A Targeted Next Generation Sequencing Panel for Non-syndromic Early Onset Severe Obesity and Identification of Novel Likely -Pathogenic Variants in the MC4R and LEP Genes

Khadilkar, Vaman; Gogate, Nikhita; Gangodkar, Priyanka; Ranade, Shatakshi; Lohiya, Nikhil; Ragte, Trupti; Patil, Kunal; Pilankar, Asawari; Anand, Siddharth; Bapat, Ashwini; Agarwal, Meenal; Kaushik, Karishma S.; Lote-Oke, Rashmi; Khadilkar, Anuradha; Phadke, Nikhil

doi:10.1007/s12098-019-03129-6

Cited by 4 publications

(6 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[5,15] NGS utilizing advanced genomic technology and bioinformatics to analyze genomic or exomic data to identify gene variants for determination of pathogenic or likely pathogenic changes impacting the coding of protein and disturbances with disease causation are becoming more recognized and clinically relevant including for obesity. [7,[16][17][18][19][20] Furthermore, at least 12 gene variants directly involved in monogenic forms of nonsyndromic human obesity have been identified [21] including a novel variant in the low-density lipoprotein receptor 2 (LRP2) gene using whole-exome sequencing of extreme morbid obese patients [22] and novel, likely pathogenic variants in the MC4R and LEP genes were found in a study of 46 patients with clinical suspicion of nonsyndromic early onset severe obesity (NEOSO). [19] Furthermore, new studies in obesity using single-cell RNA sequencing in mice models have revealed obesity-induced alterations in the Brca1 gene mutated in mouse mammary gland microenvironment led to upregulated expression of extracellular matrix genes including Col3a1, Col6a3, Eln and Sparc and down regulation of immune-regulatory genes (Ligp1 and Cxcl10) in stromal subtype cells.…”

Section: Single Gene Causes Of Obesitymentioning

confidence: 99%

“…[7,[16][17][18][19][20] Furthermore, at least 12 gene variants directly involved in monogenic forms of nonsyndromic human obesity have been identified [21] including a novel variant in the low-density lipoprotein receptor 2 (LRP2) gene using whole-exome sequencing of extreme morbid obese patients [22] and novel, likely pathogenic variants in the MC4R and LEP genes were found in a study of 46 patients with clinical suspicion of nonsyndromic early onset severe obesity (NEOSO). [19] Furthermore, new studies in obesity using single-cell RNA sequencing in mice models have revealed obesity-induced alterations in the Brca1 gene mutated in mouse mammary gland microenvironment led to upregulated expression of extracellular matrix genes including Col3a1, Col6a3, Eln and Sparc and down regulation of immune-regulatory genes (Ligp1 and Cxcl10) in stromal subtype cells. This research suggested that obesity alters the extracellular matrix composition and the immune ecosystem in mice through modulating the functionality of mammary stromal fibroblasts.…”

Section: Single Gene Causes Of Obesitymentioning

confidence: 99%

“…[23] NGS is an emerging genetic testing platform gaining ground in the research setting for better understanding of the genetics of obesity at the molecular level but also in the diagnosis and treatment of those clinically affected with syndromic or nonsyndromic obesity. [7,16,19] Standardized advanced technology and validated bioinformatics approaches are now available in CLIA approved commercial molecular genetic testing laboratories for over 100 obesity-related genes in comprehensive obesity-related DNA panels. Patients presenting for genetic evaluation with an obesity phenotype or syndrome could be identified using nextgeneration sequencing, bioinformatics, and genomic databases for any of these genes.…”

Section: Single Gene Causes Of Obesitymentioning

confidence: 99%

See 2 more Smart Citations

Syndromic and Nonsyndromic Obesity: Underlying Genetic Causes in Humans

Duis

Butler

2022

Advanced Biology

View full text Add to dashboard Cite

cardiovascular disease, hypertension, cancers, orthopedic problems, and reduced fertility.Genetic factors can be classified as monogenic or caused by variants of single genes, polygenic involving several interacting genes, or syndromes accompanying obesity and recognized phenotypes. Neurological dysfunction or abnormal regulation of energy utilization, expenditure or storage via hormone production, transport or receptors impact overall energy homeostasis. [1,2] Furthermore, heritability estimates indicate that genetic factors may contribute to up to 70% of obesity, primarily affecting genetic pathways common in lipid metabolism, fat deposition or lipid transport, eating behavior, food selection and hormones, physical activity or energy expenditure based on studies from monozygotic twins reared apart and living in a different environment. [3] Heritability estimates do increase from infancy through adolescence. Over 10 000 references in the medical literature were identified when searching for obesity genes and syndromes with approximately 80 recorded obesityrelated syndromes. [1][2][3][4][5] The prevalence estimates for monogenic obesity syndromes range from about one in 550 to aprroximately one in 1 million. [5] Clinical findings identified in genetic obesity syndromes often overlap, as found in at least 52 related obesity syndromes displaying some form of intellectual disability while seven syndromes present with macrocephaly and seven syndromes with microcephaly. [5] Obesity syndromes may exhibit complex patterns of inheritance including autosomal dominant (e.g., Alstrom), autosomal recessive (e.g., Carpenter), X-linked (e.g., Borjeson-Forssman-Lehmann), errors in genomic imprinting (e.g., Prader-Willi), triallelic inheritance (e.g., Bardet-Biedel) or chromosome anomalies (e.g., 16p11.2 deletion). Hormonal Pathways and Genetic RegulationHormones and their role in appetite control and weight regulation are now an active area of research with clinical trials often focusing on hyperphagia and overeating, common in rare obesity-related disorders such as Prader-Willi syndrome. [6] Eating hormones are becoming increasingly recognized as playing a role in the central nervous system (CNS), particularly regions Growing evidence supports syndromic and nonsyndromic causes of obesity, including genome-wide association studies, candidate gene analysis, advanced genetic technology using next-generation sequencing (NGS), and identification of copy number variants. Identification of susceptibility genes impacts mechanistic understanding and informs precision medicine. The cause of obesity is heterogeneous with complex biological processes playing a role by controlling peptides involved in regulating appetite and food intake, cellular energy, and metabolism. Evidence for heritability shows genetic components contributing to 40%-70% of obesity. Monogenic causes and obesity-related syndromes are discussed and illustrated as well as biological pathways, gene interactions, and factors contributing to the obesity phenotype. Over 550...

show abstract

Section: Single Gene Causes Of Obesitymentioning

confidence: 99%

Section: Single Gene Causes Of Obesitymentioning

confidence: 99%

Section: Single Gene Causes Of Obesitymentioning

confidence: 99%

See 1 more Smart Citation

Syndromic and Nonsyndromic Obesity: Underlying Genetic Causes in Humans

Duis

Butler

2022

Advanced Biology

View full text Add to dashboard Cite

show abstract

“…Genetically, obesity can be classified as: monogenic, primarily caused by mutations in several genes involved in the leptin/melanocortin and adipogenesis pathways (such as MC4R, LEP, LEPR, POMC and PCSK1) [20][21][22]; syndromic, associated with neurodevelopmental abnormalities and/or other malformations due to chromosomal abnormalities or single nucleotide variations affecting genes that encode pivotal proteins in the regulation of energy balance [23]; polygenic, caused by the contribution of more than one genetic variant, whose effect is amplified in a 'weight-gain-promoting' environment [24]. In the last ten years, next-generation sequencing (NGS) approaches have greatly improved the rate of molecular diagnosis because of their extremely high specificity, sensitivity, accuracy, and their timeand cost-effectiveness [20,[25][26][27][28][29][30]. To date, about 250 genetic variants associated with BMI or waist-to-hip ratio have been identified through genome-wide association studies and whole genome or exome sequencing [31].…”

Section: Introductionmentioning

confidence: 99%

Next-Generation Sequencing of a Large Gene Panel for Outcome Prediction of Bariatric Surgery in Patients with Severe Obesity

Bonetti

Dhuli

Ceccarini

et al. 2022

JCM

View full text Add to dashboard Cite

Obesity is a chronic disease in which abnormal deposition of fat threatens health, leading to diabetes, cardiovascular diseases, cancer, and other chronic illnesses. According to the WHO, 19.8% of the adult population in Italy is obese, and the prevalence is higher among men. It is important to know the predisposition of an individual to become obese and to respond to bariatric surgery, the most up-to-date treatment for severe obesity. To this purpose, we developed an NGS gene panel, comprising 72 diagnostic genes and 244 candidate genes, and we sequenced 247 adult obese Italian patients. Eleven deleterious variants in 9 diagnostic genes and 17 deleterious variants in 11 candidate genes were identified. Interestingly, mutations were found in several genes correlated to the Bardet–Biedl syndrome. Then, 25 patients were clinically followed to evaluate their response to bariatric surgery. After a 12-month follow-up, the patients that carried deleterious variants in diagnostic or candidate genes had a reduced weight loss, as compared to the other patients. The NGS-based panel, including diagnostic and candidate genes used in this study, could play a role in evaluating, diagnosing, and managing obese individuals, and may help in predicting the outcome of bariatric surgery.

show abstract

“…In this issue of the journal, Khadilkar et al, report their experience of Next generation genetic testing for two important obesity related genes, Leptin and MC4 receptor in 46 children with early onset non-syndromic obesity [3]. They identified pathological mutations in 4 (8.5%; Leptin deficiency in 3 and MC4 Receptor defects in 1) and emphasized the importance of genetic studies in these children for prognosis, treatment and genetic counseling.…”

mentioning

confidence: 99%

Early Onset Non-Syndromic Obesity- Is Next Generation Sequencing the Next in Agenda?

Bajpai¹

2020

Indian J Pediatr

View full text Add to dashboard Cite

A Targeted Next Generation Sequencing Panel for Non-syndromic Early Onset Severe Obesity and Identification of Novel Likely -Pathogenic Variants in the MC4R and LEP Genes

Cited by 4 publications

References 22 publications

Syndromic and Nonsyndromic Obesity: Underlying Genetic Causes in Humans

Syndromic and Nonsyndromic Obesity: Underlying Genetic Causes in Humans

Next-Generation Sequencing of a Large Gene Panel for Outcome Prediction of Bariatric Surgery in Patients with Severe Obesity

Early Onset Non-Syndromic Obesity- Is Next Generation Sequencing the Next in Agenda?

Contact Info

Product

Resources

About