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multiple organ damage, the heterozygous carriers may only have "mild" diabetes as a feature. One such
example is Wolfram Syndrome, also known as DIDMOAD, the acronym for Diabetes Insipidus, Diabetes
Mellitus, Optic Atrophy and Deafness [89,90] . The latter is a rare, autosomal recessive neurodegenerative
disease due to mutations in the gene encoding Wolframin ER transmembrane glycoprotein (WFS1 and
WFS2) located in the Chromosome 4p16.1 region. These genes encode a transmembrane protein causing
abnormal calcium metabolism and protein misfolding in the endoplasmic reticulum. These patients might
also have mitochondrial dysfunction with marked heterogeneity in phenotypes [89,91] .

In the 1990s, we reported a Chinese man diagnosed with diabetes at the age of 12 with progressive loss of
vision due to optic atrophy. At the age of 17, he presented with severe hyperglycemia and polyuria which
was due to diabetes insipidus. Ultrasound imaging revealed severe hydroureters associated with autonomic
dysfunction. With the loss of vision, the patient learned to tune the piano but later developed high-tone
deafness. Both his parents had mild diabetes. Although genetic diagnosis was not available at the time, his
[91]
clinical presentation suggested Wolfram Syndrome/DIDMOAD . Given the severe disabilities and
premature mortality in these homozygous carriers, preconceptual counseling would have prevented these
tragic stories while there are ongoing efforts to discover druggable pathways or use gene editing to correct
these genetic abnormalities and their consequences [89,90] .

Clinical diagnosis versus prediction by bioinformatics and algorithms
Most of the recommendations on diagnosis and treatment of MODY were based on experiences in
[79]
Europeans . The current classification of P/LP variants is largely determined by the rarity of variants,
functional annotations, experimental studies, and/or reported cases. Many of these variants were predicted
to cause amino acid change, protein truncation, premature initiation, or termination of gene transcription.
Due to their high frequency and incomplete penetration, they were often classified as variants of uncertain
significance (VUS). Although heterozygous carriers of variants with recessive mode of inheritance or
[92]
carriers of compound heterozygous mutations are not considered to have monogenic diabetes , these
carriers may develop diabetes in the presence of additional risk factors . The significance of these VUS
[51]
requires evaluation through detailed phenotyping, systematic family screening, and testing for
cosegregation, especially in populations with a high prevalence of familial YOD .
[71]

Discounting the significance of these VUS may lead to missed opportunities for early diagnosis and
intervention. As an analogy, 7% of Asians have thalassemia minor due to a single copy of mutation affecting
one of the oxygen-carrying globin proteins in the erythrocytes . The high prevalence of these mutations
[93]
may have selection advantages. Heterozygous carriers have mild anemia and an increased risk of diabetes
[94]
due to the close link between glucose and iron metabolism . Given the recessive mode of inheritance, one
[95]
in four offsprings of parents who are both carriers may suffer from thalassemia major, requiring lifelong
blood transfusion, iron overload, multi-organ failure, and premature death . In some countries,
[96]
preconception counseling for couples who are both carriers has prevented the birth of these homozygous
carriers [97,98] .

POLYGENIC RISK SCORES, RISK STRATIFICATION AND PRECISION THERAPY
Since the launching of the Human Genome Project in 1993 , a wealth of knowledge has been amassed
[99]
confirming the inter-ethnic differences in genomic architecture with hundreds of loci scattered throughout
the genome associated with complex diseases including diabetes, cardiovascular-renal disease, and
cancer [24,86] . In keeping with their frequent, albeit not invariable clustering, these diseases share common
variants, which are mainly non-coding with small effect size, suggesting perturbation of common pathways
in these disease clusters [86,100-102] . While some of these genetic loci are potential drug targets [103,104] , other