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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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          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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            Wolfram (DIDMOAD) syndrome.

            Wolfram syndrome (MIM 222300) is the association of juvenile onset diabetes mellitus and optic atrophy, also known as DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness). Patients present with diabetes mellitus followed by optic atrophy in the first decade, cranial diabetes insipidus and sensorineural deafness in the second decade, dilated renal outflow tracts early in the third decade, and multiple neurological abnormalities early in the fourth decade. Other abnormalities include primary gonadal atrophy. Death occurs prematurely, often from respiratory failure associated with brainstem atrophy. Most patients eventually develop all complications of this progressive, neurodegenerative disorder. The pathogenesis is unknown, but the prevalence is 1 in 770000 in the UK and inheritance is autosomal recessive. A Wolfram gene has recently been mapped to chromosome 4p16.1, but there is evidence for locus heterogeneity, and it is still possible that a minority of patients may harbour a mitochondrial genome deletion. The best available diagnostic criteria are juvenile onset diabetes mellitus and optic atrophy, but there is a wide differential diagnosis which includes other causes of neurodegeneration.
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              GATA6 Mutations Cause a Broad Phenotypic Spectrum of Diabetes From Pancreatic Agenesis to Adult-Onset Diabetes Without Exocrine Insufficiency

              We recently reported de novo GATA6 mutations as the most common cause of pancreatic agenesis, accounting for 15 of 27 (56%) patients with insulin-treated neonatal diabetes and exocrine pancreatic insufficiency requiring enzyme replacement therapy. We investigated the role of GATA6 mutations in 171 subjects with neonatal diabetes of unknown genetic etiology from a cohort of 795 patients with neonatal diabetes. Mutations in known genes had been confirmed in 624 patients (including 15 GATA6 mutations). Sequencing of the remaining 171 patients identified nine new case subjects (24 of 795, 3%). Pancreatic agenesis was present in 21 case subjects (six new); two patients had permanent neonatal diabetes with no enzyme supplementation and one had transient neonatal diabetes. Four parents with heterozygous GATA6 mutations were diagnosed with diabetes outside the neonatal period (12–46 years). Subclinical exocrine insufficiency was demonstrated by low fecal elastase in three of four diabetic patients who did not receive enzyme supplementation. One parent with a mosaic mutation was not diabetic but had a heart malformation. Extrapancreatic features were observed in all 24 probands and three parents, with congenital heart defects most frequent (83%). Heterozygous GATA6 mutations cause a wide spectrum of diabetes manifestations, ranging from pancreatic agenesis to adult-onset diabetes with subclinical or no exocrine insufficiency.
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                Author and article information

                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
                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.

                Article
                ejhg2015161
                10.1038/ejhg.2015.161
                4795203
                26264437
                fd3ccfd5-4ac7-46c2-84da-14755da80554
                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/

                History
                : 24 October 2014
                : 03 March 2015
                : 24 April 2015
                Categories
                Short Report

                Genetics
                Genetics

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