Pleiotropic Genetic Syndromes with Developmental Abnormalities Associated with Obesity

Kousta, Eleni; Hadjiathanasiou, Charalambos; Tolis, G.; Papathanasiou, Astéroula

doi:10.1515/jpem.2009.22.7.581

Cited by 18 publications

(14 citation statements)

References 78 publications

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“…These mutations are all rare and lead, apart from extreme obesity with an early onset, to additional phenotypical manifestations, including red hair ( POMC ), reduced or impaired fertility ( PC1 , leptin and LEPR ), adrenal insufficiency ( POMC ), and impaired immunity ( LEP ) [16, 43, 65]. The pleiotropic effects warrant the consideration that these recessive disorders are classified as syndromal forms of obesity—similar to the Bardet–Biedl, Prader–Willi and other genetic syndromes associated with obesity [43, 66]. The pleiotropic Bardet–Biedl syndrome, of which obesity is one of the main clinical features, has been shown to have an oligogenic basis [14, 19, 43].…”

Section: Introductionmentioning

confidence: 99%

From monogenic to polygenic obesity: recent advances

Hinney

Vogel

Hebebrand

2010

Eur Child Adolesc Psychiatry

206

134

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The heritability of obesity and body weight in general is high. A small number of confirmed monogenic forms of obesity—the respective mutations are sufficient by themselves to cause the condition in food abundant societies—have been identified by molecular genetic studies. The elucidation of these genes, mostly based on animal and family studies, has led to the identification of important pathways to the disorder and thus to a deeper understanding of the regulation of body weight. The identification of inborn deficiency of the mostly adipocyte-derived satiety hormone leptin in extremely obese children from consanguineous families paved the way to the first pharmacological therapy for obesity based on a molecular genetic finding. The genetic predisposition to obesity for most individuals, however, has a polygenic basis. A polygenic variant by itself has a small effect on the phenotype; only in combination with other predisposing variants does a sizeable phenotypic effect arise. Common variants in the first intron of the ‘fat mass and obesity associated’ gene (FTO) result in an elevated body mass index (BMI) equivalent to approximately +0.4 kg/m² per risk allele. The FTO variants were originally detected in a genome wide association study (GWAS) pertaining to type 2 diabetes mellitus. Large meta-analyses of GWAS have subsequently identified additional polygenic variants. Up to December 2009, polygenic variants have been confirmed in a total of 17 independent genomic regions. Further study of genetic effects on human body weight regulation should detect variants that will explain a larger proportion of the heritability. The development of new strategies for diagnosis, treatment and prevention of obesity can be anticipated.

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Section: Introductionmentioning

confidence: 99%

From monogenic to polygenic obesity: recent advances

Hinney

Vogel

Hebebrand

2010

Eur Child Adolesc Psychiatry

206

134

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“…Cette pathologie est reconnue comme une maladie à transmission autosomique dominante mais secondaire au phénomène d'empreinte transmise par l'allèle paternel [5]. Le SPW est caractérisé par une hypotonie musculaire à la naissance, une hyperphagie et impulsivité alimentaire sévère, des troubles du comportement, des traits dysmorphiques, un retard mental, une obésité progressive, un hypogonadisme [6]. La cause moléculaire la plus commune des SPW est la suppression par délétion génomique ou par anomalie fonctionnelle d'une région chromosomique située sur le chromosome 15 (15q11.2-q12).…”

Section: Quelques Exemples D'obésités Génétiquesunclassified

“…Elle est caractérisée par une petite taille, une obésité, une brachydactylie, des malformations du crâne et de la face et parfois des anomalies du développement [6]. Ce syndrome associe une résistance à diverses hormones, dont une résistance à l'action de la parathormone.…”

Section: Ostéodystrophie Héréditaire D'albrightunclassified

“…Le BBS, qui est une maladie à transmission autosomique récessive rare, se caractérise outre l'obésité par une dystrophie rétinienne, une polydactylie, des anomalies rénales, parfois un hypogonadisme et des troubles d'apprentissage [6]. L'approche génétique dans les familles affectées par le syndrome a révélé que plusieurs gènes différents sont impliqués -une douzaine au moins -mais sont tous liés au fonctionnement des cils primaires.…”

Section: Bbsunclassified

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Comment repérer une obésité génétique ?

Poitou

Clément

2010

Obes

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Le développement d'une obésité est parfois lié à des anomalies génétiques rares. On distingue les obésités syndromiques et les formes monogéniques. Les obésités syndromiques sont associées à d'autres anomalies du développement (retard mental, dysmorphie, malformations, atteintes neurosensorielles), la plus fréquente étant le syndrome de Prader-Willi (SPW) dont une des caractéristiques majeures est la présence de troubles du comportement alimentaire incontrôlables. La prise en charge de ces obésités est rendue difficile par la coexistence d'atteintes souvent pluriviscérales et d'anomalies comportementales. La mise en évidence de formes monogéniques d'obésité a permis de progresser dans la compréhension des mécanismes de régulation centrale du poids. En effet, les anomalies généti-ques en cause affectent le plus souvent des facteurs clés de la régulation du poids, intervenant dans la voie de la leptine et des mélanocortines, cible essentielle de la leptine dans l'hypothalamus. Ces obésités se caractérisent par un début précoce généralement dans l'enfance avec une prise de poids rapide et sévère. L'approche clinique est importante, car elle permet d'orienter vers une origine génétique pour ainsi permettre un éventuel diagnostic moléculaire et une prise en charge spécialisée et multidisciplinaire. Pour citer cette revue : Obes 5 (2010). Mots clés Obésités syndromiques · Monogénique · Syndrome de Prader-Willi · MC4-R · LeptineAbstract The development of obesity is sometimes related to rare genetic abnormalities. This is the case in syndromic obesities and in monogenic rare mutations. Syndromic obesities are associated with developmental abnormalities (mental retardation, dysmorphic features, malformations, sensorineural deficiency, etc.). The most common of these obesity syndromes is the Prader-Willi syndrome, one of whose major characteristics is the presence of uncontrollable eating disorders. The clinical care of these patients is complex, complicated by the co-existence with plurivisceral abnormalities and behavioral disorders and necessitates the involvement of multiple clinical expertises. Identification of monogenic forms of obesity has led to progress in understanding mechanisms of central body weight regulation. Indeed, the genetic mutations mostly affect key factors related to the leptin and the melanocortin hypothalamic pathways, involved in energy homeostasis regulation. All mutations in these candidate genes lead to hyperphagia and severe obesity occurring soon after birth. A careful clinical observation is important to highlight evidence for a genetic origin. This approach is essential for molecular diagnoses and future research and allows development of specialized and multidisciplinary care. To cite this journal: Obes 5 (2010).

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“…Indeed, twin and adoption studies have revealed that heritability of obesity is about 40–70% [5, 6]; although it may be that current heritability estimates are inflated. Furthermore, there are a number of rare monogenic causes of obesity [7] and genetic syndromes that have obesity as a central feature [8–10], which in fact provided the first indications of how obesity development might be strongly influenced by genes.…”

Section: Introductionmentioning

confidence: 99%

Copy Number Variants in Obesity-Related Syndromes: Review and Perspectives on Novel Molecular Approaches

D’Angelo

Koiffmann

2012

Journal of Obesity

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In recent decades, obesity has reached epidemic proportions worldwide and became a major concern in public health. Despite heritability estimates of 40 to 70% and the long-recognized genetic basis of obesity in a number of rare cases, the list of common obesity susceptibility variants by the currently published genome-wide association studies (GWASs) only explain a small proportion of the individual variation in risk of obesity. It was not until very recently that GWASs of copy number variants (CNVs) in individuals with extreme phenotypes reported a number of large and rare CNVs conferring high risk to obesity, and specifically deletions on chromosome 16p11.2. In this paper, we comment on the recent advances in the field of genetics of obesity with an emphasis on the genes and genomic regions implicated in highly penetrant forms of obesity associated with developmental disorders. Array genomic hybridization in this patient population has afforded discovery opportunities for CNVs that have not previously been detectable. This information can be used to generate new diagnostic arrays and sequencing platforms, which will likely enhance detection of known genetic conditions with the potential to elucidate new disease genes and ultimately help in developing a next-generation sequencing protocol relevant to clinical practice.

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Pleiotropic Genetic Syndromes with Developmental Abnormalities Associated with Obesity

Cited by 18 publications

References 78 publications

From monogenic to polygenic obesity: recent advances

From monogenic to polygenic obesity: recent advances

Comment repérer une obésité génétique ?

Copy Number Variants in Obesity-Related Syndromes: Review and Perspectives on Novel Molecular Approaches

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