Exome sequencing reveals a novel LEPR homozygous mutation in severe early-onset morbid obesity two sisters from a consanguineous family

Obesity is a severe global public health problem with an increasing prevalence in the pediatric population in recent years. Genetic components are crucial for understanding this pathology. Therefore, in this report, two patients underwent exome sequencing to analyze genetic patterns of early-onset obesity without intellectual deficits, dysmorphisms, or malformations and to investigate the hypothesis of monogenic obesity. The study was approved by the Research Ethics Committee (CEP) of HCUFG/GO and Hospital das Clínicas UFG/EBSERH (CAAE 74995023200005083). MEGS and AVGS, second and third daughters of an offspring of 3, aged 5 and 7 years old, have severe obesity that began during the exclusive breastfeeding phase, reaching a BMI of 38.3 (z/score: 7.82) and 41.5 (z/score: 8.86). The sisters presented with hyperphagia, high abdominal circumference, acanthosis nigricans, arterial hypertension, dyslipidemia, high insulin levels, and HOMA-IR. The exome revealed a homozygous mutation in the leptin receptor (LEPR) gene. The variant NM_002303.5:c.1603+3A>G was identified in a homozygous state in the splicing region (strand+, exon 11) of the LEPR gene. This gene is considered loss-of-function intolerant (pLI: 0.99). The variant severity was expected to be harmful, affecting splicing; however, it has not yet been reported in the public GnomAD and ExAC databases. This new variant leads to leptin resistance, hyperphagia, and early onset of obesity. Thus, our findings confirm the monogenic obesity diagnosis and support a better understanding of early-onset obesity. The new mutation found can also guide the designing of new therapeutic approaches to treat obesity and improve patient prognosis.