part of the Progress in Diabetes Genetics in Youth (ProDiGY) collaboration and were evaluated for variants in the rare and common MODY genes (16). Of the individuals sequenced, 93 (2.8%) had a disease-causing variant (44 in HNF1A, 23 in GCK, 16 in HNF4A, 5 in PDX1, 4 in INS, and 1 in CEL), with 83 (89%) variants having management implications. While metabolic traits differed between those with and without a known variant, no trait or set of traits could be used reliably to make the distinction without testing. These results underscored in a larger sample of overweight or obese individuals with youth-onset diabetes without autoantibodies the considerable likelihood (nearly 3%) of a true diagnosis of monogenic diabetes underlying apparent pediatric type 2 diabetes (16). Moreover, this outcome may be an underestimate given that over 300 VUS were identified. The findings also underscore the importance of utilizing biomarker information (presence of C-peptide and absence of diabetes autoantibodies) to identify individuals who should have genetic testing for monogenic diabetes.

In 2021, the University of Chicago Monogenic Diabetes Registry reported the relative frequency of monogenic diabetes and neonatal diabetes in the registry (14). Among genes that cause a MODY phenotype, GCK mutations were the most common (59%), followed by HNF1A mutations (28%). Mutations in KCNJ11 were the most common cause among genes associated with neonatal diabetes (35%), followed by INS mutations (16%) (14).

Presentation of Monogenic Forms of Diabetes

Monogenic diabetes includes neonatal, childhood, and young adult onset of diabetes (also known as MODY types) with diagnosis typically occurring at age <35 years. The initial clinical diagnosis may be erroneously reported as either type 1 diabetes or type 2 diabetes. Anti-islet antibody tests are almost always negative. In the case of a mildly positive anti-GAD (glutamic acid decarboxylase) test only, one must consider that positive anti-GAD does not always correlate with autoimmune diabetes, as there is a false positive rate in the general population. Anti-islet antibodies can also fade and become undetectable over time. Testing multiple autoantibodies at diabetes presentation, including anti-GAD, anti-IA2 (tyrosine phosphatase-related islet antigen-2), anti-ZnT8 (zinc transporter 8), and anti-insulin, can be helpful, but negative antibodies are not definitive for the absence of autoimmune type 1 diabetes. Other autoimmune diseases in the patient or their close family members may be suggestive of type 1 diabetes. For research evaluation, the type 1 diabetes genetic risk score (T1DGRS) developed by Patel, Oram, and colleagues (17) can be suggestive and has been validated in several populations. Measuring C-peptide is generally not helpful until 3–5 years after diagnosis. Detectable levels of C-peptide can persist for many years after the diagnosis of type 1 diabetes, but by 3–5 years after diagnosis, stimulated or fasting C-peptide levels collected with a simultaneous glucose level are usually reduced in those with type 1 diabetes (18). Interest is growing in evaluating urinary C-peptide levels (also developed by the Exeter group), since this assay can give a time-averaged estimate of beta cell function and can be more stable than a blood draw (19). This test is not yet generally available in the United States on a clinical basis.

Figure 1 provides an algorithm for the diagnosis of monogenic diabetes (9). A search for possible syndromic features is extremely helpful when considering monogenic diabetes testing. These features are variable in their presentation and might include developmental delay, deafness, ocular muscle defects, retinal changes, liver adenomas, renal or other organ cysts, genitourinary abnormalities, alkalosis, and hypomagnesemia. Birthweight (high or low) and any episodes of neonatal hypoglycemia are also important to review. A detailed family history can help with a diagnosis. Important findings include any first-degree relative with diabetes of any kind, as monogenic diabetes family members are also likely to be assigned an incorrect diabetes type. A family history of syndromic features or autoimmune conditions may be helpful.

FIGURE 1.

Algorithm for the Diagnosis of Monogenic Diabetes. Diagnosis of monogenic diabetes is a stepwise process (clinical assessment, diabetes-specific test, and genetic testing). Commercial panels for monogenic diabetes typically include the following genes (more...)

While most monogenic diabetes syndromes are dominantly inherited, recessive and maternal inheritance forms are known. Pedigrees with GCK-, HNF1A-, HNF4A-, or HNF1B-MODY may show three or more generations with dominantly inherited diabetes, with extended family members also possibly affected (Figure 2). Once a variant causing monogenic diabetes is confirmed, a referral should be made for genetic counseling to further discuss the findings with the patient and their family and to provide them with the necessary information to share with additional family members about the potential benefits of testing (Figure 3). Most variants are dominant, so there is a 50% chance that each child of an affected individual will have the same form of diabetes.

FIGURE 2.

HNF1A Pedigree Shows Diabetes in Multiple Generations (Autosomal Dominant). A 58-year-old female was initially found to be hyperglycemic at age 19 years with fasting blood glucose of 130 mg/dL. BMI was 19 kg/m². Blood glucose was retested at age 23 years (more...)

FIGURE 3.

Cascade Testing for Monogenic Diabetes. In any autosomal dominant disease, the diagnosis in a proband should prompt the identification of affected members. In the case of MODY, any family member should be clinically assessed to decide whether testing (more...)

Common Forms of Monogenic Diabetes

GCK-MODY

GCK was the first actual MODY gene to be identified, although it was previously referred to as MODY 2 because it was the second gene to be localized to a chromosomal region through family-based linkage studies (20,21). GCK-MODY results from decreased beta cell sensing of glucose due to loss-of-function mutations in the GCK gene on chromosome 7p15-p13, encoding the enzyme glucokinase. The estimated prevalence rate of GCK-MODY is 0.2% in the general population and 1.3% in patients with diabetes (22). These patients have stable fasting hyperglycemia (99–144 mg/dL [5.49–7.99 mmol/L]) present at birth. Hyperglycemia may be discovered as an incidental finding in a child or adult during a routine blood chemistry check performed for an unrelated illness or pregnancy screening; islet cell antibodies are negative and glucose tolerance testing shows mild hyperglycemia, rarely exceeding 200 mg/dL (11.10 mmol/L) at 2 hours with delayed return to modestly elevated basal glucose concentrations in the range of 90–130 mg/dL (5.00–7.22 mmol/L) (Figure 4). GCK-MODY patients have a uniform phenotype despite considerable functional differences in mutation severity, possibly due to compensation by overexpression of the normal allele (23,24).

FIGURE 4.

Insulin Treatment is Not Required for GCK-MODY. Average glucose levels of a patient with insulin (red, filled circles) and without insulin (blue, open triangles) are shown. After 13 years of diabetes treatment, the patient unplugged his insulin pump. (more...)

Insulin levels, if measured, are appropriate but occur at higher-than-normal glucose concentrations. A1c values are generally in the 5.6%–7.6% (38–60 mmol/mol) range (24,25). In the absence of a family history, such patients may be considered to have type 1 diabetes early in their clinical course and may be inappropriately treated with insulin. Alternatively, they may be considered to have type 2 diabetes and be treated with oral hypoglycemic agents or insulin sensitizers. Patients with GCK-MODY lack a glycemic response to oral hypoglycemic agents or low-dose insulin. Beta cell function shows minimal deterioration with increasing age, consistent with the general population. Microvascular complications occur very infrequently. Nonproliferative retinopathy is the only complication that has been reported in GCK-MODY, and its occurrence is only slightly increased when compared to healthy controls (26).

All pharmacological treatments used for GCK-MODY are minimally effective due to decreased glucokinase activity in the beta cells, liver, and brain, which also affects counterregulation. One study showed a significant drop in fasting plasma glucose after one tablet of dapagliflozin; additional studies are needed to evaluate this effect (27). Long-term clinical studies of patients with GCK-MODY treated with sodium-glucose cotransporter 2 (SGLT2) inhibitors are required to further assess this treatment due to reported risk of euglycemic diabetic ketoacidosis (DKA) (26,27). However, published data support the idea that treatment with SGLT2 inhibitors is unnecessary, based on the lack of long-term complications. In any case, precisely due to the lack of long-term complications in most people with GCK mutations, specific glucose-lowering treatment is not needed and may be harmful. Diabetes practitioners in many cases remain skeptical of this recommendation based on reasonably large-scale studies. It may be that since most people with GCK mutations are not obese and have normal lipid levels and normal blood pressure, the usual combination of features in type 2 diabetes that lead to complications is not present. If a patient’s A1c level is high, the diagnosis should be reconsidered, or the presence of additional factors, including obesity, steroid use, and even type 1 diabetes, should be considered. Rare cases have been described of patients with GCK-MODY who have developed co-occurring autoimmune (antibody-positive) type 1 diabetes; hence, an evaluation for other diabetes types, including type 1 diabetes, is recommended if glycemic levels deteriorate beyond the typical range for GCK-MODY. In these rare cases, insulin treatment would be required.

Pregnancy is an exception when treatment may be recommended for individuals with GCK mutations causing hyperglycemia based on known or suspected fetal genotype. If the fetus inherits the GCK mutation, the fetus will have the same elevated glucose set point as their mother and will regulate their blood glucose levels to that higher set point; thus, treatment of the mother is not recommended. If the fetus does not inherit the GCK mutation, the fetus will be exposed to maternal hyperglycemia in utero. In this situation, insulin treatment is recommended, aimed at lowering maternal blood glucose levels to normal pregnancy levels and avoiding possible complications. Supraphysiological insulin doses (>1 unit/kg/day) are usually required to overcome maternal counterregulatory mechanisms and can result in severe hypoglycemia in pregnant women (28). For further information on fetal testing and management of GCK-MODY during pregnancy, the reader is encouraged to refer to more detailed discussions (25,29).

HNF1A-MODY

HNF1A-MODY is due to heterozygous dominant variants in the gene encoding the transcription factor hepatocyte nuclear factor 1-alpha (HNF1α), which is expressed primarily in liver, pancreatic beta cells, and kidney cells and can be detected in many other cell types. HNF1A was the third gene chromosomally localized by linkage mapping in MODY families, hence the historical designation of HNF1A-MODY as MODY 3 (30,31). HNF1A gene expression is partially regulated by HNF4A, providing a link between these two forms of monogenic diabetes. HNF1A and HNF1B are homeobox transcription factors that function as dimers, interacting with DNA at specific target sequences and with other specific proteins. Point mutations are predominantly located in the DNA-binding domain but can occur anywhere, along with insertions and deletions. Diabetes primarily results from haploinsufficiency, meaning the functional absence of one allele is the key. The correct temporal and cell/organ-specific expression of the genes is critical for proper developmental formation of specific organs, including the islets/beta cells, and later for the maintenance of the mature cells where the factor is expressed. No specific genotype-phenotype correlation with respect to the presentation of diabetes has been found, although a relationship between the type and position of the variant with age of diagnosis has been observed (32). Birth weight is normal in patients with heterozygous HNF1A variants. Diabetes usually appears towards the end of the first decade into the third decade of life.

Presentations of HNF1A-MODY can be extremely mild with minimal symptoms, and the diagnosis may be made serendipitously, following a urinalysis for a sports physical, for example. Others present with overt diabetes and possible ketosis, although DKA is rare, which can lead to temporary or intermittent treatment with insulin. Most patients with HNF1A-MODY are initially quite responsive to sulfonylureas, even to the point of hypoglycemia with low doses. Any patient who has severe hypoglycemia in response to the usual starting doses of a sulfonylurea should be carefully considered for a HNF1A variant. Some patients with HNF1A-MODY may have progressive failure of sulfonylurea therapy, requiring insulin for treatment; excessive weight gain seems to be a risk factor for sulfonylurea failure (24). However, newer agents, including glucagon-like peptide-1 receptor agonist (GLP-1 RA) and dipeptidyl peptidase 4 (DPP4) inhibitors, combined with sulfonylureas may prove useful for good glycemic control in the absence of exogenous insulin. Variability in the age of onset of HNF1A-MODY can occur even within the same pedigree (Figure 2). The degree of sulfonylurea responsiveness can also vary. These features do not seem to be related to the specific variant (33).

Another feature of HNF1A-MODY that may occur is liver adenomas that might be large but benign, although bleeding has been reported. Subtle changes in lipid levels may occur that should lead to early consideration of lipid-lowering treatment, particularly given increased risk for adverse cardiovascular outcomes in people with HNF1A-MODY compared to their unaffected relatives. Interestingly, the kidney protein SGLT2, which is responsible for re-uptake of filtered glucose in the renal tubule, is regulated by HNF1A. In the case of HNF1A-MODY, reduction in the HNF1α protein leads to a decrease in the expression of SGLT2. This, in turn, can result in appearance of glucosuria despite normal blood glucose levels, the equivalent of reducing the renal tubular maximum for glucose from 220 mg/dL (12.21 mmol/L). This observation explains the diagnosis of HNF1A-MODY in young people with glucosuria, but normal blood glucose and A1c levels, and has resulted in the misdiagnosis of type 1 diabetes or type 2 diabetes in these individuals. Interestingly, expression of C-reactive protein (CRP), which is produced in the liver, may be partially driven by HNF1A, so that patients with HNF1A variants also have low high-sensitivity CRP (hsCRP) levels compared to all other forms of diabetes, including other forms of monogenic diabetes; however, this finding has not been confirmed in all studies (34).

Complications of diabetes due to HNF1A-MODY can be just as severe as in uncontrolled type 2 diabetes, if inadequately treated. While sulfonylurea treatment may be preferable to insulin treatment for some patients, others may not continue to show the same high degree of responsiveness with time. Several anecdotal or small studies have suggested that GLP-1 RAs may be a useful approach, possibly restoring sulfonylurea responsiveness (35). A large systematic study has not yet been reported. Other studies have suggested that SGLT2 inhibitors might be useful. A concern with that approach is that given the decrease in SGLT2 expression already seen in these individuals, further reduction in SGLT2 function may lead to a normalization of blood glucose with insufficient insulin secretion to suppress ketones. This phenomenon of euglycemic DKA has not been reported in patients with HNF1A-MODY but certainly has been seen in individuals with type 1 diabetes and type 2 diabetes with low insulin secretion. Caution in pursing this therapy outside of a clinical trial is recommended, as the lower expression of SGLT2 in these patients may increase their risk for this complication.

Genome-wide association studies have linked variants in HNF1A to the more common forms of type 2 diabetes, suggesting the existence of a spectrum of mutations with variable penetrance. Indeed, the Framingham Heart Study (36) showed that incomplete penetrance of HNF1A-MODY variants does occur. This result further suggests that other genes may be able to modulate or overcome the loss of HNF1A function in some instances.

HNF4A-MODY

HNF4A-MODY occurs due to variants in the gene encoding HNF4α. It was the first gene chromosomally localized in families for MODY (37), hence the historical designation as MODY 1, although it was the third actual gene to be identified as having variants causing MODY (38). HNF4A is expressed in the liver, kidney, intestine, and islets and at lower levels in many cell types. HNF4α is a known key regulator of hepatic gene expression, and HNF4A-MODY, like HNF1A-MODY, is characterized by progressive loss of insulin secretion with increasing age. Likewise, the clinical features of HNF4A-MODY are similar to those of patients with HNF1A-MODY. Clinical onset of symptoms and recognition of hyperglycemia can occur from the early childhood years to the third decade of life. Many affected individuals are sensitive to sulfonylurea drugs, which restore insulin secretion and lower glucose. Other individuals may develop progressive loss of insulin secretion and require insulin for treatment.

Two interesting features of HNF4A-MODY reported in some individuals are that: (1.) affected participants have been found to weigh about 800 grams more at birth than their unaffected siblings and (2.) hyperinsulinemia at birth with symptomatic neonatal hypoglycemia that resolves spontaneously may occur (39). Diazoxide has been used to reduce hypoglycemia in these babies. These findings suggest that at least some HNF4A variants at first cause excessive secretion of insulin, directly or indirectly, and only later result in impaired beta cell function with hypoinsulinemia and diabetes. Whether all babies with macrosomia and neonatal hypoglycemia go on to develop HNF4A-related diabetes is not yet known. These children should be followed with the expectation that diabetes will develop, possibly near the time of puberty.

Patients with HNF4A-MODY have lower levels of lipoprotein A2 and high-density lipoprotein (HDL) cholesterol, features commonly seen in type 2 diabetes (40). Reports of markedly lower concentrations of CRP in patients with HNF1A variants have not been replicated in HNF4A-MODY patients. Hence, hsCRP cannot be considered as a screening test to identify patients suspected of having HNF4A-MODY before embarking on molecular diagnosis (1,2,40,41,42).

HNF1B-MODY

HNF1B-MODY has historically been called MODY 5 because HNF1B was the fifth MODY gene both localized and identified (43,44). Heterozygous single nucleotide variants and large deletions in the HNF1B gene each account for about 50% of a variable, multi-organ phenotype with HNF1B-MODY, either in isolation or with other affected organs (45). Haploinsufficiency is thought to underlie the disease mechanism, and notably, no clear genotype-phenotype distinction between single nucleotide variants and large deletions of the HNF1B gene in regards to diabetes has been identified. HNF1B regulates HNF4A and, hence, may provide a link between the three main transcription factor gene causes of MODY.

Variants in HNF1B most frequently result in abnormally developed kidneys, and a common presentation is the Renal Cysts and Diabetes (RCAD) syndrome (43). Other associated anomalies include morphological and functional anomalies of the exocrine pancreas, with reduced pancreatic size and pancreatic exocrine deficiency. These anomalies may initially be subclinical but can progress with time, making surveillance with fecal elastase testing appropriate. Additionally, reproductive tract abnormalities with fertility implications, abnormal liver tests, hyperuricemia, hypomagnesemia due to renal magnesium wasting, alkalosis, and early appearance of proteinuria that is not due to diabetic renal disease are observed. End-stage kidney disease may occur, requiring hemodialysis and kidney transplantation. HNF1B variants may come to light because a patient with diabetes has siblings or parents with renal cysts and early renal failure.

The pathophysiology of HNF1B-MODY is due to a combination of beta cell dysfunction and insulin resistance. Unlike patients with HNF1A-MODY or HNF4A-MODY, most individuals with HNF1B-MODY do not respond to sulfonylurea drugs, and a large percentage require insulin for management, although alternative diabetes drugs have not been rigorously studied (1,2,41,42,46). Ray et al. published a report of three cases of patients with diabetes and refractory hypomagnesemia (47). Two patients had confirmed HNF1B mutation, and hnf1b deletions could not be ruled out in the third patient. The study demonstrated that SGLT2 inhibitors can ameliorate refractory hypomagnesemia in patients with urinary magnesium wasting, potentially by enhancing renal tubular reabsorption of magnesium. The authors did not report serum glucose levels and/or glomerular filtration rate after SGLT2 inhibitor treatment (47).

In addition to single nucleotide variants and large deletions in HNF1B (which may, in fact, be due to chromosome microdeletion), chromosome 17q12 contiguous gene microdeletions are also a cause of HNF1B-MODY. These deletions encompass 14 genes in addition to HNF1B and are associated with neurodevelopmental disorders, such as autism spectrum disorder, attention-deficit hyperactivity disorder (ADHD), and cognitive impairments. There is not yet complete agreement whether a neurocognitive phenotype is seen in HNF1B intragenic variants (48,49). Dubois-Laforgue et al. found an increase in patients with intragenic mutations, albeit at lower rates than in the patients with 17q12 deletion (49). Clissold et al. identified several genes that are differentially methylated in HNF1B-associated disease, some of which are specific to individuals with 17q12 deletion (50). They documented organized changes in DNA methylation across a large deletion region suggestive of a compensational role of this epigenetic modification. However, the relationship between the DNA methylation status of the 17q12 deletion and the increased prevalence of psychiatric symptoms was not studied due to lack of psychiatric data. Interestingly, more recent publications have suggested a genotype-phenotype correlation for renal disease in HNF1B-associated disease with 17q12 deletion, resulting in better renal function than HNF1B intragenic mutations that cause loss of function (49,50,51,52).

Care for people and families with HNF1B-associated disease is complex. The combined guidance of experts in diabetes, kidney function, gynecology/urology, gastroenterology, and neurology may be required.

Neonatal Diabetes Mellitus

Neonatal diabetes mellitus (NDM) is the term used to define a special, rare category of diabetes defined by its extremely early onset, whereby those diagnosed with diabetes at age <6 months are very likely to be due to underlying monogenic causes. Although these monogenic etiologies can very rarely cause diabetes that occurs between ages 6 and 9 months or even later, the incidence of autoimmune diabetes (type 1 diabetes) approaches ≥95% of cases. Therefore, sequencing the various genes known to be associated with NDM should be undertaken in all individuals with diabetes diagnosed at age <6 months, as well as those diagnosed at age 6–12 months (or potentially even older), if testing for islet antibodies is negative or there are other features that suggest the possibility of an underlying monogenic etiology. A classification of NDM is shown in Table 2. NDM can be permanent (PNDM) or transient (TNDM), with some overlap of genes associated with later-onset MODY-type diabetes and with type 2 diabetes.

TABLE 2.

Classification of Neonatal Diabetes Mellitus, 2022

Genetic Defects in Insulin Action: Insulin Receptor and Postreceptor Defects

The insulin receptor gene, INSR, codes for a heterotetramer protein complex consisting of two extracellular α subunits that bind insulin and two membrane-spanning β subunits with an intracellular tyrosine kinase domain that initiates a signaling cascade. Both subunits are encoded by the single gene, and variants in this gene may cause distinct syndromes, depending on the severity of disrupted insulin signaling. As many as 0.1%–1% of the population are suspected of having some variants that interfere with insulin action, but most can be overcome by increasing insulin secretion (92). Among the INSR variants that impair insulin action and cause diabetes are three syndromes: insulin resistance syndrome type A, Donohue syndrome, and Rabson-Mendenhall syndrome. All are rare, and no data on the precise incidence of these syndromes are available.

The insulin resistance syndrome type A is a relatively mild and more common form of insulin receptor abnormality defined by the presence of hyperandrogenism, acanthosis nigricans, and marked insulin resistance with glucose intolerance and hyperinsulinemia (93). Donohue syndrome is the most severe and rare form of insulin resistance and is due to near total absence of insulin receptor function. Affected individuals are characterized by severe intrauterine growth retardation, dysmorphic features, hyperinsulinemia, and abnormal glucose homeostasis. The abnormal glucose homeostasis is characterized by hyperglycemia during and after feeding, due to virtual absence of insulin action, which is essential to enable peripheral glucose uptake and utilization, as well as hypoglycemia during fasting due to the absence of insulin action, which is necessary to enable storage of glucose as glycogen (94). Patients with Rabson-Mendenhall syndrome have some residual insulin action and, therefore, somewhat different dysmorphic features, primarily involving abnormalities of teeth and nails, which are dysplastic and differ from those with Donohue syndrome. Pineal hyperplasia has been reported as well in Rabson-Mendenhall syndrome. Because the variant is not as severe, these patients are not at risk of dying early and, later in life, manifest the classic signs of insulin resistance, including acanthosis nigricans and hirsutism. Like patients with Donohue syndrome, those with Rabson-Mendenhall syndrome also manifest postprandial hyperglycemia and fasting hypoglycemia (94).

Gaps in Monogenic Diabetes Diagnosis

Multiple barriers arise on the journey to a diabetes diagnosis. A 2020 study on patient perspectives identified barriers at different levels: (a) patient-related (nature of MODY symptoms, perceived test utility, individual personality); (b) provider-related (provider awareness and knowledge, provider communication); and (c) healthcare system-related (cost of testing, access to knowledgeable providers, patient education, and support resources) (95).

Clinical Genome Resource (ClinGen) Monogenic Diabetes Expert Panels (MDEP) for Gene and Variant Curation

Next-generation sequencing has enabled high-throughput genetic testing for monogenic diabetes at a dramatically reduced cost, thereby increasing the number of patients who can benefit from a diagnosis of monogenic diabetes (along with other single gene disorders). However, this growth in testing has also increased the number of VUS identified and highlights the complexity of determining whether a variant in a relevant gene causes disease or is merely one of the millions of harmless variants in the genome.

To respond to growing awareness that many genetic variants were being interpreted differently with respect to disease causation by different labs, the ACMG and AMP developed and published a consensus statement on recommendations for “standards and guidelines for the interpretation of sequence variants.” This consensus statement provided guidance for using available clinical, family, population, and functional data on rare variants for classifying pathogenicity into five categories ranging from pathogenic to benign (96).

Subsequently, the National Institutes of Health-funded ClinGen (97) and ClinVar (98) resources have worked with members of the scientific and medical genetics and genomics communities to curate and publicize gene-disease relationship and gene-variant relationship, to continue refining the guidelines, and to develop disease- and gene-specific versions of the guidelines. This latter activity was accomplished by convening disease- and gene-specific expert panels (EPs) comprised of experts in the clinical and molecular diagnosis, management, genetics, and molecular biology of specific disease areas (99). Formation of these EPs enables members to inform curations not only through sharing of diverse expertise but also through the sharing of unpublished case data. Sharing of case data enables confident assertations to be made of the pathogenicity of a variant that may be only observed once in a single laboratory but several times in laboratories across the world with a consistent phenotype. A ClinGen EP for monogenic diabetes was convened in 2017 and approved for gene curation in 2019 (100) and variant curation in 2021 (101). ClinVar contains variant curation by both individual laboratories and by EPs; those curations completed by MDEPs, like all EP curations, are distinguished by a 3-star confidence rating and by indication of the U.S. Food and Drug Administration oversight of the EP process. MDEP specification development, variant curation, and deposit of curations into ClinVar are ongoing and expected to reduce some of the ambiguity involved in monogenic diabetes diagnosis and, thus, improve access to an accurate diagnosis for individuals with monogenic diabetes.

Concluding Remarks

Monogenic forms of diabetes are uncommon, but combined, they result in ~2%–3% of new cases of diabetes under age 35 years. Rates are 1:100,000 births for neonatal diabetes and rarer still for the syndromic forms of diabetes. Any clinician commonly seeing persons with diabetes will see people with monogenic diabetes. Mitochondrial causes of diabetes may be more common than appreciated because they are rarely considered. Defining the genetic bases for monogenic diabetes has shed light on the complexity of human pancreas formation and function, the regulation of insulin production and secretion, and important aspects of insulin action. This research has enabled a clearer understanding of the nature of dominantly and recessively inherited forms of early-onset diabetes. The use of rational treatments based on the pharmacology of the KATP channel has led to a spectacular improvement in the treatment of this rare form of KATP channel-mediated diabetes. This line of research also has led to an understanding that some of the same genes that cause monogenic diabetes are involved in the more common forms of what clinically appears to be type 1 diabetes and type 2 diabetes. Variable penetrance may affect gene variants thought previously to be highly penetrant, if not always disease-causing. Variations in onset or severity of diabetes occur within and between pedigrees and suggest the presence of modifying genes or at least compensation.

Correct diagnosis requires molecular confirmation, which enables precision treatment, avoids unnecessary use of insulin or other inappropriate agents, may lead to cascade testing of family members, and permits genetic counseling. In any autosomal dominant disease, the diagnosis in a proband should prompt the identification of affected members; in the case of MODY, any family member should be clinically assessed to decide if testing is needed. Next-generation sequencing has reduced the cost of genetic testing to the level of many routine tests, yet large barriers remain for insurance coverage, as well as diagnostic inertia, due to often convoluted approaches to ordering genetic testing. These discoveries are likely to have wide impact on clinical practice.

Resources

The following websites provide access to expert advice and assistance with possible mutation analysis in patients suspected of having monogenic forms of diabetes:

• https://monogenicdiabetes.uchicago.edu/, a monogenic diabetes registry located in the United States at the University of Chicago
• www.diabetesgenes.org, an information resource on genetic types of diabetes located in the United Kingdom at the University of Exeter
• https://www.ncbi.nlm.nih.gov/gtr/, Genetic Testing Registry, a compendium of sites and locations of mutational analyses performed for research or via CLIA-certified laboratories
• Individuals with 17q recurrent deletion syndrome may benefit from contact with the 17q12 Foundation (www.chromo17q12.org).

List of Abbreviations

A-B+

autoantibody-negative and fasting C-peptide-positive

A1c

glycated/glycosylated hemoglobin

ACMG

American College of Medical Genetics and Genomics

ADHD

attention-deficit hyperactivity disorder

AMP

Association for Molecular Pathology

ATP

adenosine triphosphate

BMI

body mass index

ClinGen

Clinical Genomic Resource

CRP

C-reactive protein

DKA

diabetic ketoacidosis

EP

expert panel

ER

endoplasmic reticulum

FSGS

focal segmental glomerulosclerosis

GAD

glutamic acid decarboxylase

GCK

glucokinase gene

GLP-1 RA

glucagon-like peptide-1 receptor agonist

HNF

hepatocyte nuclear factor

HR

hazard ratio

hsCRP

high-sensitivity C-reactive protein

INS

insulin gene

INSR

insulin receptor gene

IPEX

immune dysregulation, with polyendocrinopathy and enteropathy on the X chromosome

KATP

ATP-regulated potassium (channel)

MDEP

Monogenic Diabetes Expert Panel

MELAS

Mitochondrial Encephalopathy With Lactic Acidosis and Stroke-Like Episodes

MIDD

Maternally Inherited Diabetes and Deafness

MODY

maturity-onset diabetes of the young

NDM

neonatal diabetes mellitus

PNDM

permanent neonatal diabetes mellitus

SEARCH

SEARCH for Diabetes in Youth Study

SGLT2

sodium-glucose cotransporter 2

TNDM

transient neonatal diabetes mellitus

TODAY

Treatment Options for Type 2 Diabetes in Adolescents and Youth Study

tRNA

transfer ribonucleic acid

VUS

variants of uncertain significance

Conversions

A1c: (% x 10.93) - 23.50 = mmol/mol

C-peptide: ng/mL x 0.333 = nmol/L

Glucose: mg/dL x 0.0555 = mmol/L

Funding

Maria V. Salguero’s training is funded by the Clinical Therapeutics Training Grant (T32GM00719). This work was supported by R01DK104942 (Philipson/Greeley/Naylor), U54DK118612 (Philipson/Naylor), DRTC P30DK020595 (Graeme Bell, PhD, University of Chicago), and ADA grant 7-22-ICTSPM-17 (Naylor).

Acknowledgment

This is an update of: Sperling MA, Garg A: Monogenic Forms of Diabetes. Chapter 7 in Diabetes in America, 3rd ed. Cowie CC, Casagrande SS, Menke A, Cissell MA, Eberhardt MS, Meigs JB, Gregg EW, Knowler WC, Barrett-Connor E, Becker DJ, Brancati FL, Boyko EJ, Herman WH, Howard BV, Narayan KMV, Rewers M, Fradkin JE, Eds. Bethesda, MD, National Institutes of Health, NIH Pub No, 17-1468, 2018, p 7.1–7.27

Article History

Received in final form on April 17, 2023.

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All authors reported no conflicts of interest.