Type 1 diabetes genetic risk score discriminates between monogenic and Type 1 diabetes in children diagnosed at the age of <5 years in the Iranian population.

Abstract

AIM:

To examine the extent to which discriminatory testing using antibodies and Type 1 diabetes genetic risk score, validated in European populations, is applicable in a non-European population.

METHODS:

We recruited 127 unrelated children with diabetes diagnosed between 9 months and 5 years from two centres in Iran. All children underwent targeted next-generation sequencing of 35 monogenic diabetes genes. We measured three islet autoantibodies (islet antigen 2, glutamic acid decarboxylase and zinc transporter 8) and generated a Type 1 diabetes genetic risk score in all children.

RESULTS:

We identified six children with monogenic diabetes, including four novel mutations: homozygous mutations in WFS1 (n=3), SLC19A2 and SLC29A3, and a heterozygous mutation in GCK. All clinical features were similar in children with monogenic diabetes (n=6) and in the rest of the cohort (n=121). The Type 1 diabetes genetic risk score discriminated children with monogenic from Type 1 diabetes [area under the receiver-operating characteristic curve 0.90 (95% CI 0.83-0.97)]. All children with monogenic diabetes were autoantibody-negative. In children with no mutation, 59 were positive to glutamic acid decarboxylase, 39 to islet antigen 2 and 31 to zinc transporter 8. Measuring zinc transporter 8 increased the number of autoantibody-positive individuals by eight.

CONCLUSIONS:

The present study provides the first evidence that Type 1 diabetes genetic risk score can be used to distinguish monogenic from Type 1 diabetes in an Iranian population with a large number of consanguineous unions. This test can be used to identify children with a higher probability of having monogenic diabetes who could then undergo genetic testing. Identification of these individuals would reduce the cost of treatment and improve the management of their clinical course.

• Authors: H Yaghootkar, F Abbasi, N Ghaemi, A Rabbani, M N Wakeling, P Eshraghi, S Enayati, S Vakili, S Heidari, K Patel, F Sayarifard, S Borhan-Dayani, T J McDonald, S Ellard, A T Hattersley, M M Amoli, R Vakili, K Colclough
• Journal: Diabetic medicine : a journal of the British Diabetic Association (Diabet Med) Vol. 36 Issue 12 Pg. 1694-1702 (12 2019) ISSN: 1464-5491 [Electronic] England
• PMID: 31276222 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 Diabetes UK.

Chemical References

• Autoantibodies
• Membrane Proteins
• Membrane Transport Proteins
• Nucleoside Transport Proteins
• SLC19A2 protein, human
• SLC29A3 protein, human
• Zinc Transporter 8
• wolframin protein
• Glucokinase
• PTPRN protein, human
• Receptor-Like Protein Tyrosine Phosphatases, Class 8
• Glutamate Decarboxylase

Topics

• Autoantibodies (blood)
• Child, Preschool
• Consanguinity
• Diabetes Mellitus, Type 1 (classification, genetics, immunology)
• Female
• Genetic Predisposition to Disease
• Glucokinase (genetics)
• Glutamate Decarboxylase (immunology)
• High-Throughput Nucleotide Sequencing
• Homozygote
• Humans
• Infant
• Iran
• Islets of Langerhans (immunology)
• Male
• Membrane Proteins (genetics)
• Membrane Transport Proteins (genetics)
• Mutation
• Nucleoside Transport Proteins (genetics)
• Receptor-Like Protein Tyrosine Phosphatases, Class 8 (immunology)
• Zinc Transporter 8 (immunology)