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Page 120 Chan et al. J Transl Genet Genom 2024;8:13-34 https://dx.doi.org/10.20517/jtgg.2023.36

In 1975, Tattersall first reported a MODY family affecting three generations. The affected members had a
[68]
young age of diagnosis with non-ketotic presentation and mild clinical course . The use of family-based
linkage analysis and sequencing technology has uncovered the cosegregation of mutations of multiple genes
amongst affected family members. The “loss-of-function” and “gain-of-function” of these mutations
supported the causal roles of these genes in pancreatic islets and other insulin-sensitive tissues. These genes
often encode proteins implicated in neogenesis, differentiation, and maturation of islets, transcription
factors, enzymes, ion channels, and mitochondria. Collectively, they coordinate the complex processes of
glucose entry and sensing as well as synthesis, processing, and secretion of insulin to maintain glucose
metabolism [69-71] . Amongst the 40 subtypes of monogenic diabetes, MODY due to mutations in genes
encoding glucokinase (GCK) and transcription factors including hepatocyte nuclear factor 4α (HNF4α),
HNF1 homeobox A (HNF1α), and HNF1 homeobox B (HNF1β) were best described and most frequently
reported. These mutations may be de-novo or transmitted from one generation to another with varying ages
of diagnosis depending on the presence of other risk factors. Other rare mutations with Mendelian recessive
mode of inheritance were associated with neonatal diabetes, severe insulin resistance, lipodystrophy, and
[67]
syndromic features (e.g., deafness, visual impairment, liver/renal cysts, developmental abnormality)
[Figure 2 and Table 1].

There are considerable overlaps in the phenotypes amongst individuals with MODY, LADA, type 1
diabetes, or type 2 diabetes in whom autoimmunity, common and rare variants may coexist. In a recent
review article, the authors summarized the epidemiology, pathophysiology, diagnosis, and management of
monogenic diabetes. As many as 90% of patients with monogenic diabetes were not diagnosed or
misclassified in part due to the prohibitive cost of incorporating sequencing in routine service. Depending
on the selection criteria, amongst young patients with type 2 diabetes without autoantibodies, the frequency
of MODY ranged from less than 10% to more than 50%, with the majority having mutations in HNF1α,
[67]
GCK, and HNF1β .
In a multi-ethnic cohort of 3,333 young patients under the age of 20 with a presumptive diagnosis of type 2
diabetes, whole exome sequencing indicated that 93 (2.8%) patients carried a pathogenic/likely pathogenic
(P/LP) variant in genes encoding HNF4α (n = 16), GCK (n = 23), HNF1α (n = 44), pancreatic and duodenal
homeobox 1 (PDX1) (n = 5), insulin (INS) (n = 4) and carboxyl ester lipase (CEL) (n = 1). Compared to
those without P/LP variants, patients with MODY had a younger age of diagnosis and lower fasting plasma
C-peptide (CP) levels. They were less likely to have hypertension and had higher HDL-C levels, although
there were no distinct features that reliably distinguished MODY from other forms of diabetes. Importantly,
the diagnosis of MODY would have changed clinical management in 89% of them . Although MODY risk
[72]
calculators using age, age of diagnosis, family history of diabetes, HbA1c, fasting plasma glucose and CP,
high sensitivity C-reactive protein, autoantibodies, and syndromic features had been developed in
[73]
Europeans, their sensitivity and specificity remained suboptimal, especially in non-European populations .

Clinical implications of identifying families with MODY or monogenic diabetes
There is good evidence that patients with HNF1α and HNF4α-MODY, as well as K-ATP channel mutations,
[74]
respond particularly well to SU agents, while adding DPP4i may have incremental benefits . The use of
these oral glucose-lowering drugs enabled insulin discontinuation in some patients misdiagnosed with
type 1 diabetes. However, in many patients with MODY, notably those with transcription factor MODY,
different background genetic profiles might contribute to progressive β-cell failure. Within a MODY family,
carriers of the same rare variant might have different presentations and outcomes depending on the
presence and control of other risk factors [75,76] .