Molecular diagnosis and identification of novel genes involved in monogenic forms of diabetes and associated disorders

Research scientists and clinicians involved : Pascale Benlian, Amélie Bonnefond, Dominique Eladari, Philippe Froguel, Louise Montagne, Pierrette Perimenis, Anne Vambergue and Martine Vaxillaire

 

A major part of our activity is to identify monogenic forms of diabetes and related disorders including kidney diseases, cardiovascular disorders, and severe obesity.

After a whole-exome sequencing (or augmented whole-exome sequencing like CoDE-seq that enables the accurate detection of CNV [copy number variant]) of patients via our platform EquipEx LIGAN (dedicated to next-generation sequencing), we first look for pathogenic mutations within known genes (according to the literature). In this regard, we are implementing a quality management system in our platform EquipEx LIGAN in order to accurately follow the requirements for the molecular diagnosis of rare genetic disorders.

If the primary diagnosis is negative, then we look for new genes by detecting mutational burden in cases (by using for instance the UK Biobank or the 1000 Genomes project as control populations). Then, we perform integrative functional analyses of candidate genes and mutations, notably in collaboration with Team 2 of the lab and others teams from EGID.

 

rech-eq1-2020-fig2

 

Related major publications of the team since 2015 :

– Loss-of-function mutations in MRAP2 are pathogenic in hyperphagic obesity with hyperglycemia and hypertension. Baron M, Maillet J, Huyvaert M, Dechaume A, Boutry R, Loiselle H, Durand E, Toussaint B, Vaillant E, Philippe J, Thomas J, Ghulam A, Franc S, Charpentier G, Borys JM, Lévy-Marchal C, Tauber M, Scharfmann R, Weill J, Aubert C, Kerr-Conte J, Pattou F, Roussel R, Balkau B, Marre M, Boissel M, Derhourhi M, Gaget S, Canouil M, Froguel P, Bonnefond A. Nat Med. 2019 Nov;25(11):1733-1738.

– How Recent Advances in Genomics Improve Precision Diagnosis and Personalized Care of Maturity-Onset Diabetes of the Young. Vaxillaire M, Froguel P, Bonnefond A. Curr Diab Rep. 2019 Aug 5;19(9):79.

– CoDE-seq, an augmented whole-exome sequencing, enables the accurate detection of CNVs and mutations in Mendelian obesity and intellectual disability. Montagne L, Derhourhi M, Piton A, Toussaint B, Durand E, Vaillant E, Thuillier D, Gaget S, De Graeve F, Rabearivelo I, Lansiaux A, Lenne B, Sukno S, Desailloud R, Cnop M, Nicolescu R, Cohen L, Zagury JF, Amouyal M, Weill J, Muller J, Sand O, Delobel B, Froguel P, Bonnefond A. Mol Metab. 2018 Jul;13:1-9.

– Generation of an induced pluripotent stem cell (iPSC) line from a patient with maturity-onset diabetes of the young type 3 (MODY3) carrying a hepatocyte nuclear factor 1-alpha (HNF1A) mutation. Griscelli F, Ezanno H, Soubeyrand M, Feraud O, Oudrhiri N, Bonnefond A, Turhan AG, Froguel P, Bennaceur-Griscelli A. Stem Cell Res. 2018 May;29:56-59.

– Loss-of-function mutations in ADCY3 cause monogenic severe obesity. Saeed S, Bonnefond A, Tamanini F, Mirza MU, Manzoor J, Janjua QM, Din SM, Gaitan J, Milochau A, Durand E, Vaillant E, Haseeb A, De Graeve F, Rabearivelo I, Sand O, Queniat G, Boutry R, Schott DA, Ayesha H, Ali M, Khan WI, Butt TA, Rinne T, Stumpel C, Abderrahmani A, Lang J, Arslan M, Froguel P. Nat Genet. 2018 Feb;50(2):175-179.

High Prevalence of Rare Monogenic Forms of Obesity in Obese Guadeloupean Afro-Caribbean Children. Foucan L, Larifla L, Durand E, Rambhojan C, Armand C, Michel CT, Billy R, Dhennin V, De Graeve F, Rabearivelo I, Sand O, Lacorte JM, Froguel P, Bonnefond A. J Clin Endocrinol Metab. 2018 Feb 1;103(2):539-545.

– A novel NEUROG3 mutation in neonatal diabetes associated with a neuro-intestinal syndrome. Hancili S, Bonnefond A, Philippe J, Vaillant E, De Graeve F, Sand O, Busiah K, Robert JJ, Polak M, Froguel P, Güven A, Vaxillaire M. Pediatr Diabetes. 2018 May;19(3):381-387.

– The unique clinical spectrum of maturity onset diabetes of the young type 3. Lebenthal Y, Fisch Shvalb N, Gozlan Y, Tenenbaum A, Tenenbaum-Rakover Y, Vaillant E, Froguel P, Vaxillaire M, Gat-Yablonski G. Diabetes Res Clin Pract. 2018 Jan;135:18-22.

– Generation of an induced pluripotent stem cell (iPSC) line from a patient with maturity-onset diabetes of the young type 13 (MODY13) with a the potassium inwardly-rectifying channel, subfamily J, member 11 (KCNJ11) mutation. Griscelli F, Feraud O, Ernault T, Oudrihri N, Turhan AG, Bonnefond A, Froguel P, Bennaceur-Griscelli A. Stem Cell Res. 2017 Aug;23:178-181

– Eating Behavior, Low-Frequency Functional Mutations in the Melanocortin-4 Receptor (MC4R) Gene, and Outcomes of Bariatric Operations: A 6-Year Prospective Study. Bonnefond A, Keller R, Meyre D, Stutzmann F, Thuillier D, Stefanov DG, Froguel P, Horber FF, Kral JG. Diabetes Care. 2016 Aug;39(8):1384-92.

– Monogenic diabetes: Implementation of translational genomic research towards precision medicine. Vaxillaire M, Froguel P. J Diabetes. 2016 Nov;8(6):782-795.

– What Is the Best NGS Enrichment Method for the Molecular Diagnosis of Monogenic Diabetes and Obesity? Philippe J, Derhourhi M, Durand E, Vaillant E, Dechaume A, Rabearivelo I, Dhennin V, Vaxillaire M, De Graeve F, Sand O, Froguel P, Bonnefond A. PLoS One. 2015 Nov 23;10(11):e0143373.

– Genetic variants in LEP, LEPR, and MC4R explain 30% of severe obesity in children from a consanguineous population. Saeed S, Bonnefond A, Manzoor J, Shabbir F, Ayesha H, Philippe J, Durand E, Crouch H, Sand O, Ali M, Butt T, Rathore AW, Falchi M, Arslan M, Froguel P. Obesity (Silver Spring). 2015 Aug;23(8):1687-95.

– A girl with incomplete Prader-Willi syndrome and negative MS-PCR, found to have mosaic maternal UPD-15 at SNP array. Morandi A, Bonnefond A, Lobbens S, Carotenuto M, Del Giudice EM, Froguel P, Maffeis C. Am J Med Genet A. 2015 Nov;167A(11):2720-6.

 
 
 
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