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      Biallelic RFX6 mutations can cause childhood as well as neonatal onset diabetes mellitus

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          Abstract

          Neonatal diabetes is a highly genetically heterogeneous disorder. There are over 20 distinct syndromic and non-syndromic forms, including dominant, recessive and X-linked subtypes. Biallelic truncating or mis-sense mutations in the DNA-binding domain of the RFX6 transcription factor cause an autosomal recessive, syndromic form of neonatal diabetes previously described as Mitchell–Riley syndrome. In all, eight cases have been reported, with the age at onset of diabetes in the first 2 weeks of life. Here we report two individuals born to double first cousins in whom intestinal atresias consistent with a diagnosis of Mitchell–Riley syndrome were diagnosed at birth, but in whom diabetes did not present until the ages of 3 and 6 years. Novel compound heterozygous RFX6 nonsense mutations (p.Arg726X/p.Arg866X) were identified at the 3′ end of the gene. The later onset of diabetes in these patients may be due to incomplete inactivation of RFX6. Genetic testing for RFX6 mutations should be considered in patients presenting with intestinal atresias in the absence of neonatal diabetes.

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          Most cited references 13

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          Improved genetic testing for monogenic diabetes using targeted next-generation sequencing

          Aims/hypothesis Current genetic tests for diagnosing monogenic diabetes rely on selection of the appropriate gene for analysis according to the patient’s phenotype. Next-generation sequencing enables the simultaneous analysis of multiple genes in a single test. Our aim was to develop a targeted next-generation sequencing assay to detect mutations in all known MODY and neonatal diabetes genes. Methods We selected 29 genes in which mutations have been reported to cause neonatal diabetes, MODY, maternally inherited diabetes and deafness (MIDD) or familial partial lipodystrophy (FPLD). An exon-capture assay was designed to include coding regions and splice sites. A total of 114 patient samples were tested—32 with known mutations and 82 previously tested for MODY (n = 33) or neonatal diabetes (n = 49) but in whom a mutation had not been found. Sequence data were analysed for the presence of base substitutions, small insertions or deletions (indels) and exonic deletions or duplications. Results In the 32 positive controls we detected all previously identified variants (34 mutations and 36 polymorphisms), including 55 base substitutions, ten small insertions or deletions and five partial/whole gene deletions/duplications. Previously unidentified mutations were found in five patients with MODY (15%) and nine with neonatal diabetes (18%). Most of these patients (12/14) had mutations in genes that had not previously been tested. Conclusions/interpretation Our novel targeted next-generation sequencing assay provides a highly sensitive method for simultaneous analysis of all monogenic diabetes genes. This single test can detect mutations previously identified by Sanger sequencing or multiplex ligation-dependent probe amplification dosage analysis. The increased number of genes tested led to a higher mutation detection rate. Electronic supplementary material The online version of this article (doi:10.1007/s00125-013-2962-5) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
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            Molecular mechanism for distinct neurological phenotypes conveyed by allelic truncating mutations.

            The molecular mechanisms by which different mutations in the same gene can result in distinct disease phenotypes remain largely unknown. Truncating mutations of SOX10 cause either a complex neurocristopathy designated PCWH or a more restricted phenotype known as Waardenburg-Shah syndrome (WS4; OMIM 277580). Here we report that although all nonsense and frameshift mutations that cause premature termination of translation generate truncated SOX10 proteins with potent dominant-negative activity, the more severe disease phenotype, PCWH, is realized only when the mutant mRNAs escape the nonsense-mediated decay (NMD) pathway. We observe similar results for truncating mutations of MPZ that convey distinct myelinopathies. Our experiments show that triggering NMD and escaping NMD may cause distinct neurological phenotypes.
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              GATA6 haploinsufficiency causes pancreatic agenesis in humans.

              Understanding the regulation of pancreatic development is key for efforts to develop new regenerative therapeutic approaches for diabetes. Rare mutations in PDX1 and PTF1A can cause pancreatic agenesis, however, most instances of this disorder are of unknown origin. We report de novo heterozygous inactivating mutations in GATA6 in 15/27 (56%) individuals with pancreatic agenesis. These findings define the most common cause of human pancreatic agenesis and establish a key role for the transcription factor GATA6 in human pancreatic development.
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                Author and article information

                Affiliations
                [1 ]Institute of Biomedical and Clinical Science, University of Exeter Medical School , Exeter, UK
                [2 ]Endocrinology Unit, Faculty of Medicine, Department of Pediatrics, Eskişehir Osmangazi University , Eskişehir, Turkey
                Author notes
                [* ]Royal Devon and Exeter NHS Trust, Institute of Biomedical Science , Barrack Road, Exeter EX2 5DW, UK. Tel: +01392 411611; E-mail: sian.ellard@ 123456nhs.net
                [3]

                Current address: St Michael's Hospital, University Hospitals Bristol NHS Foundation Trust, Southwell Street, Bristol, UK.

                [4]

                These authors contributed equally to this work.

                Journal
                Eur J Hum Genet
                Eur. J. Hum. Genet
                European Journal of Human Genetics
                Nature Publishing Group
                1018-4813
                1476-5438
                December 2015
                12 August 2015
                1 December 2015
                : 23
                : 12
                : 1744-1748
                26264437 4795203 ejhg2015161 10.1038/ejhg.2015.161
                Copyright © 2015 Macmillan Publishers Limited

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                Categories
                Short Report

                Genetics

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