Prevalence of maturity onset diabetes of the young in a Western Australian paediatric diabetes clinic using targeted massively parallel sequencing

Abstract

Objectives: Maturity Onset Diabetes of the Young (MODY) is an autosomal dominant diabetes with 13 known genes. To date, no prevalence study has assessed for variants in all MODY genes. We aimed to assess MODY prevalence in a paediatric diabetic population, using massively parallel sequencing (MPS). Methods: All West Australian children diagnosed with type 1 diabetes (T1DM) and many with type 2 diabetes (T2DM) are seen at The Princess Margaret Hospital (total clinic = 1052 cases). 13 cases had been previously diagnosed with MODY. Of the remainder, 60 of 104 antibody negative (ab-ve) T1DM and 18 of 62 T2DM samples were available for MPS, assessing all exons of known MODY genes (268 amplicons). Primers were designed using Illumina Design Studio. DNA libraries were constructed using Illumina TruSeqDNA sample preparation kit, then multiplexed and sequenced using Illumina MiSeq. Data were demultiplexed using CASAVA, aligned to the human genome (hg19) using the Novoalign alignment tool and converted using SAMtools and Picard tools. Single nucleotide polymorphisms and indels were called using GATK and annotated using ANNOVAR. After QC, data were filtered for coding variants with minor allele frequency <1% predicted to be deleterious/damaging by SIFT and/or Polyphen. Results: Damaging variants in MODY genes were seen in 6/60 cases with ab-ve T1DM (10%) and 3/18 cases with T2DM (17%): two with HNF1A and ABCC8, one each with HNF4A, GCK, HNF1B, KCNJ11 and one with both PDX1 and PAX4 mutations. The 13 previously identified cases had variants in GCK (9), HNF1B (1), PDX1 (1) and one unknown. The prevalence of MODY in the entire clinic was 2.1%; however, this is an underestimate due to lack of testing in missing samples. Conclusions: The prevalence of MODY is at least 2.1% in a paediatric diabetic population but is 10% in presumed ab-ve T1DM and even higher in presumed T2DM. MODY is under diagnosed; however, MPS is an efficient and cost-effective means of screening patients at risk.L720731672015-11-20 <br />