Clinical and molecular characteristics of patients with type 1 and type 2 DM
Of the 276 patients, 206 patients (74.6%) were diagnosed with type 1 DM, 49 patients (17.8%) were diagnosed with type 2 DM, and 21 patients (7.6%) were diagnosed with clinically suspected monogenic diabetes. The clinical characteristics at diagnosis of type 1 DM, type 2 DM, and monogenic diabetes are shown in Table 1.
Table 1
Clinical features of patients with diabetes mellitus (DM) at diagnosis
| Type 1 DM | Type 2 DM | MODY | Neonatal DM | CFRD | Genetic syndromes | MIDD |
Patients, n (%) | 206 (74.6) | 49 (17.8) | 8 (2.9) | 2 (0.7) | 2 (0.7) | 6 (2.2) | 3 (1.1) |
Age at diagnosis, years | 9.9 ± 3.8 | 13.7 ± 2.1 | 13.5 ± 2.8 | 0.1 | 10.6 | 2.1 ± 2.7 | 4.1 ± 0.9 |
BMI Z-score | -0.83 ± 1.22 | 2.59 ± 1.47 | -0.33 ± 1.00 | NA | 0.45 ± 4.01 | NA | -3.29 ± 2.05 |
HbA1c, % | 12.1 ± 2.5 | 10.0 ± 2.0 | 9.7 ± 3.0 | NA | 6.9 | 9.4 ± 2.9 | 8.2 ± 2.8 |
C-peptide, ng/mL | 0.9 ± 1.0 | 4.7 ± 2.7 | 2.2 ± 1.9 | 0.45 | 3.1 | 22.9 ± 38.8 | 6.3 ± 4.9 |
Antibody positivity, n (%) | 137/190 (72.1) | 7/49 (14.3) | 0 | 0 | 0 | 0 | 0 |
DKA at diagnosis, n (%) | 40 (19.4) | 1 (2.0) | 0 | 0 | 0 | 0 | 0 |
BMI, body mass index; CFRD, cystic fibrosis-related diabetes; DKA, diabetic ketoacidosis; MIDD, maternally inherited diabetes and deafness; NA, not available |
Of these 206 patients with type 1 DM, the mean age at diagnosis was 9.9 ± 3.8 years (median, 10.4 years; range, 0.8–17.6 years). The frequency of DKA at diagnosis in the type 1 DM group was 19.4% (40 patients). The β-cell autoantibodies of 190 patients were analyzed. Among them, 137 patients (72.1%) had at least one β-cell autoantibody. The mean serum C-peptide level at diagnosis was 0.9 ± 1.0 ng/mL (reference range, 0.48–3.3 ng/mL).
Among 49 patients with type 2 DM (17.8%), the mean age at diagnosis was 13.7 ± 2.1 years (median, 13.5 years; range, 8.0–16.8 years). The mean fasting serum C-peptide level (available for 44 patients) was 4.7 ± 2.7 ng/mL. DKA and hyperosmolar hyperglycemic state were observed at diagnosis in 1 patient (2.0%) with type 2 DM. Antibody positivity was 14.3% (7 patients) in the type 2 DM group.
Clinical and molecular characteristics of patients with genetically confirmed monogenic diabetes
Of the 276 patients, 21 patients (7.6%) were suspected to have monogenic diabetes: 8 patients had clinical MODY, and the remaining 13 patients had other types of monogenic diabetes. Among them, genetic etiologies were identified in 14 patients (5.1%) from 13 families (Table 2, Supplementary Table 1).
Table 2
Mutations in genes associated with monogenic diabetes
Gene | Nucleotide change | Amino acid change | Exon/Intron | Segregation data | ACMG/AMP guidelines | Phenotype |
HNF1B | c.443C > T | p.S148L | 1 | NA | Pathogenic | MODY 5 |
KCNJ11 | c.602G > A | p.R201H | 1 | NA | Pathogenic | DEND syndrome |
WFS1 | c.2171C > T | p.P724L | 8 | Sibling | Pathogenic | Wolfram syndrome |
WFS1 | c.1725_1742del | p.G587_G592del | 8 | Sibling | Likely pathogenic | Wolfram syndrome |
INSR | c.3196C > T | p.R1066* | 17 | Paternal | Pathogenic | Donohue syndrome |
INSR | c.3614C > T | p.Q1232* | 21 | Maternal | Pathogenic | Donohue syndrome |
FOXP3 | c.201 + 1G > A | Splice site | 1 | Maternal | Pathogenic | IPEX syndrome |
SLC2A2 | c.13A > T | p.K5* | 1 | NA | Pathogenic | Fanconi-Bickel syndrome |
EIF2AK3 | c.1293G > A | p.W431* | 6 | NA | Likely pathogenic | Wolcott-Rallison syndrome |
CFTR | c.4056G > C | p.Q1352H | 25 | NA | Uncertain significance | CFRD |
CFTR | c.1322T > C | p.L441P | 10 | NA | Uncertain significance | CFRD |
MTTL1 | m.3243A > G | Mitochondrial gene | Mitochondrial gene | NA | Pathogenic | MIDD |
Bold, novel mutation; ACMG/AMP, interpretation according to the guidelines of the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) [24]; NA, not available. |
MODY. Eight patients were suspected to have clinical MODY. Their mean age at diagnosis was 13.5 ± 2.8 years (range, 9.4–18.5 years). All patients were non-obese with body mass index of 19.3 ± 1.3 kg/m2 and normal serum C-peptide level at diagnosis (2.2 ± 1.9 ng/mL). A 14.6-year-old girl was diagnosed with MODY 5 with heterozygous mutations in HNF1B [c.443C > T (p.S148L) in exon 2], which was previously reported to be pathogenic [25]. She underwent renal transplantation at the age of 16.1 years because of chronic renal failure. Whole exome sequencing for the remaining 7 patients did not identify any rare sequence variants in the genes associated with monogenic diabetes.
Neonatal diabetes mellitus. Two patients were diagnosed with neonatal DM: one with a transient form caused by paternal uniparental disomy of 6q24 and the other with a permanent form with a heterozygous mutation [c.602G > A (p.R201H)] in KCNJ11, leading to developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome [18]. The patient was initially misdiagnosed as having type 1 DM; however, insulin therapy was successfully switched to oral sulfonylurea therapy.
Wolfram syndrome. Two male siblings were initially misdiagnosed as having type 1 DM at the age of 4.9 and 6.1 years, respectively, until urinary incontinence and bilateral optic nerve atrophy occurred. They were compound heterozygous for a known pathogenic c.2171C > T (p.P724L) mutation [26] and a novel c.1725_1742del (p.G587_G592del) mutation in WFS1.
Donohue syndrome. A male newborn with acanthosis nigricans, hirsutism, high insulin level, and intrauterine growth retardation was compound heterozygous for c.3196C > T (p.R1066*) and c.3614C > T (p.Q1232*) in the tyrosine kinase domain of the β-subunit in INSR [19].
IPEX syndrome. The patient was initially misdiagnosed as having type 1 DM at the age of 11 months. However, he showed unusual clinical features including pure red cell aplasia and membranous glomerulopathy at the age of 39 months, and posterior reversible encephalopathy syndrome after a vaccination against influenza A (H1N1) virus at the age of 11 years. DNA analysis of the FOXP3 gene identified a splice site mutation of c.201 + 1G > A, which was inherited from his mother [17].
Fanconi-Bickel syndrome. A 3-day-old female presented with hyperglycemia, glycosuria, and galactosemia. She failed to grow during the follow-up period, and her liver function deteriorated with micronodular cirrhosis and marked fatty changes on liver biopsy. Homozygous mutation of c.13A > T (p.K5*) in exon 1 was identified by Sanger sequencing of SLC2A2 [20].
Wolcott-Rallison syndrome. A 3-month-old Arab girl presented with neonatal DM, epiphyseal dysplasia, and liver failure and was diagnosed with Wolcott-Rallison syndrome caused by the pathogenic homozygous mutation of c.1293G > A (p.W431*) in EIF2AK3, which was previously reported to be pathogenic [27].
Cystic fibrosis-related diabetes. Cystic fibrosis-related diabetes was detected in two patients with CFTR mutations. They showed pancreatitis-related hyperglycemia at the age of 7.7 and 14.2 years, respectively, without β-cell autoantibodies.
Maternally inherited diabetes and deafness (MIDD). Three patients with m.3243A > G mutation in MTTL1 were diagnosed as having MIDD with an HbA1c level of 8.2 ± 2.8% without β-cell autoantibodies. All patients have been treated with insulin injection.