A preliminary study to evaluate the strategy of combining clinical criteria and next generation sequencing (NGS) for the identification of monogenic diabetes among multi-ethnic Asians

• Published in: Diabetes research and clinical practice Vol. 119; pp. 13 - 22
• Main Authors: Ang, Su Fen, Lim, Su Chi, Tan, Clara SH, Fong, Jessie CW, Kon, Winston YC, Lian, Joyce X, Subramanium, Tavintharan, Sum, Chee Fang
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier Ireland Ltd 01.09.2016
• Subjects: Asian Continental Ancestry Group - ethnology; Diabetes Mellitus - diagnosis; Diabetes Mellitus - ethnology; Endocrinology & Metabolism; Female; Genetic testing; Genetic Testing - methods; High-Throughput Nucleotide Sequencing - methods; Humans; MODY; Monogenic diabetes; Next-generation sequencing; MODY; Next-generation sequencing; Genetic testing; Monogenic diabetes
• ISSN: 0168-8227; 1872-8227; 1872-8227
• DOI: 10.1016/j.diabres.2016.06.008

•Genetic testing was conducted for Asians exhibiting MODY clinical phenotypes.•15.5% of our study cohort harbored likely pathogenic/pathogenic variants.•Prevalence of MODY is non-trivial among Asians with young-onset diabetes.•MODY probability calculator (Exeter, UK) performed relatively well in our multi-ethnic cohort. Diabetes is increasing globally and Asia is the epicenter. Among those with young-onset diabetes (<45years), the prevalence of monogenic diabetes is estimated to be non-trivial (∼5%). An accurate diagnosis of monogenic diabetes is important to inform treatment, prognosis and genetic counseling. Therefore, a robust clinical algorithm to identify probands for testing is needed. Our aims are (1) to select probands for genetic testing and variant identification based on their clinical phenotype and (2) to evaluate the MODY probability calculator in our multi-ethnic Asian population. Eighty-four potential probands, identified in accordance with clinical practice guidelines, were subjected to re-sequencing of 16 monogenic diabetes genes and targeted genotyping for mitochondrial 3243A>G point-mutation. Variants, confirmed by bi-directional Sanger sequencing, were classified as pathogenic if they fulfilled the criteria adapted from American College of Medical Genetics. Performance of MODY calculator (with positive-predictive threshold set at >62.4%) for those with diabetes-onset ⩽35years (data input-limit) (n=71) was also evaluated. Thirteen subjects (15.5%) harbored likely pathogenic/pathogenic variants: 6 (2 novel) in HNF1A (1 subject concomitantly had another HNF4A variant), 1 in HNF4A, 2 in mt3243A>G and 1 each in GCK, KCNJ11 (novel), ABCC8 (novel) and PAX4 (novel). Performance of the MODY calculator was: sensitivity 0.769, specificity 0.603 and negative predictive value 0.921. When analysis was restricted to MODY1-3, the performance was: 0.875, 0.587 and 0.974, respectively. The prevalence of MODY is non-trivial (∼15%) among Asians with young-onset diabetes. MODY calculator performs well in our population in nominating probands for genetic testing.