Reinaldo Sousa Dos Santos, 1 Mathilde Daures, 2 Anne Philippi, 2 Sophie Romero, 2 Lorella Marselli, 3 Piero Marchetti, 3 Valérie Senée, 2 Delphine Bacq, 4 Céline Besse, 4 Baz Baz, 5 Laura Marroquí, 1 Sarah Ivanoff, 6 Julien Masliah-Planchon, 6 Marc Nicolino, 7 Jean Soulier, 6 Gérard Socié, 8 Decio L. Eizirik, 1 Jean-François Gautier, 5 and Cécile Julier 2 dUTPase (DUT ) Is Mutated in a Novel Monogenic Syndrome With Diabetes and Bone Marrow Failure Diabetes 2017;66:1086–1096 | DOI: 10.2337/db16-0839 We describe a new syndrome characterized by early- onset diabetes associated with bone marrow failure, affecting mostly the erythrocytic lineage. Using whole- exome sequencing in a remotely consanguineous patient from a family with two affected siblings, we identified a single homozygous missense mutation (chr15.hg19:g.48,626,619A>G) located in the dUTPase (DUT ) gene (National Center for Biotechnology Informa- tion Gene ID 1854), affecting both the mitochondrial (DUT-M p.Y142C) and the nuclear (DUT-N p.Y54C) iso- forms. We found the same homozygous mutation in an unrelated consanguineous patient with diabetes and bone marrow aplasia from a family with two affected siblings, whereas none of the >60,000 subjects from the Exome Aggregation Consortium (ExAC) was homozygous for this mutation. This replicated observation probability was highly significant, thus confirming the role of this DUT mutation in this syndrome. DUT is a key enzyme for main- taining DNA integrity by preventing misincorporation of uracil into DNA, which results in DNA toxicity and cell death. We showed that DUT silencing in human and rat pancreatic b-cells results in apoptosis via the intrinsic cell death pathway. Our findings support the importance of tight control of DNA metabolism for b-cell integrity and warrant close metabolic monitoring of patients treated by drugs affecting dUTP balance. Diabetes may be caused by rare monogenic mutations, accounting for 1%–5% of all cases of the disease (1,2), i.e., .2 million individuals worldwide. These mutations have been identified in the context of familial or atypical clinical presentations, which may affect various organs (1,2). Some of these monogenic diabetes entities remain unrecognized as such and are currently misdiagnosed as type 1 diabetes (T1D) or type 2 diabetes (T2D). Rare syn- dromic associations may be particularly challenging to rec- ognize as specific entities due to the high prevalence of diabetes. The identification and study of familial cases is of critical importance in this situation. The recognition of these rare monogenic entities and their clinical and genetic characterization is important for correct diagnosis and to improve patient’s treatment, besides providing informa- tion on disease mechanisms. Here, we studied two index patients from two unrelated families having two siblings affected by a novel syndrome associating diabetes and bone 1 ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium 2 INSERM UMRS 958, Faculté de Médecine Paris Diderot, Université Paris Diderot- Paris 7, Université Sorbonne Paris Cité, Paris, France 3 Department of Clinical and Experimental Medicine, Islet Cell Laboratory, Univer- sity of Pisa, Pisa, Italy 4 Centre National de Génotypage, Institut de Génomique, Commissariat à l’Energie Atomique, Evry, France 5 Hôpital Lariboisière, Assistance Publique-Hôpitaux de Paris, Department of Diabetes and Endocrinology, Université Paris Diderot-Paris 7, Université Sorbonne Paris Cité, Paris, France 6 Aplastic Anemia Reference Centre, Hematology Laboratory, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, INSERM U944, Université Paris Diderot-Paris 7, Université Sorbonne Paris Cité, Paris, France 7 Hôpital Femme-Mère-Enfant, Division of Pediatric Endocrinology, Hospices Civils de Lyon, Université Lyon 1, Lyon, France 8 Hematology Transplantation, Department of Hematology, Immunology and On- cology, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, Paris, France Corresponding author: Cécile Julier, cecile.julier@inserm.fr. Received 10 July 2016 and accepted 5 January 2017. This article contains Supplementary Data online at http://diabetes .diabetesjournals.org/lookup/suppl/doi:10.2337/db16-0839/-/DC1. R.S.D.S., M.D., and A.P. contributed equally to this work. D.L.E., J.-F.G., and C.J. contributed equally to this work. © 2017 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals .org/content/license. 1086 Diabetes Volume 66, April 2017 GENETICS/GENOMES/PROTEOMICS/METABOLOMICS