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Chan et al. J Transl Genet Genom 2024;8:13-34 https://dx.doi.org/10.20517/jtgg.2023.36 Page 123

underwent oral glucose tolerance tests and the younger brother had a high 2-h plasma glucose level of
17 mmol/L at the age of 17. All siblings were lean. The two younger siblings detected by screening and put
on insulin remained complications-free in their late 40s, while the index case died of end-stage kidney
disease (ESKD) in her 50s. We later confirmed the cosegregation of a splice site mutation of HNF1α
amongst all affected members despite their different outcomes depending on the timing of diagnosis and
[77]
intervention .
Glucokinase MODY
Distinct from transcription factor MODY, GCK-MODY is characterized by isolated fasting hyperglycemia
due to suboptimal glucose sensing with normal post-prandial insulin secretion once glucose sensing is
[78]
triggered . In European patients, carriers of GCK mutations usually have mild disease and do not require
[79]
treatment . In Asia, patients with GCK-MODY share features similar to those of their European
counterparts, with multiple generations being affected, suggestive of autosomal dominant inheritance.
However, the high prevalence of common variants for type 2 diabetes genes and beta-cell dysfunction in
young Asian patients, along with other lifecourse factors, may lead to considerable variations in terms of age
of diagnosis and subphenotypes both within and across GCK-MODY families [4,80,81] .

Additionally, maternal-offspring GCK genotype concordance or discordance can affect the pregnancy
outcome, which is highly relevant to young women with diabetes. Intensive insulin treatment in a GCK-
MODY non-carrier may cause low birth weight in an offspring carrier who requires a high fasting plasma
glucose to trigger insulin secretion. On the other hand, high fasting plasma glucose in an affected mother
may lead to high birthweight in an offspring non-carrier due to fetal hyperinsulinemia [82,83] . The newly
developed GCK activator improved glucose sensing and triggered early insulin secretion. This new class
[84]
of drug may provide precision therapy in patients with GCK-MODY, although more RCTs are needed to
confirm this hypothesis .
[85]
The discovery of these MODY families due to “gain-of-function” or “loss-of-function” of genetic mutations
supports the biological importance of proteins encoded by these genes. Some of their common variants may
cause qualitative or quantitative changes in gene expression to increase the risk of type 2 diabetes and its
complications. Indeed, some of the loci associated with type 2 diabetes lie within the coding or non-coding
regions of MODY genes [24,25,86] . One example is the common variants of GCK and GCK-regulating proteins
[87]
associated with glucose/lipid traits and ESKD . Mendelian randomization analysis suggested that genetic
proxies of GCK were causally linked to cardiovascular disease .
[88]
Thus, using multiomic analysis including whole exome sequencing focusing on coding regions and whole
genome SNP arrays is complementary in identifying high-risk individuals with abnormal biology.
Multiomic analysis in prospective cohorts with risk factors, interventions, and outcomes can provide
valuable information in our pursuit of genomic medicine. However, the under-presentation of non-
European populations, along with differences in ancestry, genomic architecture, and lifecourse factors,
means major knowledge gaps in the heritability of YOD remain. Here, supported by other scientists,
physicians with knowledge in human biology, pathophysiology, clinical medicine, drug mechanisms,
technologies, and care delivery are in a good position to use these technologies and analytical tools to
formulate hypotheses for translational purposes.

Wolfram syndrome/DIDMOAD
Currently, there are no guidelines on cascade family screening for heterozygous carriers of MODY genes
with recessive mode of inheritance. While the homozygous carriers may suffer from severe disease with