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


  • Renata Machado Pinto
  • Lorena de Oliveira Silva
  • Lorraine Vieira Cruz Fukushima
  • Vanessa Santos Moreira
  • Cristiane Simões Bento de Souza
  • Irene Plaza Pinto
  • Ricardo Goulart Rodovalho




Obesity, Leptin, LEPR Gene, Melanocortin, Type 4, Child, Genetics


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.


BESCI, O. et al. A National Multicenter Study of Leptin and Leptin Receptor Deficiency and Systematic Review. J Clin Endocrinol Metab., v. 108, n. 9, p. 2371–2388, 2023.

DAYAL, D.; SEETHARAMAN, K.; PANIGRAHI, I.; MUTHUVEL, B.; AGARWAL, A. Severe Early Onset Obesity due to a Novel Missense Mutation in Exon 3 of the Leptin Gene in an Infant from Northwest India. J Clin Res Pediatr Endocrinol., v. 10, n. 3, p. 274–278, 2018.

DUNCAN, J. S.; SCHOFIELD, G.; DUNCAN, E. K. Pedometer-determined physical activity and body composition in New Zealand children. Med Sci Sports Exerc., v. 38, n. 8, p. 1402–1409, 2006.

FERNANDEZ-TWINN, D. S.; HJORT, L.; NOVAKOVIC, B.; OZANNE, S. E.; SAFFERY, R. Intrauterine programming of obesity and type 2 diabetes. Diabetologia, v. 62, n. 10, p. 1789–1801, 2019.

LOBSTEIN, T.; JACKSON-LEACH, R.; POWIS, J.; BRINSDEN, H.; GRAY, M. World Obesity Atlas 2023. [s. l.], 2023. Disponível em: https://data.worldobesity.org/publications/?cat=19. Acesso em: 7 maio. 2024.

MAZEN, I.; EL-GAMMAL, M.; ABDEL-HAMID, M.; FAROOQI, I. S.; AMR, K. Homozygosity for a novel missense mutation in the leptin receptor gene (P316T) in two Egyptian cousins with severe early onset obesity. Mol Genet Metab., v. 102, n. 4, p. 461–464, 2011.

NG, marie et al. Global, regional and national prevalence of overweight and obesity in children and adults 1980-2013: A systematic analysis. Lancet, v. 384, n. 9945, p. 766, 2014.

PINTO, R. M.; STEINMETZ, L. S.; BARBOSA, J. M. G.; MENDES, A. F. C. S.; CURADO, M. P.; CRUZ, A. D. The Role of Genetics in the Pathophysiology of Obesity: A Systematic Review. Obes Res Open J., v. 6, n. 1, p. 11–17, 2019.

SAEED, S. et al. High morbidity and mortality in children with untreated congenital deficiency of leptin or its receptor. Cell Rep Med., v. 4, n. 9, p. 101187, 2023.

SWINBURN, B. A.; CATERSON, I.; SEIDELL, J. C.; JAMES, W. P. T. Diet, nutrition and the prevention of excess weight gain and obesity. Public Health Nutr., v. 7, n. 1A, p. 123–146, 2004.

TIRTHANI, E.; SAID, M. S.; REHMAN, A. Genetics and Obesity. StatPearls, 2023. Disponível em: https://www.ncbi.nlm.nih.gov/books/NBK573068/. Acesso em: 7 maio. 2024.




How to Cite

Pinto, R. M., Silva , L. de O., Fukushima, L. V. C., Moreira, V. S., Souza, C. S. B. de, Pinto, I. P., & Rodovalho, R. G. (2024). Exome sequencing reveals a novel LEPR homozygous mutation in severe early-onset morbid obesity two sisters from a consanguineous family. Caderno Pedagógico, 21(6), e2513 . https://doi.org/10.54033/cadpedv21n6-055