Abstract
Early childhood obesity is a real public health problem worldwide. Identifying the etiologies, especially treatable and preventable causes, can direct health professionals toward proper management. Measurement of serum leptin levels is helpful in the diagnosis of congenital leptin and leptin receptor deficiencies which are considered important rare causes of early childhood obesity. The main aim of this study was to investigate the frequency of LEP, LEPR, and MC4R gene variants among a cohort of Egyptian patients with severe early onset obesity. The current cross-sectional study included 30 children who developed obesity during the first year of life with BMI > 2SD (for age and sex). The studied patients were subjected to full medical history taking, anthropometric measurements, serum leptin and insulin assays, and genetic testing of LEP, LEPR and MC4R. Disease causing variants in LEP and LEPR were identified in 10/30 patients with a detection rate of 30%. Eight different homozygous variants (two pathogenic, three likely pathogenic, and three variants of uncertain significant) were identified in the two genes, including six previously unreported LEPR variants. Of them, a new frameshift variant in LEPR gene (c.1045delT, p.S349Lfs*22) was recurrent in two unrelated families and seems to have a founder effect in our population. In conclusion, we reported ten new patients with leptin and leptin receptor deficiencies and identified six novel LEPR variants expanding the mutational spectrum of this rare disorder. Furthermore, the diagnosis of these patients helped us in genetic counseling and patients’ managements specially with the availability of drugs for LEP and LEPR deficiencies.
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The data supporting the findings of this study are available with the corresponding author upon request.
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Acknowledgements
We are deeply thankful for the late Prof. Mona Elruby for referring one of the families.
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All authors contributed to the study. Recruitment of patients and writing the clinical data were performed by IHM, Mona AEG, AAE, GMA, and EAA. Molecular analysis was performed by MS. A-H and SF. AG. The first draft of the manuscript was written by MS. A-H, AAE, and IHM, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
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This study was approved by the Medical Research Ethical Committee of the National Research Centre (NRC), Cairo, Egypt, and conducted in accordance with the Declaration of Helsinki ethical principles for medical research involving human subjects.
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Mazen, I.H., El-Gammal, M.A., Elaidy, A.A. et al. Congenital leptin and leptin receptor deficiencies in nine new families: identification of six novel variants and review of literature. Mol Genet Genomics 298, 919–929 (2023). https://doi.org/10.1007/s00438-023-02025-1
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DOI: https://doi.org/10.1007/s00438-023-02025-1