Track topics on Twitter Track topics that are important to you
Syndromic obesity are rare forms of obesity (1% of cases), involving severe obesity and early to multi organ involvement (mental retardation, dysmorphic, sensorineural damage and / or endocrine). To date, the genetic defects are identified in only 5% of cases (Prader-Willi syndrome, Bardet-Biedl syndrome, mutation of leptin or its receptor, the proconvertase-1, proopiomelanocortin or SIM-1 and TRKB genes, high resolution karyotype or abnormal DNA chips, ...). Precocity and severity of obesity are those for a little dependent genetic environment.
The investigators aim is to identify new gene variants in subjects with syndromic obesity sharing common phenotypic features.
Sequencing of exons :
To date, most of syndromic obesities have not been elucidated. But, the lack of identification of molecular abnormalities involved limits information to families about the risk of recurrence and optimal support of patient.
A new molecular biology tool called sequencing of exons ("exome") or targeted sequencing subset of the genome that code for proteins showed its power to identify mutations responsible for rare diseases, in a small number of individuals achieved unrelated. Indeed, this tool helped to identify two mutations in the gene TSPAN12 (Tetraspanin 12) in 23 subjects with exudative vitreo-retinopathy, 3 mutations in the gene PRRT2 (proline-rich transmembrane protein 2) in 8 Chinese families with kinesigenic paroxysmal dyskinesia, 2 nonsense mutations in the gene ANGPTL3 (angiopoietin-like 3) in 2 subjects with familial combined hypolipidemia, a mutation of the gene RBM10 (RNA binding motif 10) in 3 patients with syndromic form of cleft palate (TARP syndrome) or a mutation of the gene PALB2 (partner and localizer of BRCA2) in a patient with pancreatic cancer. The investigators believe that this tool could identify new molecular abnormalities in individuals with syndromic obesity. The detailed analysis of phenotypic data could identify a group of obese patients (at least 10) sharing clinical and biological phenotype and in which this technique would be used.
The exome sequencing will be conducted in subjects selected from their phenotype but also among their relatives (2 parents and a sibling) to provide additional discriminative capacity. Every new variant found at the homozygous state in obese patients and unaffected relatives will be immediately excluded from the list of candidate mutations. Conversely, any variant found in patients but absent in both parents and sibling is a potential de novo mutation. The presence of any variant candidate will be sought in the different exome public databases (dbSNP, 1000 Genomes, Exome Variant Server) and, in the case of an unlisted variant, it will be possible to genotype in cohorts of children with common obesity and non-obese in order to determine its frequency and thus provide additional information about its potential involvement in the syndromic obesity phenotype. The last step that will validate the role of the variant gene in the clinical picture will be in vitro analysis of the functional consequences on the protein and then in vivo in an animal models.
The sequencing of all exons ("exomes") of the 40 selected subjects (10 probands with both parents and non-obese sibling) will be performed on genomic platform using a new type of generation sequencer Illumina HiSeq 2000. To do this, DNA 3μg (15μL concentration to 200 ng/uL) will be needed per sample with then sequencing of type "paired-end" on 2 x 75bp. The generated sequences will be aligned with the reference genome (build hg19) using the BWA Software. Duplicates (PCR duplicates' and 'optical duplicates') will be eliminated as non-paired and misaligned sequences (Q-score <20). The generated sequences will then be recalibrated by GATK software to improve detection of such variations insertion / deletion. Detecting variants will be carried out using tools software and annotation will use the annovar software. Analyzes will focus on detected variants with a depth of at least 10x. The investigators will select any variant found in the homozygous state in the patient and in the heterozygous state with his parents (recessive hypothesis). Variants also found homozygous among the unaffected relatives will be excluded from the list of candidates. Any variant found in patients but absent in both parents may also be a potential candidate in case de novo The investigators believe that this strategy could facilitate diagnosis but also, after validation of the role of this variant in the pathology, assess the risk of recurrence for families by offering prenatal diagnosis if necessary. It also will provide a support as early as possible to these children, like the medical, psychological and social care of children with Prader-Willi syndrome. Indeed, the existence of a genetic diagnosis responsible for the phenotype allows the development of specific life project adapted to the patient and facilitates the development aid for disability through the reference centers and collaboration with departmental homes of disabled people (MDPH). Finally, the progress in understanding the mechanisms of these obesities may help to better understand the pathophysiology of the most common forms of obesity and improve the management.
Patient Selection :
For children and adults with syndromic obesity, day hospitalization is systematically planned in usual care to perform a complete clinical and biological assessment. The information about the various examinations made during the day of hospitalization are given during a consultation. The genetic study will be proposed It was proposed during this consultation to patients, children and adults, and their families. The hospitalization date is usually in the month following the consultation.
Inclusion - patient day hospitalization :
As part of usual care, a precise phenotypic characterization is performed by the investigator day hospitalization : family weight history, retrospective analysis of the personal weight history, clinical examination, anthropometry, dietary consultation, measures of body composition and expenditure energy of rest, food and physical activity questionnaires, endocrine and metabolic balanced.
The research will consist of a blood sample of 20 mL extra for the genetic study and will be conducted in obese subjects after signing a consent. Patients for whom analyzable samples are already stored in the DNA bank No. DC2009-957 will not be sampled again.
Observational Model: Family-Based
Gastroentérologie et Nutrition Pédiatriques , Hôpital Trousseau
Not yet recruiting
Assistance Publique - Hôpitaux de Paris
Published on BioPortfolio: 2015-07-29T14:08:21-0400
This is an open label-pilot study to assess the efficacy and safety of a novel cholesterol-lovastatin topical solution in children with rare syndromic ichthyoses. Often times, these childr...
Background: Nowadays, despite a large number of studies about schizophrenia and genetics, clinical red flags for syndromic forms of schizophrenia remain poorly documented.
Syndromic congenital neutropenia (SCN) includes a heterogeneous group of diseases characterized by congenital neutropenia associated with the involvement of other organs. Most patients hav...
ExoDent specifically aims to discover new genes and new mutations causing isolated amelogenesis imperfecta (AI) and dentinogenesis imperfecta (DI) and other dentin anomalies. The key point...
The inflammatory process is involved in the pathogenesis of obesity. Prader-Willi syndrome (PWS) is a genetic model of syndromic obesity. Adiponectin is an adipokine with potent anti-infla...
Obesity is a very heterogeneous disorder at both the clinical and molecular levels and with high heritability. Several monogenic forms and genes with strong effects have been identified for non-syndro...
Prader-Willi syndrome (PWS) represents the most common genetic-derived obesity disorder caused by the loss of expression of genes located on the paternal chromosome 15q11.2-q13. The PWS phenotype show...
Tooth agenesis (TA) is featured by congenital loss of teeth, and can be divided into two subtypes, non-syndromic TA (NSTA) and syndromic TA (STA). Although 12 candidate genes of NSTA have been reveale...
Childhood obesity is occurring at alarming rates in both developed and developing countries. "Obesogenic" environmental factors must be associated with variants of different risk alleles to determine ...
Background Obesity has become one of the greatest health risks worldwide. Recently, there was an explosion of information regarding the role of the central nervous system (CNS) in the development of m...
A condition of having excess fat in the abdomen. Abdominal obesity is typically defined as waist circumferences of 40 inches or more in men and 35 inches or more in women. Abdominal obesity raises the risk of developing disorders, such as diabetes, hypertension and METABOLIC SYNDROME X.
The condition of weighing two, three, or more times the ideal weight, so called because it is associated with many serious and life-threatening disorders. In the BODY MASS INDEX, morbid obesity is defined as having a BMI greater than 40.0 kg/m2.
A sub-PHENOTYPE of obese individuals who have a risk for CARDIOVASCULAR DISEASES between that of healthy individuals with normal weight and unhealthy individuals with obesity.
BODY MASS INDEX in children (ages 2-12) and in adolescents (ages 13-18) that is grossly above the recommended cut-off for a specific age and sex. For infants less than 2 years of age, obesity is determined based on standard weight-for-length percentile measures.
Agents that increase energy expenditure and weight loss by neural and chemical regulation. Beta-adrenergic agents and serotoninergic drugs have been experimentally used in patients with non-insulin dependent diabetes mellitus (NIDDM) to treat obesity.
Diabetes Diabetes Endocrine Disorders Obesity Oxycontin Renal Disease Thyroid Disorders Endocrinology is the study of the endocrine glands and the hormones that they secrete (Oxford Medical Dictionary). There are several g...
Women's Health - key topics include breast cancer, pregnancy, menopause, stroke Follow and track Women's Health News on BioPortfolio: Women's Health News RSS Women'...
Alternative Medicine Cleft Palate Complementary & Alternative Medicine Congenital Diseases Dentistry Ear Nose & Throat Food Safety Geriatrics Healthcare Hearing Medical Devices MRSA Muscular Dyst...