Genetics of non-syndromic childhood obesity and the use of high-throughput DNA sequencing technologies

Fonseca, Ana Carolina Proença da; Mastronardi, Claudio A.; Johar, Angad; Arcos‐Burgos, Mauricio; Paz-Filho, Gilberto

doi:10.1016/j.jdiacomp.2017.04.026

Cited by 55 publications

(67 citation statements)

References 139 publications

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“…Obesity is a complex disease with various contributing environmental and genetic factors. To uncover the principal genetic factors behind obesity, several advanced research strategies have been used, including twin studies, genome-wide association studies (GWASs), chromosomal microarray analyses and next generation sequencing (1). For example, common single nucleotide polymorphisms (SNPs) in multiple genes have been shown to modulate the risk of obesity, although each of these have only a minor effect on body mass index (BMI) variation (2,3).…”

Section: Introductionmentioning

confidence: 99%

“…The discovery of these monogenic mutations has increased our understanding of the mechanisms controlling energy balance. Single-gene mutations are estimated to account for ∼7% of cases of non-syndromic severe obesity (1). Of them, MC4R mutations are the most frequent with over 300 reported variants (9).…”

Section: Introductionmentioning

confidence: 99%

“…SIM1 and BDNF are transcription and neurotropic factors that control the neuronal differentiation of the hypothalamus and mutations in genes encoding these proteins have been associated with obesity (1). Recently, new obesity related genes involved in hypothalamic development or melanocortin pathway have been identified, such as ADCY3, MYT1L, POU3F2, GRPR, and LRP2 (1,5,(18)(19)(20)(21)(22).…”

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: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

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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“…Childhood obesity is a main public health problem of the 21 st century as defined by the World Health Organization (WHO). 21 It affects the child's psychological, mental, and physical health. The study of different forms of childhood obesity is mandatory due to its extremely complex etiology.…”

Section: Discussionmentioning

confidence: 99%

Monogenic leptin deficiency in early childhood obesity

et al. 2019

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Summary Background Early childhood obesity is a public health problem worldwide. It affects different aspects of physical and mental child's health. Identifying the etiologies, especially treatable and preventable causes, can direct health professionals toward proper management. Analysis of serum leptin levels and leptin gene mutations is a rapid and easy step toward the diagnosis of congenital leptin deficiency that is considered an important cause in early childhood obesity. Objectives The aim of this study was to diagnose monogenic leptin deficiency in Egyptian children presenting with early onset obesity (EOO). Methods The current cross‐sectional study included 80 children who developed obesity during the first year of life with BMI > 2 SD (for age and sex). The studied population was subjected to history taking, auxological assessment, serum leptin assay, and leptin gene sequencing. Results Ten cases had leptin deficiency (12.5%), while 18 cases showed elevated leptin levels (22.5%). Leptin gene variants in the coding region were identified in 30% of the leptin‐deficient group: two novel homozygous disease‐causing variants (c.104 T > G and c.34 delC) and another previously reported homozygous pathogenic variant (c.313C > T). Conclusion Leptin deficiency is considered a significant cause of monogenic obesity in Egyptian children with early‐onset obesity as the diagnosis of these patients would be a perfect target for recombinant leptin therapy.

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“…The elevated prevalence of obesity is mostly due to the lifestyle changes in the last decades. These changes have resulted in an increased consumption of hypercaloric foods and reduced physical activity [7]. Energy expenditure, especially during exercise, plays an important role in combatting the development of obesity and related features.…”

Section: Introductionmentioning

confidence: 99%

Genetic Variants in the Activation of the Brown-Like Adipocyte Pathway and the Risk for Severe Obesity

Fonseca

Marchesini

et al. 2020

Obes Facts

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Background: Regular physical activity has an important role in energy expenditure and combats the development of obesity. During exercise, PPARGC1A is overexpressed, stimulating an increase of the expression of FNDC5. This protein is cleaved to release the hormone irisin, which activates a browning process in white adipose tissue through an increase in UCP1 expression. As a result, irisin leads to mitochondrial heat production and energy expenditure. Objectives: The aim of this study was to investigate whether genetic variants in genes related to browning are associated with severe obesity and obesity-related features. This case-control study comprised 210 individuals with severe obesity (median body mass index [BMI] 45.6 [range 40.5-52.2]) and 191 normal-weight subjects ). Methods: Genomic DNA was extracted from peripheral blood and the genotypes of the PPARGC1A (rs8192678, rs3736265, rs2970847, and rs3755863) and UCP1 (rs6536991 and rs12502572) genes were obtained using Taqman ® assay. For the FNDC5 gene, screening of exons 3-5 as well as their intron-exon boundaries was performed using automatic sequencing. Results: Our results demonstrated that PPARGC1A rs2970847 and UCP1 rs12502572 are associated with severe obesity. Furthermore, these polymorphisms influence anthropometric traits, such as BMI, body weight, and body adiposity index. Our findings also showed a dose-effect relationship between PPARGC1A rs8192678 and fasting plasma glucose. Finally, 5 rare mutations were identified in FNDC5, and 1 of these is a novel missense mutation. Conclusion: This study shows that genetic variants in the activation of brown-like adipocyte pathway play an important role in the susceptibility to severe obesity.

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Genetics of non-syndromic childhood obesity and the use of high-throughput DNA sequencing technologies

Abstract: The understanding of the genetic causes of obesity and the usefulness and limitations of the genetic diagnostic approaches can contribute to the development of new personalized therapeutic targets against obesity.

Cited by 55 publications

References 139 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

Monogenic leptin deficiency in early childhood obesity

Genetic Variants in the Activation of the Brown-Like Adipocyte Pathway and the Risk for Severe Obesity

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