Heterozygous rare genetic variants in non-syndromic early-onset obesity

Abstract

Background Obesity is a very heterogeneous disorder at both the clinical and molecular levels and with high heritability. Several monogenic forms and genes with strong effects have been identified for non-syndromic severe obesity. Novel therapeutic interventions are in development for some genetic forms, emphasizing the importance of determining genetic contributions. Objective We aimed to define the contribution of rare single-nucleotide genetic variants (RSVs) in candidate genes to nonsyndromic severe early-onset obesity (EOO; body mass index (BMI) >+3 standard deviation score, <3 years). Methods Using a pooled DNA-sequencing approach, we screened for RSVs in 15 obesity candidate genes in a series of 463 EOO patients and 480 controls. We also analysed exome data from 293 EOO patients from the "Viva la Familia" (VLF) study as a replication dataset. Results Likely or known pathogenic RSVs were identified in 23 patients (5.0%), with 7 of the 15 genes (BDNF, FTO, MC3R, MC4R, NEGR1, PPARG and SIM1) harbouring RSVs only in cases (3.67%) and none in controls. All were heterozygous changes, either de novo (one in BDNF) or inherited from obese parents (seven maternal, three paternal), and no individual carried more than one variant. Results were replicated in the VLF study, where 4.10% of probands carried RSVs in the overrepresented genes. RSVs in five genes were either absent (LEP) or more common in controls than in cases (ADRB3, LEPR, PCSK1 and PCSK2) in both obese datasets. Conclusions Heterozygous RSVs in several candidate genes of the melanocortin pathway are found in~5.0% patients with EOO. These results support the clinical utility of genetic testing to identify patients who might benefit from targeted therapeutic intervention.

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

“…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.…”

“…We and others have also shown that rare copy number variants (CNVs) are enriched in patients with early-onset severe obesity (4)(5)(6). Recently, it has also been suggested that obesity could be a consequence of rare genetic variants with strong effect (7,8). Despite these advancements, the genetic causes and underlying molecular mechanisms behind obesity are still inadequately understood.…”

“…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).…”

Ethnicity Strongly Influences Body Fat Distribution Determining Serum Adipokine Profile and Metabolic Derangement in Childhood Obesity

“…To exclude secondary causes of obesity in the study cohort, every patient's clinical record was reviewed, and the patients underwent a full obesity-oriented clinical examination by the same physician in all cases and complementary tests to rule out underlying pathologies (including thyroid function and cortisol production assessment) were performed. Additionally, no patient was found to exhibit pathologic findings in analysis by MS-MLPA for the detection of imprinting disorders, studies of CNVs (copy number variant) or in the sequencing of a panel of 15 obesity candidate genes ( 26 – 28 ).…”

MECHANISMS IN ENDOCRINOLOGY: Update on treatments for patients with genetic obesity

“…In heterozygous subjects, phenotypic expression may depend in part on the environment and the influence of other genes. These forms of obesity account for at least 5% of the causes of early and severe obesity (19), but this prevalence is probably underestimated and may be higher in certain populations, especially those in which consanguinity is frequently observed (16,20,21). Patients with compound heterozygous or homozygous variants for the LEP, LEPR, POMC, PCSK1, and MC4R genes show early severe obesity accompanied by impaired hunger and satiety signals (22,23,24,25,26,27,28).…”