Table 1:

Important summary of findings from sequencing studies for monogenic diabetes

Diabetes population studied (country/ ancestry of population)	Genetic testing methodology	Number of studies (Range of sample size tested)	Yield by key characteristics of diabetes population tested	Grade of evidence
Neonatal diabetes diagnosed < 6m (International)	>5 genes (23 gene panel)	1 study (n=1020)	Neonatal diabetes diagnosed <6 months should be offered genetic testing using large-gene panel Yield in a large, unselected other than by age at diagnosis, international study: 840/1020 (82%)	A
Neonatal diabetes diagnosed < 6m (UK, Saudi Arabia, India)	≤5 genes including KCNJ11, ABCC8	3 studies (n=165-750)	Neonatal diabetes diagnosed <6 months tested with small gene panel including KCNJ11/ABCC8 has high yield UK:598/750 (78%), Saudi/UK: 56/88 (64%) Saudi, 32/77 (42%) British India: 39/181 (22%)	A
Neonatal diabetes diagnosed < 6m (International cohorts)	Single genes: INS, or SLC19A2 or after excluding INS, ABCC8, KCNJ11 then PDX1 or GCK	4 studies (n=103-212)	Neonatal diabetes diagnosed <6 months tested for single genes with or without excluding more common gene etiologies have lower yields INS: 33/141 (23%) SLC19A2: 3/212 (1%) PDX1: 3/103 (3%) GCK homozygous: 1/17 (6%)	A
Neonatal diabetes diagnosed <12m (Spain, France, India)	≤5 genes Including INS or KCNJ11 and ABCC8	3 studies (n=189-405)	Neonatal diabetes diagnosed <12 months tested for common genes has a lower yield than for those diagnosed <6 months and there are less cases Spain: 263/405 (65%) diagnosed <6m, and 9/145 (6%) diagnosed 6-12m France: 64/155 (41%), diagnosed <6m and 5/18 diagnosed 6-12m (28%) India: INS only in PNDM, Ab-ve, CP+ve, diagnosed<9m: 8/189 (4%)	A
Neonatal diabetes diagnosed <24 months (UK, International samples)	KCNJ11 only or INS after KCNJ11 negative	3 studies (n=58-70)	There were no cases of monogenic diabetes found in children diagnosed age 12-24 months although only limited genes were tested 0/70 KCNJ11 0/63 KCNJ11 0/58 INS	B
Gestational Diabetes (GDM) European cases	GCK only	3 Studies (n=188-400)	In European women with GDM, yield for GCK-MODY was 1%-6% when otherwise unselected, rising to 31% when only women without obesity were selected ~UK and Ireland: overall 4/356 (1%) ~Diet-treated Danish GDM: 21/354 (6%) mean BMI 28 ~Non-obese Russian GDM: 59/188 (31%)	A
Gestational Diabetes (GDM) China	GCK only	1 Study (n=411)	There is a lack of studies in non-European individuals to define the best testing criteria for GCK-MODY in pregnancy In Chinese women with GDM the yield for GCK was 4% (15/411) when otherwise unselected	C
Children and adults with diabetes, not GDM. Predominantly European ancestry	GCK only	12 Studies (n =100-722)	In European cases, the yield for GCK-MODY in studies with a high clinical suspicion e.g. those with persistent, stable, mild hyperglycemia or fasting hyperglycaemia is high ranging from 30-74%. Adding other MODY criteria such as absence of obesity or family history of diabetes does not consistently increase the yield (27-88%).	A
Children and adults with diabetes, not GDM. Predominantly non-European ancestry	GCK only	3 studies (n=24 and 679)	In a Chinese study with mild fasting hyperglycaemia (5.4-8.3) and low triglycerides, yield was much lower than in the European groups: Discovery group 11/545 (2%) and replication groups 1/207 (0.5%) In the US MODY registry, there were small numbers of non-European participants but the proportion of GCK-MODY was similar at 11/24 (46%) in a Turkish study	B
Children and adults with diabetes, not GDM Predominantly European ancestry	Large monogenic diabetes panels (5-28 genes)	16 studies (n-178-6888)	Yield in Europeans using large MD gene panel varies by selection criteria from 0.7% to 34%. A large study of older, unselected adults showed low yields. In suspected MODY cohorts yield was 16%-23% (4 studies) In the Norwegian Childhood Registry, yield in Ab-ve children diagnosed <15y was 19/462(4.1%) In Turkish children diagnosed <18 years atypical for T1D or T2D, yield was 24/330 (10%) In those Ab-ve diagnosed<30y and either C-peptide positive or non-insulin treated, yield was 4% (51/1407) in a UK study, and higher at 21% (38/178) in additionally non-obese French individuals diagnosed <35 years Comparative yield for 2-3 clinical criteria of diagnosed 15-40y, BMI<30, FH was 16-20% vs diagnosed <40y and BMI<25 was 34% in 1 French study (n= 1564) In a large, relatively unselected and older onset study of “non-T1D” there was a low yield diagnosed>40y at 0.7% (18/2670) and diagnosed<40y at 2% (29/1346) (1 German study)	A
Children and adults with diabetes, not GDM Predominantly Non-European ancestry	Large MD gene panel (>5 genes) or sequential targeted exome/whole exome sequencing	6 studies n=184-488	Yield in mixed ethnicity cohorts using large MD gene panel was similar to that seen in the European cohorts at 13%-26% using various selection criteria: Turkish children diagnosed 5-12y, either low T1D GRS or mod T1D GRS with Ab-ve had yield 34/236 (14%), 14 of the 34 were autosomal recessive diseases (~20% consanguinity) USA/India cohort diagnosed<30y, Ab-ve, FH: 39/152 (26%) France cohort Ab-ve and 2 or more of diagnosed<40y, BMI<30 at diagnosis, FH: 315/1975 (16%) Suspected MODY cohorts 13% and 15% in Brazil and Singapore	A
Children and adults with diabetes, not GDM Mixed ethnicity	Small MODY panels or 3-5 individual genes	7 studies n=100-4010	Yield from testing 3-5 common MD genes varies widely by age and selection criteria (from 8-97%): Suspected MODY (4 studies) ranged from 13% in South Asians, 29% in other UK cohort, 40% in French, 57% in Slovakia/Czech, to 97% in German study In those diagnosed 1-18 years, 4 comparative selection criteria yields ranged from 0% (0/182) in Ab+ve, vs 15% (46/303) in Ab-ve, vs 30% (29/96) with additional FH vs 34% (44/131) with additional FH or HbA1c<7.5% at diagnosis The USA SEARCH cohort with a high level of obesity and non-white ethnicity, diagnosed <20 years, Ab-ve, C-pep +ve, had yield 8%	B