Novel Variants in the<i>MC4R</i>and<i>LEPR</i>Genes among Severely Obese Children from the Iberian Population

Albuquerque, David; Estévez, Manuela Núñez; Beato-Víbora, Pilar Isabel; Giralt, P; Balsera, Aránzazu Margallo; Cortés, Pedro Gil; López, Mercedes Jiménez; Luego, Luis Miguel; Gervasini, Guillermo; Hernández, Sergio Barroso; Arroyo-Díez, Javier; Vacas, Manuel Arrobas; Nóbrega, Clévio; Manco, Licínio; Rodríguez‐López, Raquel

doi:10.1111/ahg.12058

Cited by 15 publications

(6 citation statements)

References 52 publications

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“…In Hispanics, G323E previously reported in Iberians, was also detected in three Hispanics including an obese pediatric individual ( Supplementary Table S2), [36]. I269N is another known pathogenic variant exclusively seen in Hispanic ethnicity with penetrance of 100% for obesity in our collection ( Supplementary Table S2) [15].…”

Section: Discussionsupporting

confidence: 58%

Evaluation of the MC4R gene across eMERGE network identifies many unreported obesity-associated variants

et al. 2020

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Background/Objectives Melanocortin-4 receptor (MC4R) plays an essential role in food intake and energy homeostasis. More than 170 MC4R variants have been described over the past two decades, with conflicting reports regarding the prevalence and phenotypic effects of these variants in diverse cohorts. To determine the frequency of MC4R variants in large cohort of different ancestries, we evaluated the MC4R coding region for 20,537 eMERGE participants with sequencing data plus additional 77,454 independent individuals with genome-wide genotyping data at this locus. Subjects/Methods The sequencing data were obtained from the eMERGE phase III study, in which multisample variant call format calls have been generated, curated, and annotated. In addition to penetrance estimation using body mass index (BMI) as a binary outcome, GWAS and PheWAS were performed using median BMI in linear regression analyses. All results were adjusted for principal components, age, sex, and sites of genotyping. Results Targeted sequencing data of MC4R revealed 125 coding variants in 1839 eMERGE participants including 30 unreported coding variants that were predicted to be functionally damaging. Highly penetrant unreported variants included (L325I, E308K, D298N, S270F, F261L, T248A, D111V, and Y80F) in which seven participants had obesity class III defined as BMI ≥ 40 kg/m2. In GWAS analysis, in addition to known risk haplotype upstream of MC4R (best variant rs6567160 (P = 5.36 × 10−25, Beta = 0.37), a novel rare haplotype was detected which was protective against obesity and encompassed the V103I variant with known gain-of-function properties (P = 6.23 × 10−08, Beta = −0.62). PheWAS analyses extended this protective effect of V103I to type 2 diabetes, diabetic nephropathy, and chronic renal failure independent of BMI. Conclusions MC4R screening in a large eMERGE cohort confirmed many previous findings, extend the MC4R pleotropic effects, and discovered additional MC4R rare alleles that probably contribute to obesity.

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Section: Discussionsupporting

confidence: 58%

Evaluation of the MC4R gene across eMERGE network identifies many unreported obesity-associated variants

et al. 2020

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“…Notably, variant pathogenicity interpretation can evolve over time; new clinical, genetic, or functional data may influence pathogenicity calls and result in differences between labs. For example, the genetics lab used for this study reported the PCSK1 (ClinVar ID 14040) variant as “risk” and the LEPR (ClinVar ID 631614) variant as uncertain which is discrepant from current ClinVar reports [ 29 , 30 , 36 – 51 ] (Supplementary Table 2 ), highlighting the importance of variant reanalysis. Without extensive efforts to provide genetic and functional evidence of variant effect, such as segregation analysis to establish inheritance patterns, more extensive examination of phenotypic characteristics, assessment in physiologically relevant experimental systems, and transcriptomic analysis of subject biospecimens, interpretation of whether these variants of uncertain significance do or do not impart risk for obesity is limited.…”

Section: Discussionmentioning

confidence: 71%

Testing for rare genetic causes of obesity: findings and experiences from a pediatric weight management program

et al. 2022

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Background Genetic screening for youth with obesity in the absence of syndromic findings has not been part of obesity management. For children with early onset obesity, genetic screening is recommended for those having clinical features of genetic obesity syndromes (including hyperphagia). Objectives The overarching goal of this work is to report the findings and experiences from one pediatric weight management program that implemented targeted sequencing analysis for genes known to cause rare genetic disorders of obesity. Subjects/Methods This exploratory study evaluated youth tested over an 18-month period using a panel of 40-genes in the melanocortin 4 receptor pathway. Medical records were reviewed for demographic and visit information, including body mass index (BMI) percent of 95th percentile (%BMIp95) and two eating behaviors. Results Of 117 subjects: 51.3% were male; 53.8% Hispanic; mean age 10.2 years (SD 3.8); mean %BMIp95 157% (SD 29%). Most subjects were self- or caregiver-reported to have overeating to excess or binge eating (80.3%) and sneaking food or eating in secret (59.0%). Among analyzed genes, 72 subjects (61.5%) had at least one variant reported; 50 (42.7%) had a single variant reported; 22 (18.8%) had 2–4 variants reported; most variants were rare (<0.05% minor allele frequency [MAF]), and of uncertain significance; all variants were heterozygous. Nine subjects (7.7%) had a variant reported as PSCK1 “risk” or MC4R “likely pathogenic”; 39 (33.3%) had a Bardet-Biedl Syndrome (BBS) gene variant (4 with “pathogenic” or “likely pathogenic” variants). Therefore, 9 youth (7.7%) had gene variants previously identified as increasing risk for obesity and 4 youth (3.4%) had BBS carrier status. Conclusions Panel testing identified rare variants of uncertain significance in most youth tested, and infrequently identified variants previously reported to increase the risk for obesity. Further research in larger cohorts is needed to understand how genetic variants influence the expression of non-syndromic obesity.

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“…In total, 5175 records were screened (Fig. 1), of which 24 records presented unique patients with LepR deficiency and were eligible for inclusion (2,4,5,7,9,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35). From these 24 records, we identified n = 86 unique patients with LepR deficiency from 57 different families.…”

Section: Systematic Literature Search and Overview Of Published Casesmentioning

confidence: 99%

Leptin receptor deficiency: a systematic literature review and prevalence estimation based on population genetics

Kleinendorst

Abawi

Kamp

et al. 2020

European Journal of Endocrinology

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Objective Leptin receptor (LepR) deficiency is an autosomal-recessive endocrine disorder causing early-onset severe obesity, hyperphagia and pituitary hormone deficiencies. As effective pharmacological treatment has recently been developed, diagnosing LepR deficiency is urgent. However, recognition is challenging and prevalence is unknown. We aim to elucidate the clinical spectrum and to estimate the prevalence of LepR deficiency in Europe. Design Comprehensive epidemiologic analysis and systematic literature review. Methods We curated a list of LEPR variants described in patients and elaborately evaluated their phenotypes. Subsequently, we extracted allele frequencies from the Genome Aggregation Database (gnomAD), consisting of sequencing data of 77 165 European individuals. We then calculated the number of individuals with biallelic disease-causing LEPR variants. Results Worldwide, 86 patients with LepR deficiency are published. We add two new patients, bringing the total of published patients to 88, of which 21 are European. All patients had early-onset obesity; 96% had hyperphagia; 34% had one or more pituitary hormone deficiencies. Our calculation results in 998 predicted patients in Europe, corresponding to a prevalence of 1.34 per 1 million people (95% CI: 0.95–1.72). Conclusions This study shows that LepR deficiency is more prevalent in Europe (n = 998 predicted patients) than currently known (n = 21 patients), suggesting that LepR deficiency is underdiagnosed. An important cause for this could be lack of access to genetic testing. Another possible explanation is insufficient recognition, as only one-third of patients has pituitary hormone deficiencies. With novel highly effective treatment emerging, diagnosing LepR deficiency is more important than ever.

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Novel Variants in theMC4RandLEPRGenes among Severely Obese Children from the Iberian Population

Cited by 15 publications

References 52 publications

Evaluation of the MC4R gene across eMERGE network identifies many unreported obesity-associated variants

Evaluation of the MC4R gene across eMERGE network identifies many unreported obesity-associated variants

Testing for rare genetic causes of obesity: findings and experiences from a pediatric weight management program

Leptin receptor deficiency: a systematic literature review and prevalence estimation based on population genetics

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