Genetic obesity: next-generation sequencing results of 1230 patients with obesity

Kleinendorst, Lotte; Massink, Maarten P.G.; Cooiman, Mellody I.; Savas, Mesut; Baan-Slootweg, Olga H van der; Roelants, Roosje J; Janssen, I.; Meijers-Heijboer, Hanne; Knoers, Nine V A M; Amstel, Hans Kristian Ploos van; Rossum, Elisabeth F.C. van; Akker, Erica L T van den; Haaften, Gijs van; Zwaag, Bert van der; Haelst, Mieke M. van

doi:10.1136/jmedgenet-2018-105315

Cited by 73 publications

(62 citation statements)

References 28 publications

(12 reference statements)

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“…The prevalence of pathogenic variants in MC4R in our cohort was 2% (2/92), which is comparable to previous reports (7,(10)(11)(12)(13)(14). The patients in our study with the novel MC4R frameshift deletion had severe childhood obesity and hyperphagia.…”

Section: Discussionsupporting

confidence: 87%

“…We performed a literature search to identify genes related to the melanocortin pathway and the development of the hypothalamus (1,5,12,18,19,21,(26)(27)(28)(29)(30)(31)(32)(33). The 24 genes included in the panel were: (1) genes in which variants have previously been reported to cause or associate with obesity (ADCY3, BDNF, CPE, GRPR, LEP, LEPR, LRP2, MC3R, MC4R, MRAP2, MYT1L, NPY, NTRK2, PCSK1, POMC, SH2B1, SIM1, TUB) and (2) genes previously reported in animal models/linkage analysis/CNV studies to be involved in the melanocortin pathway or development of hypothalamus (ARNT2, ISL1, NEUROG3, OTP, OXT, POU3F2).…”

Section: Genes In the Panelmentioning

confidence: 99%

“…Of them, MC4R mutations are the most frequent with over 300 reported variants (9). The prevalence of pathogenic variants in MC4R in Finnish patients with early-onset obesity was reported to be 1.8% (10), and in other populations 1.5-5.8% (7,(11)(12)(13)(14). Patients with loss-of-function MC4R mutations typically present with severe childhood obesity, hyperphagia, hyperinsulinemia, and increased linear growth (11,15).…”

Section: Introductionmentioning

confidence: 99%

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Rare Variants in Genes Linked to Appetite Control and Hypothalamic Development in Early-Onset Severe Obesity

et al. 2020

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Context: The hypothalamic circuit has an essential role in the regulation of appetite and energy expenditure. Pathogenic variants in genes involved in the hypothalamic leptin-melanocortin pathway, including melanocortin-4-receptor (MC4R), have been associated with monogenic obesity.Objective: To determine the rate and spectrum of rare variants in genes involved in melanocortin pathway or hypothalamic development in patients with severe early-onset obesity (height-adjusted weight >60% before age 10 years). Methods:We used a custom-made targeted exome sequencing panel to assess peripheral blood DNA samples for rare (minor allele frequency <0.5%), pathogenic/likely pathogenic variants in 24 genes related to the hypothalamic circuit in 92 subjects (51% males, median age 13.7 years) with early-onset severe obesity (median body mass index (BMI) Z-score + 4.0).

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Section: Discussionsupporting

confidence: 87%

Section: Genes In the Panelmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Rare Variants in Genes Linked to Appetite Control and Hypothalamic Development in Early-Onset Severe Obesity

et al. 2020

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“…Although obesity is suggested to be a multifactorial condition, mostly caused by our changing obesogenic environment, an underlying genetic defect has been reported in approximately 2%-15% of morbidly obese patients (Foucan et al, 2017;Kleinendorst et al, 2018). Mutations in the melanocortine-4 receptor (MC4R) gene are the most common cause of monogenic obesity, with a prevalence of 0.5%-5.8%, with the highest values expected in cohorts with early onset obesity (Valette et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Genetic analysis in the bariatric clinic; impact of a PTEN gene mutation

Cooiman

Kleinendorst

Zwaag

et al. 2019

Molec Gen & Gen Med

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Background Pathogenic PTEN gene mutations are known to cause PTEN tumor hamartoma syndrome. Recent studies also suggest a role for PTEN mutations in the pathogenesis of obesity. No PTEN mutations have been reported among bariatric surgery patients and obesity treatment results are unknown. Since preventive screening for associated tumors is offered to patients with molecular proven PTEN hamartoma tumor syndrome, recognition of this condition in the bariatric surgery clinic is important. Method We present a patient with morbid obesity who carries a known pathogenic PTEN mutation, identified at the bariatric surgery clinic using an obesity gene panel consisting of 52 obesity–associated genes. We analyzed the weight loss response during the first 3 years after Sleeve Gastrectomy. Results At 1, 2 and 3 years after surgery, the patient achieved a Total Body Weight Loss of 39.4%, 48.8% and 44.9%, respectively. This corresponds to the results of a control group of 18 female patients with normal genetic test results. Conclusion Our patient illustrates the importance of recognizing this serious genetic condition for which preventive cancer screening options are available. The positive weight loss results after Sleeve Gastrectomy suggest that this could be a successful treatment option for obesity patients with PTEN mutations.

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“…As new therapies are arising that target specific types of obesity, we here plead for screening for genetic obesity in a subgroup of patients who have a high clinical suspicion for these types of genetic obesity. A recent study found a confirmed diagnosis of genetic obesity in 3.9% of patients who were clinically suspected of genetic obesity . Indications for genetic screening include an early age of onset, below 5 years of age, (or in adult populations a prepubertal onset), a family history with striking weight differences between family members (which may indicate monogenic obesity), and severe hyperphagia (which can be seen in monogenetic obesity‐with and without intellectual deficit).…”

Section: Assessment Of Obesity—clinical Historymentioning

confidence: 99%

A comprehensive diagnostic approach to detect underlying causes of obesity in adults

et al. 2019

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SummaryObesity is a worldwide growing problem. When confronted with obesity, many health care providers focus on direct treatment of the consequences of adiposity. We plead for adequate diagnostics first, followed by an individualized treatment. We provide experience‐based and evidence‐based practical recommendations (illustrated by clinical examples), to detect potential underlying diseases and contributing factors. Adult patients consulting a doctor for weight gain or obesity should first be clinically assessed for underlying diseases, such as monogenetic or syndromic obesity, hypothyroidism, (cyclic) Cushing syndrome, polycystic ovarian syndrome (PCOS), hypogonadism, growth hormone deficiency, and hypothalamic obesity. The most important alarm symptoms for genetic obesity are early onset obesity, dysmorphic features/congenital malformations with or without intellectual deficit, behavioral problems, hyperphagia, and/or striking family history. Importantly, also common contributing factors to weight gain should be investigated, including medication (mainly psychiatric drugs, (local) corticosteroids, insulin, and specific β‐adrenergic receptor blockers), sleeping habits and quality, crash diets and yoyo‐effect, smoking cessation, and alcoholism. Other associated conditions include mental factors such as chronic stress or binge‐eating disorder and depression.Identifying and optimizing the underlying diseases, contributing factors, and other associated conditions may not only result in more effective and personalized treatment but could also reduce the social stigma for patients with obesity.

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Genetic obesity: next-generation sequencing results of 1230 patients with obesity

Cited by 73 publications

References 28 publications

Rare Variants in Genes Linked to Appetite Control and Hypothalamic Development in Early-Onset Severe Obesity

Rare Variants in Genes Linked to Appetite Control and Hypothalamic Development in Early-Onset Severe Obesity

Genetic analysis in the bariatric clinic; impact of a PTEN gene mutation

A comprehensive diagnostic approach to detect underlying causes of obesity in adults

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