Genetic mutations associated with neonatal diabetes mellitus in Omani patients

• Published in: Journal of Pediatric Endocrinology & Metabolism Vol. 31; no. 2; pp. 195 - 204
• Main Authors: Al Senani, Aisha, Hamza, Nishath, Al Azkawi, Hanan, Al Kharusi, Manal, Al Sukaiti, Nashat, Al Badi, Maryam, Al Yahyai, Moza, Johnson, Matthew, De Franco, Elisa, Flanagan, Sarah, Hattersley, Andrew, Ellard, Sian, Mula-Abed, Waad-Allah
• Format: Journal Article
• Language: English
• Published: Germany De Gruyter 26.01.2018; Walter de Gruyter GmbH
• Subjects: Adaptor Proteins, Signal Transducing - chemistry; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Amino Acid Substitution; Chromosomes, Human, Pair 6 - metabolism; Cohort Studies; Consanguinity; Diabetes; Diabetes Mellitus - epidemiology; Diabetes Mellitus - genetics; Diabetes Mellitus - metabolism; Diabetes Mellitus - physiopathology; DNA Methylation; DNA Mutational Analysis; Exons; Female; genetics; Germinal Center Kinases; Glucose Transporter Type 2 - chemistry; Glucose Transporter Type 2 - genetics; Glucose Transporter Type 2 - metabolism; Humans; Infant; Infant, Newborn; Interleukin-2 Receptor alpha Subunit - chemistry; Interleukin-2 Receptor alpha Subunit - genetics; Interleukin-2 Receptor alpha Subunit - metabolism; Male; Mutation; neonatal diabetes; next-generation sequencing; Oman - epidemiology; Pedigree; Potassium Channels, Inwardly Rectifying - chemistry; Potassium Channels, Inwardly Rectifying - genetics; Potassium Channels, Inwardly Rectifying - metabolism; Prevalence; Protein-Serine-Threonine Kinases - chemistry; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Oman; mutation; neonatal diabetes; genetics; next-generation sequencing
• ISSN: 0334-018X; 2191-0251
• DOI: 10.1515/jpem-2017-0284

Neonatal diabetes mellitus (NDM) is a rare disorder worldwide where diabetes is diagnosed in the first 6 months of life. However, Oman has a relatively high incidence of NDM. In this study, we investigated the genetic etiologies underlying NDM and their prevalence in Oman. We collected a cohort of 24 NDM patients, with and without genetic diagnosis, referred to our center from 2007 to 2015. All patients without a genetic diagnosis were tested for mutations in 23 NDM-associated genes using a custom-targeted next-generation sequencing (NGS) panel and methylation analysis of the 6q24 locus. A genetic abnormality was detected in 15/24 (62.5%) of our Omani NDM patients. We report the detection of 6q24 methylation abnormalities and KCNJ11 mutations for the first time in Omani NDM patients. Unlike Western populations where NDM is predominantly due to mutations in the KCNJ11, ABCC8 and INS genes, NDM due to homozygous GCK gene mutations were most prevalent in Oman, having been observed in seven out of 15 NDM patients in whom we established the genetic etiology. This reflects the high degree of consanguinity which makes recessive conditions more likely. The results of this study are likely to impact any future strategy to introduce genetic testing for NDM disorders within the national healthcare system in Oman.