Joint Transnational Call 2009 (JTC2009)
Rare monogenic disorders of pancreatic -cell insufficiency cause non autoimmune diabetes mellitus in newborns, in infants/children or in adolescents and young adults. A broad spectrum of often severe clinical conditions have been recognized as neonatal diabetes mellitus (NDM), non autoimmune monogenic diabetes of infancy (MDI), or as maturity-onset diabetes of the young (MODY). Specific mechanisms of -cell dysfunction have been identified in those conditions, which have improved our views of the control of insulin secretion in humans, and had a great clinical impact in the patients care and genetic counseling of families. However, in numerous patients with isolated diabetes or presenting with extra-pancreatic features, the genetic subtype of the -cell defect was still unelucidated at the beginning of our project, suggesting that unrecognized additional defects in important pathways in the insulin-secreting -cell remain to be identified. Within the EuroGeBeta consortium, gathering together six partners in France, Italy, Spain and Israel with complementary expertises in paediatric endocrinology, in genetic diagnosis and counselling, in human genetics and genomic research applied to metabolic diseases, our objectives were: 1/ to establish a transnational European cohort of patients (and families) with non auto-immune neonatal/infancy/childhood -cell insufficiency; 2/ to carry out state-of-the-art genomic studies (using genome-wide SNP-arrays and next-generation sequencing [NGS]) to unravel novel genes and cellular pathways controlling insulin secretion; 3/ to characterize the clinical features and pathophysiological consequences associated with the novel causal mutations; and 4/ to establish an integrated multidisciplinary network for molecular diagnosis, genetic counselling and patient care, with the aim to transfer when possible the new results from basic genetic research into clinical practice. Expected perspectives of our project are to provide a nosological reappraisal of these disorders and their clinical outcomes, and to propose a genetic counselling and personalized treatment based on genomic medicine.
After the three years completion of the project, our major results are:
1/ Establishment of an European cohort of patients with NDM/MDI/MODY, with extensive clinical data for phenotype description and biological samples for genetic/metabolic studies.
2/ Identification of several genetic etiologies (both known and novel subtypes) in patients with NDM/MDI/MODY, with carefull clinical evaluation and impact on treatment; and identification of patients tested negative for the know genes (involved in NDM/MDI/MODY), who are eligible for further genetic studies within the consortium.
3/ Implementation and validation of several high throughput genomic research tools (whole exome sequencing (WES) combined with NGS, SNP-array genotyping) with appropriate analysis pipelines; proof-of-concept that the WES analysis is a powerful approach for discovering novel causal mutations in specific forms of diabetes. Five papers reporting novel mutations (in KCNJ11, ABCC8, GATA6 and MNX1) in five families have been published.
4/ Partners 1 and 2 recently developed new amplicons-sequencing methods combined with NGS for a comprehensive, accurate and cost-effective genetic screening of NDM/MDI/MODY patients; these new diagnostic methods have been fully validated for their use in routine genetic testing offering new perspectives of genetic diagnosis and clinical translation towards the patients.
5/ Description of genotype-phenotype correlations in patients according to genetic subtypes, with evidence of clinical variability within specific subtypes. Several papers on these clinical aspects have been published: on the metabolic control and follow-up of sulphonylurea therapy in patients with a KATP channel mutation, or on a novel frameshift GATA6 mutation associated with NDM/MDI, pancreas hypoplasia/agenesis and heart defects.
6/ The multidisciplinary approach of the EuroGeBeta consortium based on integrated genomic and clinical research resulted in a better management of the therapeutic options in the young studied patients, as well as in a more personalized genetic counselling.
- Vaxillaire, Martine (Coordinator)
CNRS Genomic and Molecular Physiology of Metabolic Diseases Biologie de Lille-Institut [FRANCE]
- Luis Cuesta-Munoz, Antonio
IMABIS Foundation Hospital Carlos Haya Center for the Study of Pancreatic B-Cell Disease [SPAIN]
- Bellan-Echantelot, Christine
AP.MP Groupe Hospitalier Pitié-Salpêtrière Department of Genetics [FRANCE]
- Barbetti, Fabrizio
Bambino Gesù Pediatric Hospital, IRCCS Laboratory of Molecular Endocrinology and Metabolism [ITALY]
- Polak, Michel
Hôpital Necker – Enfants Malades Inserm U845 Pediatric Endocrinology [GERMANY]
- Moshe, Philip
Schneider Children Medical Center Lea Shafer Institute of Endocrinology and Diabetes [ISRAEL]