Abstract
BackgroundNeonatal diabetes mellitus (NDM) is a rare condition that occurs within the first six months of life. Permanent NDM (PNDM) is caused by mutations in specific genes that are known for their expression at early and/or late stages of pancreatic beta‐ cell development, and are either involved in beta‐cell survival, insulin processing, regulation, and release. The native population in Qatar continues to practice consanguineous marriages that lead to a high level of homozygosity. To our knowledge, there is no previous report on the genomics of NDM among the Qatari population. The aims of the current study are to identify patients with NDM diagnosed between 2001 and 2016, and examine their clinical and genetic characteristics.MethodsTo calculate the incidence of PNDM, all patients with PNDM diagnosed between 2001 and 2016 were compared to the total number of live births over the 16‐year‐period. Whole Genome Sequencing (WGS) was used to investigate the genetic etiology in the PNDM cohort.ResultsPNDM was diagnosed in nine (n = 9) patients with an estimated incidence rate of 1:22,938 live births among the indigenous Qatari. Seven different mutations in six genes (PTF1A, GCK, SLC2A2, EIF2AK3, INS, and HNF1B) were identified. In the majority of cases, the genetic etiology was part of a previously identified autosomal recessive disorder. Two novel de novo mutations were identified in INS and HNF1B.ConclusionQatar has the second highest reported incidence of PNDM worldwide. A majority of PNDM cases present as rare familial autosomal recessive disorders. Pancreas associated transcription factor 1a (PTF1A) enhancer deletions are the most common cause of PNDM in Qatar, with only a few previous cases reported in the literature.
Highlights
Neonatal diabetes mellitus (NDM) or “early‐onset” diabetes is a rare form of diabetes characterized by hyperglycemia that presents during the first six months of life
We have identified several autosomal recessive disorders associated with Permanent NDM (PNDM), including isolated pancreatic agenesis (OMIM 615935) due to pancreas associated transcription factor 1a (PTF1A) mutation, Fanconi– Bickel syndrome (FBS) due to solute carrier family 2 member 2 (SLC2A2) mutation (OMIM 227810), Wollcot– Ralison Syndrome (WRS) due to eukaryotic translation initiation factor 2 alpha kinase 3 (EIF2AK3) mutation (OMIM 226980), and homozygous recessive glucokinase (GCK, OMIM 138079) and insulin (INS, OMIM 176730) mutations
We discuss the first data on PNDM from The State of Qatar
Summary
Neonatal diabetes mellitus (NDM) or “early‐onset” diabetes is a rare form of diabetes characterized by hyperglycemia that presents during the first six months of life. NDM is a monogenic disorder that occurs due to mutations in genes that play an important role in pancreatic development, beta‐cell survival, insulin processing, regulation, and release. Permanent NDM (PNDM) is caused by mutations in specific genes that are known for their expression at early and/or late stages of pancreatic beta‐ cell development, and are either involved in beta‐cell survival, insulin processing, regulation, and release. Results: PNDM was diagnosed in nine (n = 9) patients with an estimated incidence rate of 1:22,938 live births among the indigenous Qatari. In the majority of cases, the genetic etiology was part of a previously identified autosomal recessive disorder. Pancreas associated transcription factor 1a (PTF1A) enhancer deletions are the most common cause of PNDM in Qatar, with only a few previous cases reported in the literature
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