Background: Pancreas aplasia (PA) and neonatal diabetes mellitus (NDM) syndrome is a rare disease that usually presents in the 1st months of life.
Objective and hypotheses: We aimed to characterize molecular genetic defects in a cohort of six NDM/PA patients with up-to-date unknown pathogenesis with optimum genetic testing.
Method: As part of our ESPE-RU-project Understanding the molecular basis of diabetes mellitus associated with novel syndromes, we established a cohort of six patients with neonatal diabetes (five onset <6 months of life, one at 2.5 years) and pancreas aplasia or hypoplasia. In detail, four of six individuals had consanguineous parents, two had complete pancreas aplasia, three pancreas hypoplasia and one had aplasia of the dorsal pancreas. For genetic analysis, we performed Nextera Rapid Capture exome assay, a custom-designing target enrichment (including 57 genes coding for monogenic diabetes, type 2 diabetes risk or pancreas development, including the PTF1A enhancer region).
Results: We identified one homozygous PTF1A enhancer mutation (Hg19: Chr 10: 23508437 A>G) in four of our six individuals with three families having known consanguinity. All individuals had a reduced exocrine pancreas function, but applying pancreas imaging only two had complete pancreas aplasia while two had pancreas hypoplasia. From the additional two individuals the first had dorsal pancreas aplasia and a de-novo mutation V252M (c.G754A) in KCNJ11 explaining NDM but not PA. In the second individual from one consanguineous family, we could not identify any genetic cause, including NGS and haplotype mapping of his family.
Conclusion: The known homozygous mutation in the distal enhancer region of PTF1A was the commonest cause of PA/NDM in our cohort and the novel KCNJ11 mutation could at least explain neonatal diabetes in the fifth case. The high rate detecting disease-causing mutations reflects the contribution of new genetic knowledge and systematic use of novel techniques (targeted enrichment, NGS).
Funding: This work was supported by the ESPE-RU-project Understanding the molecular basis of diabetes mellitus associated with novel syndromes.
01 - 03 Oct 2015
European Society for Paediatric Endocrinology