A clinical practice review of monogenic diabetes: a paradigm for precision medicine in endocrinology

Introduction

Background

The field of adult inherited metabolic disorders is being revolutionised by the principles of precision medicine, with monogenic diabetes standing as a paradigm for this approach. With a revised prevalence of approximately 1–2% (1), monogenic diabetes presenting in childhood and early adulthood is frequently misdiagnosed as type 1 (T1D) or type 2 diabetes (T2D), leading to inappropriate treatment and missed opportunities for personalised care (2).

This typical presentation of monogenic diabetes seen in our clinical practice highlights such misdiagnosis leading to delays in correct treatment.

A correct molecular diagnosis can dramatically alter clinical management, prognostication and genetic counselling. Building on this precision framework, the genetic architecture of monogenic diabetes has become increasingly well defined. The genetic landscape is evolving and more than 40 genes have been described as causing monogenic diabetes including maturity-onset diabetes of the young (MODY) (14 genes), neonatal diabetes and inherited causes of insulin resistance (3).

The classic term MODY is increasingly being replaced by a more precise, genetic aetiology-based nomenclature such as HNF1A-diabetes or GCK-related hyperglycaemia (1). Initially used numbers to describe MODY type (e.g., MODY1 for HNF4A-diabetes) are no longer recommended.

Rationale and knowledge gap

Identifying a monogenic form of diabetes has profound implications for family screening, allowing for predictive testing and early intervention in relatives. Individuals with monogenic diabetes present usually before age 35 years with an autosomal dominant inheritance pattern and normal body weight. Unlike in T1D, there is an absence of pancreatic islet-cell autoantibodies especially if measured close to diagnosis [glutamic acid decarboxylase (GAD), insulinoma associated protein 2 (IA2) and zinc transporter 8 (ZnT8) antibodies], and persistent endogenous insulin secretion beyond 3 years from diagnosis [C-peptide above 0.2 nmol/L (200 pmol/L) with glucose above 4 mmol/L (72 mg/dL)]. In monogenic diabetes, ketoacidosis is very rare even if insulin is not taken regularly and insulin requirements are low (<0.4 Units/kg) (1,4).

To distinguish MODY from T2D, obesity and features of metabolic syndrome such as acanthosis nigricans are typically absent (1,4). The aspects differentiating MODY from common forms of diabetes are summarized in Table 1 and form the basis of precision diagnostic algorithms.

The most common types of monogenic diabetes are from pathogenic heterozygous variants in genes encoding for the transcription factors, which together account for around 53% of MODY in the UK (5). Those include hepatocyte nuclear factor 1-alpha (HNF1A) explaining around 33% of MODY, 4-alpha (HNF4A) 14% and 1-beta (HNF1B) 6%, followed by mild hyperglycaemia due to glucokinase gene (GCK) mutations (22%), and maternally inherited diabetes and deafness (MIDD, 8%) in the UK (5-7). Three genes previously presumed to be causal for monogenic diabetes (BLK, PAX4, and KLF11) have been removed from MODY panel due to poor co-segregation with diabetes and being too common in non-diabetic populations (8). The other causes of monogenic diabetes, are detailed later and in Table 2 (4).

Furthermore, the clinical presentation is no longer viewed as uniform. Certain mutations, particularly in HNF1A and HNF4A, consistently produce classical monogenic diabetes, whereas variants in genes like GCK and HNF1B show wider expressivity, often resulting in non-classical presentations that fail to meet standard diagnostic criteria (4). This variability highlights the importance of recognizing rare subtypes and associated syndromic features, such as the renal phenotype of HNF1B variants carriers and next-generation sequencing have helped in new genes discoveries and improving precision management (1).

Consequently, genetic testing is warranted in cases meeting specific clinical criteria, and probability calculators have been developed and validated to guide clinicians in decision-making process. The MODY calculator developed by the genetic diabetes team from the University of Exeter helps to estimate the individual’s pre-test probability of having monogenic diabetes and score of >25% was suggests to trigger genetic testing (25). The limitations of this tool include its inapplicability to individuals diagnosed with diabetes above the age 35 years and the fact that it was developed using data primarily from White European populations. Recently, the MODY calculator including clinical features and also biomarkers have been published (26).

Experts recommend genetic testing in all diagnosed with diabetes under the age of 1 year, people without obesity and diabetes diagnosed under the age of 30 years with negative islet-cell antibodies and preserved endogenous insulin production, women with gestational diabetes and fasting glucose above 5.5 mmol/L without obesity, and people with persistent mild hyperglycaemia (fasting glucose 5.5–7.8 mmol/L, HbA1c <62 mmol/mol) in absence of obesity (1).

Figure 1 depicts a suggested algorithm to identify patients suitable for monogenic diabetes testing. An early and accurate diagnosis is crucial, as it prevents patient misclassification and avoids unnecessary insulin therapy or oral agents that are inappropriate for the specific genetic subtype (27).

Figure 1 An algorithm for MODY testing stratification. Modified from Colclough and Patel [2022] (5). BMI, body mass index; DKA, diabetic ketoacidosis; FH, family history; GAD, glutamic acid decarboxylase; IA2, insulinoma-associated antigen-2; MODY, maturity-onset diabetes of the young; NGS, next generation sequencing; ZnT8, zinc transporter 8.

Objective

Several comprehensive reviews have addressed the principles of precision medicine in monogenic diabetes and summarised the expanding list of causal genes, molecular mechanisms, and advances in therapeutic strategies (2,4,28,29). The specific aim of this review is to complement those works by providing a pragmatic, clinically focused guide that emphasises diagnostic “red flags”, genetic testing, and genotype specific management across common and syndromic subtypes, with attention to pregnancy care and multidisciplinary co-ordination, aiming to support earlier recognition of monogenic diabetes and more precise, individualised patient care.

This review will focus on the practical aspects of recognizing and managing the most common types of monogenic diabetes, as well as some rarer forms, highlighting how genetic testing translates directly into precise clinical management.

Case presentation

A 23-year-old woman presented to the diabetes clinic with poorly controlled diabetes [glycosylated haemoglobin (HbA1c) >100 mmol/mol]. She was diagnosed with presumed type T1D at the age of 10 years and admitted to not taking her insulin with last prescription ordered 8 months ago. Despite this, she had not had any episodes of diabetic ketoacidosis. Her body mass index (BMI) was 22 kg/m². She had a strong family history of diabetes; her father, paternal grandfather, two paternal half-sisters and two nieces (daughters of the half-sister) all having a young-age onset diabetes treated as T1D. Of note, she had two children who had been born with weight of 8–10 lb and her son had hypoglycaemia after birth. She underwent monogenic diabetes testing and was found to have the start loss variant c.1A>G in the HNF4A, confirming HNF4A-diabetes. Gliclazide was started and titrated, insulin was weaned off with improvement of her HbA1c to 74 mmol/mol. All affected family members were confirmed to have HNF4A-diabetes and all but 1 had insulin replaced successfully with gliclazide.

Monogenic diabetes subtypes

HNF1A-diabetes

Mutations in the HNF1A are responsible for HNF1A-diabetes; accounting for 33% of patients with monogenic diabetes in the UK, making it the most common monogenic diabetes (5,30). HNF1A is expressed in the liver, kidney, intestine and pancreas and encodes a transcription factor crucial in regulating the expression of genes that encode insulin and glucose transporters (INS, GLUT 1, GLUT 2 and SGLT2) as well as β-cell function (13). Over 400 HNF1A mutations in 1,200 families have been found leading to progressive β-cell dysfunction and reduced renal threshold of glucose (13,31). Glycosuria often predates diabetes, and is secondary to reduced sodium glucose co-transporter 2 (SGLT2) expression in the proximal renal tubule (6). Mutations are highly penetrant with 96% of affected patients being diagnosed with diabetes by age 55 years (32), but most develop diabetes by age 25 years (13). Although it should be noted, that the penetrance levels were reported much lower in the non-selected population, with only 32% of the people with a mutation in HNF1A or HNF4A going on to develop diabetes (33).

HNF1A mutation carriers are usually normoglycaemic until puberty (6). Initially, their fasting plasma glucose levels are normal but have impaired glucose tolerance with a glucose increment of >4.5 mmol/L from baseline after an oral glucose tolerance test (34). Eventually, their fasting plasma glucose also increases and often develops marked hyperglycaemia, leading to a misdiagnosis of T1D (10).

Another characteristic finding that can help differentiate HNF1A-diabetes from other subtypes is a very low high-sensitivity C-reactive protein (hsCRP) (14). They also have a favourable lipid profile; typically, with higher high-density lipoprotein (HDL) and lower triglycerides (TG) compared with their BMI-matched counterparts with T2D (35).

HNF1A-diabetes should be considered, as with all MODY, in young patients with diabetes, not initially requiring insulin or suffering with ketosis, a normal BMI and a family history of diabetes. Whilst there are characteristics described above (e.g., low CRP and glycosuria pre-dating diabetes), they may not necessarily be picked up routinely, be practical to assess nor are they specific enough to the disease to be used diagnostically. The diagnostic procedure should be undertaken as per Figure 1, by assessing all MODY genes with next generation sequencing (NGS) with or without prior use of a MODY calculator.

Patients with HNF1A-diabetes are classically very sensitive to sulphonylurea treatment, often only requiring low doses, such as 20–40 mg of gliclazide or 1.25–2.5 mg of glibenclamide daily (6). Patients are stable on gliclazide for many years when they maintain normal weight. Bacon et al. looked at 60 patients with HNF1A-diabetes, 80% of whom were still insulin independent after 84 months of sulphonylurea therapy (36). However, given progressive β-cell dysfunction, patients with this monogenic diabetes are likely to end up on insulin therapy later in the disease process (37). Glinides have been proposed as a second line treatment for HNF1A-diabetes. Naylor et al. performed a systematic review on precision treatment of β-cell monogenic diabetes, and described nateglinide as a viable and effective alternative to sulphonylurea, especially in cases of problematic hypoglycaemia, such as post-exercise (38). They found a mild, but significant reduction in HbA1c (−0.5%) in adding a dipeptidyl peptidase-4 inhibitor (DPP4i) to a sulphonylurea, vs. sulphonylurea alone. In a randomised controlled trial, glucagon-like peptide-1 receptor agonist (GLP1RA) monotherapy was as effective as sulphonylurea monotherapy, with a lower risk of hypoglycaemia and in those who gain weight subsequently (39).

Hypertension and dyslipidaemia should be managed as in T1D and T2D.

Micro- and macrovascular complications are comparable to those of T1D and T2D, especially if diabetes is not well controlled. Zhao et al. in a retrospective review of 1,325 patients with HNF1A-diabetes found that almost 50% had microvascular complications and over 10% had macrovascular complications (10).

HNF4A-diabetes

The HNF4A is expressed in the liver, pancreas and kidney (13). HNF4A protein is a member of a family of transcription factors that regulate the expression of HNF1A, as well as having importance in gluconeogenesis and lipoprotein biosynthesis (40). The heterozygous pathogenic variants in the HNF4A lead to HNF4A-diabetes having a similar phenotype to HNF1A-diabetes with slowly progressive β-cell failure and impaired glucose-stimulated insulin secretion (6). In contrast to HNF1A-diabetes however, patients with HNF4A-diabetes have high low-density lipoprotein (LDL) and low HDL and TG (13,40,41).

HNF4A-diabetes accounts for around 14% of all monogenic diabetes patients in the UK (5,35), making it the third most common cause of monogenic diabetes. However, in a study done by Mirshahi et al. the frequency of a mutation in HNF4A in a UK biobank unselected cohort of almost 200,000 people was 0.015% (29 people) and higher than HNF1A mutations (0.011%; 22 people) (33).

One significant feature of HNF4A-diabetes that helps separate it from other types is transient neonatal hyperinsulinaemic hypoglycaemia and macrosomia. Pearson et al. compared rates of macrosomia (birth weight >4,000 g) and hypoglycaemia amongst carrier and non-carrier infants born to 108 families with HNF4A mutations. 56% of HNF4A-mutation carriers had macrosomic babies compared to 13% of non-carriers, equating to a median increased weight of 790 g (42). Transient neonatal hypoglycaemia was present in 14% of the mutation-carriers, but none of the non-carriers. The same study looked similarly at 134 families with HNF1A mutations; there was no increase in neonatal hyperglycaemia or macrosomia (42). However, this has now since been described (43). Another distinguishing feature is the normal renal threshold for glucose, unlike in HNF1A-diabetes; patients therefore do not have glycosuria that predates diabetes (6).

As a common cause of MODY similar to HNF1A-diabetes, HNF4A-diabetes should be considered when there are clinical features of typical MODY as per Figure 1 (young age of onset, normal BMI, family history and lack of T1D features e.g., ketosis, insulin requirement). If possible, a neonatal history in the patient and in any children of the patient should be taken, paying special attention to hypoglycaemia and birth weight as in the example case described at the beginning of this review. However, a lack of this clinical information should not prevent consideration of this diagnosis with proper investigations.

HNF4A-diabetes is sensitive to sulphonylureas; a highly effective treatment. The evidence for 2nd line treatment in patients with HNF4A-diabetes is lacking (38). Patients with increased BMI are responding very well to GLP-1 analogues (personal experience). Vascular complications, especially if poorly controlled, occur at the same rate as in T1D and T2D (11).

HNF1B-diabetes

HNF1B protein is another nuclear transcription factor that regulate organogenesis of the pancreas, liver, kidneys, genitourinary tract, intestine and lungs (13,37). Mutations in HNF1B lead to an array of extra-pancreatic congenital malformations, commonly in the renal and genitourinary tract. Renal cysts are the most common; when present, collectively known as renal cysts and diabetes (RCAD) syndrome (13,41,44). Other renal abnormalities include horseshoe kidney, renal dysplasia, familial hypoplastic glomerulocystic kidney disease, collecting system abnormalities and genital tract abnormalities, such as hypospadias in men and bicornuate uterus in females (6,41).

HNF1B heterozygous mutations cause alteration in the differentiation of the process of pancreatic multipotent cells into endocrine, ductal and acinar cells, resulting in pancreatic abnormalities ranging from pancreatic agenesis to mild pancreatic atrophy (18). Progressive β-cell dysfunction and insulin resistance leads to diabetes which accounts for 6% of MODY (5). Patients with HNF1B-diabetes also can get liver dysfunction due to biliary tract abnormalities, hyperuricaemia with or without gout and hypomagnesaemia (6,37,41).

Around 50% of patients with HNF1B-diabetes have de novo mutations, so parents do not need to have diabetes (9). Of note, unlike other types of monogenic diabetes, which are often associated with single-nucleotide mutations, whole gene deletion and large genomic rearrangements are found in 50% of HNF1B-diabetes patients (37). Whilst HNF1B is included in the monogenic diabetes panel, HNF1B-diabetes should be considered in patients with diabetes and non-diabetic renal dysfunction/ genitourinary abnormalities, regardless of family history. Despite its stereotypical multisystemic phenotype, the diagnosis is often delayed. Amaral et al. found that the average time from diabetes diagnosis to HNF1B-diabetes genetic confirmation in 10 patients was 16.5 years. Interestingly, diabetes was the first manifestation in half the patients (18). Other studies suggest that renal disease presents in childhood and diabetes arises in adolescence or early adulthood (6,13).

In summary, HNF1B-diabetes should be considered in patients with typical MODY characteristics (young age of onset, normal BMI and lack of T1D features) and other organ abnormalities, typically in the genitourinary tract or pancreatic atrophy. As 50% of patients have de novo mutations family history of diabetes is not essential. As well as the MODY genetic panel, patients should undergo imaging of their abdomen and pelvis.

Patients with HNF1B-diabetes are not sensitive to sulphonylureas, due to hepatic insulin resistance (37). If renal function allows, patients can be trialled on metformin as a first line therapy (6), however they often quickly progress to insulin (13,41,44). Dubois-Laforgue et al. reported that amongst 201 patients with HNF1B-diabetes, 49% were started on insulin at diagnosis which increased to 79% at follow-up, as they were not adequately controlled on diet or oral hypoglycaemic agents (OHAs) (45). Despite insulin resistance, patients frequently have low insulin dose requirements, even with normal renal function (6).

Reports of micro- and macrovascular complications from diabetes are varied, with one study suggesting complications are common (18). Over half of patients develop end-stage-renal-failure requiring renal transplant by age 45 years (44), but this is likely due to the underlying renal structural abnormalities, rather than a consequence of hyperglycaemia.

GCK-related hyperglycaemia

GCK-related hyperglycaemia is caused by heterozygous inactivating mutations in GCK, which encodes glucokinase and accounts for 22% of MODY in the UK (5). Glucokinase acts as the glucose sensor for the pancreatic β-cell, setting the threshold for insulin secretion (46). An inactivating heterozygous mutation raises this threshold, resulting in a stable, mild fasting hyperglycaemia (typically 5.5–8.0 mmol/L; 100–144 mg/dL) that is present from birth.

From a clinical perspective, the combination of persistent mild fasting hyperglycaemia, minimal postprandial glucose excursions, lack of progression over time, and a family history of similar glycaemic patterns across generations should prompt suspicion of GCK-related hyperglycaemia rather than type 1 or type 2 diabetes (2,47). The hyperglycaemia is non-progressive, and complications do not occur with the exception of slightly increased rate of background retinopathy which does not progress (47). Importantly, patients are generally asymptomatic because their beta-cells can still respond to a glucose load, albeit from a higher baseline. Being asymptomatic, women are often diagnosed during pregnancy diabetes screening, when glucose increases typically by <4.5 mmol/L during oral glucose tolerance test (34). A study by Chakera et al. found that 1.6% of pregnant women with fasting plasma glucose above 5.1 mmol/L were confirmed to have GCK-related hyperglycaemia (48).

The cornerstone of precision medicine for GCK-related hyperglycaemia is the avoidance of pharmacological treatment. Insulin secretion is normal for the individual’s raised glucose set-point, and therefore medications like insulin or sulfonylureas are ineffective and unnecessary (49). A landmark study by Shepherd et al. demonstrated that transferring patients misdiagnosed with T1D off insulin therapy after a GCK-related hyperglycaemia diagnosis was safe and improved quality of life (50).

Diagnosis of GCK-related hyperglycaemia is crucial during pregnancy, as foetal growth and maternal treatment decisions depends on the foetal genotype; if the foetus does not inherit the mutation, maternal insulin treatment may be required to prevent macrosomia, whereas it is not needed if the foetus is also affected. Treatment options for patients whose babies have not inherited the mutation include metformin, insulin and early delivery at 38 weeks. To ensure the correct diagnosis of the inherited mutation, maternal peripheral blood samples can be tested after 15 weeks of pregnancy for cell free foetal DNA showing a mutation in GCK with 95% sensitivity (5).

Mitochondrial diabetes

Mitochondrial diabetes can be differentiated from other causes of monogenic diabetes by its characteristic maternal inheritance pattern, low BMI, later age of onset (typically >35 years) (51) and the presence of multi-organ involvement. In clinical practice, it should be considered particularly in lean individuals with diabetes who have a clear maternal family history of diabetes and/or sensorineural deafness or young-age onset cerebrovascular events across successive generations, especially when insulin is needed within a few years of diagnosis despite negative islet autoantibodies, or when there is a poor or short lived response to OHAs (17,52,53).

Mitochondrial diabetes accounts for 8% of MODY in the UK and is most commonly caused by the m.3243A>G mutation in MT-TL1 in mitochondrial DNA, leading to MIDD (5). MIDD is characterised by bilateral sensorineural hearing loss, which develops in over 75% of affected individuals and frequently precedes the onset of diabetes by several years (51).

Additional multisystem features may occur, including ophthalmic manifestations (notably macular retinal dystrophy), myopathy (reported in approximately 43% of patients, typically presenting with proximal muscle weakness), and cardiac involvement in around 25% of the affected individuals such as non-ischaemic cardiomyopathy, arrhythmias, and heart failure (17).

Neurological involvement is also common, occurring in around 50% of cases, often as part of syndromic presentations such as mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). Kearns-Sayre syndrome is another metabolic disorder associated with mitochondrial diabetes, which usually results from a sporadic deletion in mitochondrial DNA (mtDNA). It presents with progressive external ophthalmoplegia, retinitis pigmentosa, cardiomyopathy and endocrine abnormalities. Several other mitochondrial mutations have also been associated with diabetes (51).

Penetrance of mitochondrial diabetes approaches 100% by 70 years of age (4). Because each cell contains thousands of mitochondria, each harbouring multiple copies of mtDNA, heteroplasmy, the coexistence of wild-type and mutant genomes, occurs. Levels of heteroplasmy typically range from 3–50%, and may differ across tissues, contributing to the considerable phenotypic variability seen in mitochondrial disorders (17).

Currently, few effective disease-targeted treatments exist for mitochondrial disorders. Management therefore focuses on supportive measures, lifestyle adaptations, and treatment of the specific complications arising from mitochondrial dysfunction (51). Diabetes is initially managed with diet and/or OHAs, but most patients progress to insulin therapy, with a mean interval of 2–4 years from diagnosis to insulin initiation (17). As the underlying pathophysiology involves progressive insulin deficiency, insulin is a rational and often necessary treatment. There are no randomised controlled trials evaluating treatment in patients with m.3243A>G-related diabetes. In a review by Naylor et al., 72% of patients with mitochondrial diabetes were treated with insulin, but no clear data were available regarding the use or effectiveness of OHAs (38).

Metformin is generally avoided due to concerns about lactic acidosis; however, this caution is not strongly evidence-based. The argument against metformin use stems from only three case reports, each with limited detail (38). Conversely, although statins are sometimes avoided because of concerns about exacerbating mitochondrial-related myopathy, current evidence supports their use in patients with mitochondrial disease who are at risk, given their proven benefits in reducing cardiovascular and cerebrovascular morbidity (17). Bempedoic acid could be useful alternative especially that unlike statins, it is activated only in the liver and not in muscles. Therefore, should be considered in patients who are affected by myopathy.

Rare causes of monogenic diabetes

While much of the focus in monogenic diabetes lies on the most commonly involved genes, there is a broad spectrum of rarer subtypes with important clinical and therapeutic implications. These include neonatal diabetes, non-neonatal (MODY-like) and syndromic forms.

Neonatal diabetes mellitus (NDM)

KCNJ11 and ABCC8, encoding the Kir6.2 and SUR1 subunits of the pancreatic β-cell KATP channel, are the most common causes of NDM (54). Activating mutations in these genes keep the KATP channel open, thereby hyperpolarizing the β-cell and preventing insulin secretion. A hallmark of precision management in this subtype is the exceptional responsiveness to high-dose sulfonylureas, which close the mutant channel via an alternative binding site. Over 90% of patients can transition safely from insulin to oral sulfonylureas, with marked improvements in glycaemic control and quality of life (55,56).

Classically, these variants are known to cause permanent NDM (PNDM), but a substantial proportion lead to transient NDM (TNDM), which remits in infancy but relapses in adolescence or adulthood, during periods of increased insulin resistance or demand such as, puberty or pregnancy (4,57). Importantly, beta-cells in these individuals remain highly responsive to sulfonylureas at relapse. Milder KCNJ11 and ABCC8 mutations may also present as monogenic diabetes without a NDM history (4) and account for 4% (ABCC8) and 2% (KCNJ11) of MODY in the UK (5). In such cases, the genetic diagnosis is crucial, as these patients also may demonstrate sustained sulfonylurea sensitivity (58).

KATP-related NDM frequently exhibits neurodevelopmental complications, including DEND syndrome (developmental delay, epilepsy and neonatal diabetes), reflecting the widespread expression of KATP channels in neuronal tissue (57,59). The therapeutic responsiveness of KATP-related NDM to sulfonylureas is well established, with landmark data demonstrating successful transition from insulin to oral sulfonylureas (56) and long-term safety and efficacy shown in international cohorts (55,60).

6q24-related NDM represents the other major cause of transient neonatal diabetes. It results from overexpression of the paternally imprinted genes PLAGL1 and HYMAI due to paternal disomy, duplication, or methylation defects (59,61). Clinically, 6q24-related disease tends to present in the neonatal period and usually resolves by 18 months. It is strongly associated with intrauterine growth restriction and affected infants present with hyperglycaemia and dehydration usually in the first week of life. Other clinical features may include congenital anomalies such as macroglossia and umbilical hernia (58,62). Management during infancy typically involves insulin, with relapse later in life managed individually using insulin, sulfonylureas, or DPP-4 inhibitors (63).

PDX1-related PNDM arises from complete penetrance biallelic mutations in the Pancreatic and Duodenal Homeobox 1 (PDX1) gene, which encodes a transcription factor essential for pancreatic development (12). These mutations typically result in diabetes presenting in the neonatal period, requiring immediate lifelong insulin therapy due to severe insulin deficiency (64). Although classically associated with pancreatic agenesis, some patients may exhibit preserved exocrine pancreatic function due to phenotype variability, alongside developmental abnormalities affecting the duodenum and/or hepatobiliary tract (65).

INS-diabetes

Pathogenic heterozygous mutations in the insulin gene (INS) are a well-established cause of monogenic diabetes, with mutations typically disrupting insulin’s secondary structure, which impair insulin folding, secretion or stability. This leads to misfolded insulin accumulation that subsequently leads to endoplasmic reticulum (ER) stress, and beta-cell destruction (66).

On the other hand, homozygous INS mutations result in significantly reduced synthesis or complete loss of functional insulin. This genetic diversity is the foundation of a broad clinical spectrum, where the age of diagnosis, birth weight, and disease trajectory can vary significantly, even among individuals sharing an identical mutation.

All forms of INS-diabetes require lifelong insulin therapy, as the underlying defect in insulin production makes sulfonylureas and other oral agents ineffective (66,67). Although insulin remains the standard treatment, confirming the genetic cause is still essential for genetic counselling. Early, intensive insulin therapy may also lessen ER stress by reducing the load of misfolded insulin, helping to preserve remaining B-cells. This residual B-cell function may be important for future therapies aimed at boosting insulin production from the unaffected INS allele (15,66).

SLC19A2-diabetes

Thiamine-responsive megaloblastic anaemia (TRMA) syndrome results from bi-allelic loss-of-function mutations in the SLC19A2 gene, which encodes thiamine transporter 1 (THTR-1), a high-affinity transporter essential for cellular uptake of thiamine (also known as Rogers’ syndrome) (68). The protein is a multi-pass membrane transporter critical for thiamine transport, facilitating vitamin B1 entry into cells, which is vital for carbohydrate metabolism and normal function of multiple organ systems including the pancreas, bone marrow, and inner ear (24). The classical clinical triad includes diabetes, megaloblastic anaemia and sensorineural deafness, but the severity and age of onset can vary. Zhang et al. reported novel compound heterozygous variants in SLC19A2 and demonstrated notable improvement of anaemia and diabetes with thiamine supplementation, although hearing loss was typically irreversible (4). Jungtrakoon et al. further elucidated the pathophysiology showing that SLC19A2 mutations cause impaired thiamine uptake leading to mitochondrial dysfunction, oxidative stress, and beta-cell failure, resulting in early-onset non-autoimmune diabetes (24). Crucially, early intervention with high-dose thiamine can partially restore beta-cell function and optimise glycaemic control, highlighting TRMA as a compelling example of precision medicine in monogenic diabetes (4,24).

NEUROD1-diabetes

NEUROD1-diabetes is caused by heterozygous pathogenic variants in the neurogenic differentiation factor 1 (NEUROD1) gene, which encodes a transcription factor essential for pancreatic β-cell development, maturation, and insulin gene transcription. Unlike the highly penetrant mutations in HNF1A or GCK, many NEUROD1 variants exhibit low penetrance, meaning a significant proportion of mutation carriers may never develop diabetes or may present with very mild, often asymptomatic hyperglycaemia (4).

RFX6-diabetes

RFX6-diabetes accounts for 3% of monogenic diabetes cases in the UK and it arises from heterozygous protein-truncating variants in the regulatory factor X6 (RFX6) gene, leading to haploinsufficiency of a transcription factor essential for beta-cell development and function (5,69). Evidence suggests that RFX6 is also critical for maintaining gene expression in adult alpha-cells, indicating broader endocrine involvement (70).

Diabetes develops in only ~30% of mutation carriers with markedly reduced penetrance (69) and the clinical spectrum is wide, ranging from severe neonatal diabetes with pancreatic hypoplasia, gallbladder agenesis, and intestinal atresia seen in Mitchell-Riley syndrome, to later-onset MODY-like presentations. A distinctive biochemical feature is markedly reduced gastric inhibitory polypeptide (GIP) levels, which may suggest good potential responsiveness to incretin-based therapies, including DPP-4 inhibitors or GLP-1 receptor agonists in the young adult onset (16).

Rare syndromic monogenic diabetes

Syndromic monogenic diabetes is characterised by diabetes occurring alongside additional systemic features caused by mutations in described above mitochondrial diabetes or HNF1B-diabetes but also in CEL, PAX6, WSF1, and GATA6. These conditions show complex multisystem involvement alongside impaired pancreatic beta-cell function.

Carboxyl ester lipase (CEL)-diabetes

CEL is a pancreatic enzyme essential for hydrolyzing dietary fats, cholesteryl esters, and fat-soluble vitamins in the duodenum, uniquely requiring bile salts for activation (71). CEL-diabetes is a very rare autosomal dominant diabetes accounting for under 1% of monogenic diabetes (21). The frameshift mutations in the variable number tandem repeat (VNTR) region of the CEL gene result in an altered C-terminal tail that causes misfolding and intracellular aggregation of the CEL protein (21,72). This leads to ER stress and activation of the unfolded protein response, leading to pancreatic acinar cell apoptosis and progressive pancreatic damage that eventually impacts on beta-cells (71). In heterozygous carriers, the mutant CEL protein is synthesised but less efficiently secreted, this interferes with normal protein secretion, exacerbating cellular dysfunction and disease progression (73). Clinically, the condition is characterised by low faecal elastase levels and pancreatic lipomatosis, which typically occurs before the age of twenty, with diabetes and pancreatic cysts developing later on (21,72,74). Precision management requires a multidisciplinary approach by treating exocrine pancreatic insufficiency with enzyme replacement and insulin as the mainstay treatment for this type of diabetes.

PAX6 (paired box 6)-diabetes

PAX6 is a critical transcription factor involved in the development of pancreatic islets, eyes, and brain, and haploinsufficiency mutations in this gene cause a rare form of dominantly-inherited diabetes (75,76). The disease results in a gradual disruption of beta-cell identity and impaired insulin secretion due to altered transcriptional regulation (20,77). Clinically, PAX6-diabetes present as PNDM accompanied by aniridia, and may also include microphthalmia and other neurological anomalies (76,78,79). Some missense mutations may produce diabetes with minimal or no ocular involvement (77,79). Precision management involves insulin therapy tailored to beta-cell dysfunction, and a multidisciplinary approach including ophthalmologic and neurologic evaluations to address systemic manifestations (20,78).

Wolfram syndrome (WS)

WFS1 (Wolfram syndrome 1)-related diabetes occurs in two genetically and clinically distinct forms, reflecting recessive and dominant inheritance patterns. The recessive form, traditionally known as WS or DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy and Deafness), is caused by biallelic loss-of-function mutations in WFS1, which leads to disruption of ER homeostasis and the unfolded protein response, provoking chronic ER stress that leads to beta-cell apoptosis and progressive insulin deficiency (19,80). The autosomal dominant mutations provoke ER stress via toxic protein aggregation and impaired resolution of the stress response, further compromising beta-cell function (81).

WS is a multisystem disorder typically manifesting with childhood-onset diabetes mellitus usually diagnosed around age 6–8.7 years (19,82). Following diabetes onset, patients sequentially develop optic atrophy, generally around age 11 years, characterised by loss of colour and peripheral vision leading to blindness over subsequent years (83). Diabetes insipidus due to impaired vasopressin secretion, arises around adolescence or early adulthood and affects approximately 70% of patients (19).

Sensorineural deafness, bladder dysfunction, neurological problems, psychiatric disturbances, and central hypogonadism, all of which impact growth and sexual development, typically manifest later in the clinical course of WS. These complications contribute significantly to the progressive disability seen in affected individuals (19,84).

In contrast, the autosomal dominant WFS1 mutations, lead to neonatal or infancy-onset diabetes, congenital cataracts and hearing loss, lacking the full spectrum of DIDMOAD features (80,81). Precision management includes early genetic diagnosis, insulin therapy tailored to beta-cell failure, and multidisciplinary care targeting endocrine, ophthalmologic, neurologic, and urologic complications to optimise outcomes (19,80,81).

GATA6 (GATA-binding protein 6)-diabetes

GATA6 is a zinc finger transcription factor essential for endodermal and mesodermal development, with critical roles in the formation of the pancreas, heart, and biliary system (22). GATA6 mutations lead to the autosomal dominant diabetes, accounting for less than 1% of monogenic diabetes, and various extra-pancreatic manifestations. The underlying mechanism of diabetes involves impaired pancreatic beta-cell development and function that lead to disrupted transcriptional regulation during embryogenesis, resulting in insufficient beta-cell mass and insulin deficiency (85). Clinical spectrum is variable, ranging from PNDM with pancreatic agenesis and congenital heart defects to later-onset diabetes without overt structural abnormalities (22,23).

Not all mutation carriers develop diabetes, and several reports have demonstrated incomplete penetrance of GATA6-diabetes (22,85). Precision management requires insulin therapy according to the degree of beta-cell failure, and multidisciplinary surveillance for cardiac and hepatobiliary complications (22,23,85).

Strengths and limitations and review

This review has several strengths and limitations. It synthesizes data from landmark genetic and clinical studies alongside contemporary practice guidelines to provide a pragmatic, clinician focused summary of monogenic diabetes, with particular emphasis on disease specific diagnostic “red flags”, pregnancy management and real-world decision-making.

However, much of the existing evidence is derived from observational cohorts in highly selected, predominantly White European populations, with limited representation of diverse ethnic groups, which may restrict generalisability of reported prevalence estimates, genotype-phenotype correlations and treatment responses (86,87). In addition, as a narrative rather than systematic review, article selection may be influenced by the authors’ clinical experience and focus, although this approach was chosen to maximise practical relevance for front line clinicians. These limitations highlight the need for prospective, multi-ethnic studies and research to better define optimal diagnostic pathways and long-term outcomes of genetically informed care.

Conclusions

Monogenic diabetes is an excellent example of precision medicine as an accurate diagnosis guides treatment, screening for associated conditions and allows cascade screening of the affected family members, enabling tailored treatment. A precise genetic diagnosis dictates targeted therapy in the most common forms of monogenic diabetes; it can prevent unnecessary insulin treatment for decades in sulphonylurea-responsive types such as HNF1A- or HNF4A-related diabetes and avoid pharmacological treatment in GCK-related hyperglycaemia. As access to genomic testing and integrated biomarker panels continues to improve, embedding structured clinical assessment, validated probability calculators and streamlined genetic testing pathways into routine diabetes care will be crucial to extend these benefits beyond specialist centres. As the field continues to evolve, personalised genotype-guided management will become central to future diagnostic and therapeutic frameworks in monogenic diabetes to improve long-term outcomes across all subtypes.

Future precision medicine in monogenic diabetes will depend not only on technological advances in sequencing technologies, but also on heightened clinician awareness, multidisciplinary collaboration, and equitable implementation of genetic services. Integrating these principles into standard diabetes care pathways holds the potential to substantially reduce misdiagnosis, optimise long-term outcomes, and deliver truly individualised care.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editors (Nathan Lorde and Amro Maarouf) for the series “Adult Inherited Metabolic Disorders” published in Journal of Laboratory and Precision Medicine. The article has undergone external peer review.

Peer Review File: Available at https://jlpm.amegroups.com/article/view/10.21037/jlpm-2025-1-75/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jlpm.amegroups.com/article/view/10.21037/jlpm-2025-1-75/coif). The series “Adult Inherited Metabolic Disorders” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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