Abstract
Objectives
To screen for variants in the MC4R and LEP genes in 46 patients with clinical suspicion of non-syndromic early onset severe obesity (NEOSO).
Methods
Children with early onset obesity satisfying WHO criteria of obesity were studied. The MC4R and LEP genes were sequenced using a PCR amplicon based NGS on Illumina MiSeq next generation sequencer using an in-house developed protocol.
Results
Of the 46 children tested, four were found to have novel pathogenic/likely-pathogenic variants (one in the MC4R gene and three in the LEP gene). In three out of the 4 families, the presence of the variants was confirmed using standard bidirectional capillary sequencing in the probands.
Conclusions
Four children with novel likely pathogenic variants in the MC4R and LEP genes are reported. Genetic analysis is crucial in children with early onset obesity and should be considered.
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References
Roberto CA, Swinburn B, Hawkes C, et al. Patchy progress on obesity prevention: emerging examples, entrenched barriers, and new thinking. Lancet. 2015;385:2400–9.
Stunkard AJ, Harris JR, Pedersen NL, McClearn GE. The body-mass index of twins who have been reared apart. N Engl J Med. 1990;322:1483–7.
Stunkard AJ, Foch TT, Hrubec Z. A twin study of human obesity. JAMA. 1986;256:51–4.
Carnell WS, Haworth CM, Plomin R. Evidence for a strong genetic influence on childhood adiposity despite the force of the obesogenic environment. Am J Clin Nutr. 2008;87:398–404.
O'Rahilly S, Farooqi IS. Genetics of obesity. Philos Trans R Soc Lond Ser B Biol Sci. 2006;361:1095–105.
Huvenne H, Dubern B, Clément K, Poitou C. Rare genetic forms of obesity: clinical approach and current treatments in 2016. Obes Facts. 2016;9:158–73.
Paz-Filho G, Mastronardi C, Delibasi T, Wong ML, Licinio J. Congenital leptin deficiency: diagnosis and effects of leptin replacement therapy. Arq Bras Endocrinol Metabol. 2010;54:690–7.
Farooqi IS, Wangensteen T, Collins S, et al. Clinical and molecular genetic spectrum of congenital deficiency of the leptin receptor. N Engl J Med. 2007;356:237–47.
Farooqi IS, Keogh JM, Yeo GS, Lank EJ, Cheetham T, O'Rahilly S. Clinical spectrum of obesity mutations in the melanocortin 4 receptor gene. N Engl J Med. 2003;348:1085–95.
Locke AE, Kahali B, Berndt SI, et al. Genetic studies of body mass index yield new insights for obesity biology. Nature. 2015;518:197–206.
O'Rahilly S. Human genetics illuminates the paths to metabolic disease. Nature. 2009;462:307–14.
Styne DM, Arslanian SA, Connor EL, et al. Pediatric obesity—assessment, treatment, and prevention: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2017;102:709–57.
de Onis M, Onyango AW, Borghi E, Siyam A, Nishida C, Siekmann J. Development of a WHO growth reference for school-aged children and adolescents. Bull World Health Organ. 2007;85:660–7.
Strobel A, Issad T, Camoin L, Ozata M, Strosberg AD. A leptin missense mutation associated with hypogonadism and morbid obesity. Nat Genet. 1998;18:213–5.
Lek M, Karczewski KJ, Minikel EV, et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016;536(7616):285–91.
Farooqi IS, Jebb SA, Langmack G, et al. Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N Engl J Med. 1999;341:879–84.
Dubern B, Clément K, Pelloux V, et al. 2001. Mutational analysis of melanocortin-4 receptor, agouti-related protein, and alpha-melanocyte-stimulating hormone genes in severely obese children. J Pediatr. 2001;139:204–9.
Farooqi IS, Yeo GS, Keogh JM, et al. Dominant and recessive inheritance of morbid obesity associated with melanocortin 4 receptor deficiency. J Clin Invest. 2000;106:271–9.
Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24.
Nordang GBN, Busk ØL, Tveten K, et al. Next-generation sequencing of the monogenic obesity genes LEP, LEPR, MC4R, PCSK1 and POMC in a Norwegian cohort of patients with morbid obesity and normal weight controls. Mol Genet Metab. 2017;121:51–6.
Rouskas K, Meyre D, Stutzmann F, et al. Loss-of-function mutations in MC4R are very rare in the Greek severely obese adult population. Obesity (Silver Spring). 2012;20:2278–82.
Farooqi IS, Keogh JM, Kamath S, et al. Partial leptin deficiency and human adiposity. Nature. 2001;414:34–5.
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VK: Concept, patient management and manuscript draft; NP: NGS assay design; NG, PG, RLO: Data collection and manuscript draft; NP, MA, AK, NL: Patient management and manuscript draft. SR, TR, KP, AP, SA, AB: Manuscript draft. KK: Data collection, analysis and manuscript writing. AK is the guarantor for this paper.
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Khadilkar, V., Gogate, N., Gangodkar, P. et al. A Targeted Next Generation Sequencing Panel for Non-syndromic Early Onset Severe Obesity and Identification of Novel Likely -Pathogenic Variants in the MC4R and LEP Genes. Indian J Pediatr 87, 105–110 (2020). https://doi.org/10.1007/s12098-019-03129-6
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DOI: https://doi.org/10.1007/s12098-019-03129-6