Genetic and Clinical Characteristics of Monogenic Diabetes in Japan: A Nationwide Study by the Japan Diabetes Society
Authors' conclusion
We established a nationwide genetic testing platform and identified carriers of actionable variants, offering possibilities for precision medicine. Neither classical criteria nor the MODY probability calculator identified all monogenic cases, highlighting the need for broader genetic testing.
Study context
- Population
- Probands with diabetes onset before age 35, BMI <30 kg/m² and negative islet autoantibodies, Japan, recruited 2019–2024
- Participants
- 232 probands
- Exposure
- P/LP variant carriers vs noncarriers
- P/LP variant carriersn = 67
- Outcome
- P/LP variants identified
Methodological detailsnationwide, targeted sequencing of 11 causal genes, Multiplex ligation-dependent probe amplification when indicated
- Nationwide
- Targeted sequencing of 11 causal genes
- Multiplex ligation-dependent probe amplification when indicated
Main finding
As reported in the abstract
- Probands with P/LP variants
- 67 (28.9%)
- GCK
- 25
- HNF1A
- 22
- HNF1B
- 7
- HNF4A
- 6
- ABCC8
- 4
- NEUROD1, PDX1 and INSR
- 1 each
- Carriers with P/LP variants in actionable genes (GCK, HNF1A, HNF1B, HNF4A, ABCC8)
- 64 (95.5%)
Observational data: associations, not effects.
Further findings
| Outcome | P value |
|---|---|
| MODY probability scores, probands with vs without P/LP variants | P < 0.001 |
- Maturity-onset diabetes of the young (MODY) probability scores, probands with vs without P/LP variants: MODY probability scores higher in probands with P/LP variants
P/LP variants in actionable genes (GCK, HNF1A, HNF1B, HNF4A, ABCC8)
- Carriers of P/LP variants in actionable genes, of the 67 P/LP carriers
- 64 (95.5%)
Clinical characteristics, P/LP variant carriers vs noncarriers
- P/LP variant carriers were younger at diagnosis, had lower BMI and better metabolic control than noncarriers; clinical heterogeneity was substantial
MODY probability scores, probands with vs without P/LP variants
- Early insulin initiation substantially lowered the probability scores
P/LP cases not meeting classical screening criteria (young onset ≤25 years and three-generation family history)
- Cases not meeting classical screening criteria
- 35 (52.2%)
Original publication
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