Population-Based Assessment of a Biomarker-Based Screening Pathway to Aid Diagnosis of Monogenic Diabetes in Young-Onset Patients
Article Figures & Tables
Figures
- Figure 1
The UNITED biomarker screening pathway to investigate etiology of diabetes in patients diagnosed at age 30 years or younger. Genetic testing is carried out on all patients who have endogenous insulin (UCPCR ≥0.2 nmol/mmol) and do not have either GAD or IA2 islet autoantibodies. Patients without endogenous insulin or with GAD and/or IA2 islet autoantibodies are classed as having type 1 diabetes.
- Figure 2
Flow chart of patients recruited as part of UNITED. Biomarker screening pathway in 1,376 patients with no known genetic cause for their diabetes in Exeter and Tayside. Eleven dropped out. Seventeen new cases of monogenic diabetes detected (*one case identified through exome sequencing).
Tables
- Table 1
Characteristics of patients diagnosed with monogenic diabetes and details of mutations found for those recruited but diagnosed with monogenic diabetes prior to the study and those diagnosed as a result of the biomarker pathway
ID Genetic characteristics Clinical characteristics Gene Method Zygosity DNA level description Age at diagnosis (years) Treatment Parent with diabetes BMI HbA1c Age at recruitment (years) Additional clinical features Recruited but diagnosed prior to the UNITED study 211 GCK Sanger Het c.97_117dup 3 Diet Yes 34.0 48 16 523 GCK Sanger Het c.97_117dup 27 Diet No 51.7 55 43 537 GCK Sanger Het c.683C>T 11 Diet Yes 13 538 GCK Sanger Het c.683C>T 9 Diet Yes 11 542 GCK Sanger Het c.184G>A 29 Diet Yes 38.9 48 39 543 GCK Sanger Het c.184G>A 4 Diet Yes 4 544 GCK Sanger Het c.184G>A 3 Diet Yes 5 1155 GCK Sanger Het c.1343G>T 25 Diet Yes 19.3 50 25 82095 GCK Sanger Het c.1019G>T 9 Diet Yes 21.9 45 14 535 HNF1A Sanger Het c.379_381del 24 OHA Yes 25.9 51 47 547 HNF1A Sanger Het c.1748G>A 22 Diet Yes 24.4 40 30 Low renal threshold 554 HNF1A Sanger Het c.872dup 18 OHA Yes 30 86 39 566 HNF1A Sanger Het c.872dup 17 OHA Yes 29.2 51 42 Sulphonylurea sensitivity, low renal threshold 603 HNF1A Sanger Het c.1420C>T 20 OHA Yes 26.5 56 42 Low renal threshold 617 HNF1A Sanger Het c.779C>T 25 Diet Yes 25.4 44 26 892 HNF1A Sanger Het c.476G>A 14 Insulin Yes 30.0 63 40 1370 HNF1A Sanger Het c.872dup 21 Diet Yes 36.1 83 21 1409 HNF1A Sanger Het c.872dup 21 OHA+Ins Yes 32.8 95 42 Sulphonylurea sensitivity 80480 HNF1A Sanger Het c.1093_1107+6del 19 OHA 22.9 73 40 82261 HNF1A Sanger Het c.185del 12 OHA+Ins Yes 23.7 73 25 Low renal threshold 82276 HNF1A Sanger Het c.434C>T 13 Insulin Yes 23.8 60 27 82301 HNF1A Sanger Het c.1340C>T 20 OHA Yes 27.4 91 37 82310 HNF1A Sanger Het c.185del 18 OHA Yes 24.4 48 45 Low renal threshold 82374 HNF1A Sanger Het c.1093_1107+6del 19 OHA Yes 23.8 83 20 Sulphonylurea sensitivity 82258 HNF4A Sanger Het c.322G>A 28 Insulin Yes 20.9 60 31 600 HNF1B Sanger Het c.982_986del 20 Insulin No 23.4 122 35 Renal cysts 82033 HNF1B Sanger Het c.466A>G 17 Insulin No 25.3 54 35 Genital tract malformations, renal hypoplasia 82006 KCNJ11 Sanger Het c.601C>T 0 OHA No 26.6 33 35 Diagnosed at 12 weeks of age 539 LMNA Sanger Het c.1930C>T 17 OHA+Ins Yes 24.2 114 49 Lipodystrophy 595 LMNA Sanger Het c.1444C>T 21 OHA+Ins Yes 25.1 62 34 604 3243 Hp m.3243A>G 27 Insulin Yes 26.9 54 36 80541 3243 Hp m.3243A>G 28 Insulin Yes 26.4 83 48 82399 3243 Hp m.3243A>G 29 Insulin Yes 26.4 56 41 Deafness 540 NEUROD1 Sanger Het c.616dup 21 OHA+Ins Yes 49.8 83 36 Lipodystrophy and necrobiosis Identified as part of the biomarker pathway 82372 GCK Sanger Het c.1340G>A 18 Diet No 25.5 46 19 82316 HNF4A Sanger Het c.1064–5_1070del 14 Diet Yes 32.3 38 33 377 HNF4A Sanger Het c.-12G>A 11 Insulin Yes 28.4 104 14 80089 HNF1A Sanger Het c.1349dup 30 Insulin Yes 31.0 72 48 80170 HNF1A Sanger Het c.391C>T 21 Insulin No 23.5 52 35 Low renal threshold 80173 HNF1A Sanger Het c.495G>C 17 Insulin Yes 24.5 56 46 82003 HNF1A Sanger Het c.28A>C 26 Diet Yes 29.8 73 26 82352 HNF1A Sanger Het c.814C>T 13 Insulin Yes 32.3 91 45 82013 HNF1A tNGS Het c.-258A>G 24 OHA Yes 39.6 75 43 307 HNF1B tNGS Het c.1-?_1674+?del 29 Insulin No 22.7 62 31 Asperger syndrome, renal cysts, low fecal elastase, low magnesium 82014 NEUROD1 tNGS Het c.616dup 21 OHA No 35.3 88 31 183 NEUROD1 tNGS Het c.616dup 29 Insulin No 27.1 55 46 82010 3243 tNGS Hp m.3243A>G 27 OHA+Ins Yes 28.6 91 46 82038 PPARG tNGS Het c.1154G>A 22 OHA No 26.6 53 36 Lipodystrophy, acanthosis 80925 TRMT10A tNGS Hom c.79G>T 23 OHA+Ins No 33.0 69 28 Microcephaly, learning difficulties, epilepsy 17 WFS1 tNGS C/Het c.874C>T & c.877del 20 Insulin n/k 21.8 42 24 Bilateral optic atrophy, neurogenic bladder, diet treatment, muscle pain on exercise 175 POLD1 Exome Het c.1812–1814del 14 OHA No 18.6 30 21 Total lipodystrophy, sensorineural deafness, mandibular hypoplasia, hypogonadism, undescended testes, severe insulin resistance References for the genes and further details of the mutations are in Supplementary Table 3.
C/Het, compound heterozygous; Het, heterozygous; Hom, homozygous; Hp, Hp gene deletion; Ins, insulin; OHA, oral hypoglycemic agent; tNGS, targeted next-generation sequencing.
- Table 2
PPV and NPV values for the biomarker pathway, traditional MODY criteria (age at diagnosis younger than 25 years, non–insulin-treated, and parent affected with diabetes), and the MODY probability calculator (using a probability >25%, the pickup rate for the diagnostic laboratory)
N Prevalence of monogenic diabetes PPV (%) NPV (%) Percentage of monogenic cases missed Number needed to test Biomarker pathway 1,407 3.6% (51/1,407) 20.0 99.91 0 5 Traditional MODY criteria 1,362 3.6% (49/1,362) 57.6 97.7 63 2 MODY probability calculator 1,347 3.3% (45/1,347) 40.4 98.3 55 3 Prevalence is the proportion of diagnosed monogenic diabetes, percentage of monogenic cases missed is the proportion of monogenic cases not picked up by the approach, and number needed to test is 1/PPV.
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