Genes Predisposing to Monogenic, Polygenic, and Syndromic Obesity: A Review of Current Trends and Prospects for Standard Obesity Genetic Testing

Yahaya, Tajudeen; Oladele, Esther; Shemishere, Ufuoma; Liman, Umar Usman; Boniface Gomo, Clement; L. Abubakar, Aminu; Muhammad Marafa, Balkisu

doi:10.18502/ijdo.v14i4.11233

Volume 14, Issue 4 (volume 14, number 4 2022) IJDO 2022, 14(4): 248-264 | Back to browse issues page

‎ 10.18502/ijdo.v14i4.11233

Mendeley

Zotero

RefWorks

Yahaya T, Oladele E, Shemishere U, Liman U U, Boniface Gomo C, L. Abubakar A et al . Genes Predisposing to Monogenic, Polygenic, and Syndromic Obesity: A Review of Current Trends and Prospects for Standard Obesity Genetic Testing. IJDO 2022; 14 (4) :248-264
URL: http://ijdo.ssu.ac.ir/article-1-751-en.html

Genes Predisposing to Monogenic, Polygenic, and Syndromic Obesity: A Review of Current Trends and Prospects for Standard Obesity Genetic Testing

Tajudeen Yahaya ^*

, Esther Oladele

, Ufuoma Shemishere

, Umar Usman Liman

, Clement Boniface Gomo

, Aminu L. Abubakar

, Balkisu Muhammad Marafa

Department of Biological Sciences, Federal University Birnin Kebbi, PMB 1157, Kebbi State, Nigeria.

Abstract: (751 Views)

Objective: The burden of obesity is currently enormous, necessitating a novel strategy to complement the existing ones. Accordingly, genetic predisposition is suspected in many cases of the disease, which can potentially be used as therapeutic targets. However, there are differing viewpoints on the suspect genes, prompting the current review to articulate the genes and their mechanisms. Eight (16%) of the genes singularly predispose humans to obesity (called monogenic obesity), 22 (43%) interact with other genes and the environment to predispose humans to obesity (called polygenic obesity), and 21 (41%) cause syndromic obesity. Monogenic obesity is often caused by three genes [the leptin (LEP), the leptin receptor (LEPR), and the melanocortin 4 receptor (MC4R) genes], polygenic obesity [fat mass and obesity-associated (FTO) gene], and syndromic obesity (Prader-Willi Syndrome). These genes control food intake and energy expenditure, and so mutations in them cause overeating, adiposity, and hyperphagia. Based on these findings, two genetically-based drugs, named recombinant human leptin and setmelanotide, have been formulated and shown to significantly reduce food intake, body weight, and fat mass. This suggests that when the genetic etiology of obesity is fully understood, the disease’s treatment and prevention will improve. Healthcare providers are urged to develop genetically-based personalized treatments for obese patients.

Keywords: Adiposity, Body weight, Hyperphagia, Leptin, Obesity

Full-Text [PDF 407 kb] (222 Downloads)

Type of Study: Research | Subject: Special
Received: 2022/07/28 | Accepted: 2022/10/4 | Published: 2022/11/19

References

1. Tremmel M, Gerdtham UG, Nilsson PM, Saha S. Economic burden of obesity: a systematic literature review. International journal of environmental research and public health. 2017;14(4):435. [DOI:10.3390/ijerph14040435]

2. World Health Organization. Obesity. 2021.https://www.2WHO.int/health-topics/obesity #tab=tab_1

3. Ghesmaty Sangachin M, Cavuoto LA, Wang Y. Use of various obesity measurement and classification methods in occupational safety and health research: a systematic review of the literature. BMC obesity. 2018;5(1):1-24. [DOI:10.1186/s40608-018-0205-5]

4. Harvard T.H. Chan. 2021. Measuring Obesity. https://www.hsph.4Harvard.edu/obesity-prevention-source/obesity-definition/how-to-measure-body-fatness/

5. Center for Disease Control and Prevention. About Adult BMI. 2021. https://www.cdc.gov /healthyweight/assessing/bmi/adult_bmi/index.html

6. Jan A, Weir CB. BMI Classification Percentile and Cut Off Points. StatPearls: Treasure Island, FL, USA. 2021.

7. National Center for Chronic Disease Prevention and Health Promotion. Defining Adult Overweight & Obesity. 2021. https://www.CDC.gov/ obesity/adult/defining.html

8. Ross R, Neeland IJ, Yamashita S, Shai I, Seidell J, Magni P, et al. Waist circumference as a vital sign in clinical practice: a Consensus Statement from the IAS and ICCR Working Group on Visceral Obesity. Nature Reviews Endocrinology. 2020;16(3):177-89. [DOI:10.1038/s41574-019-0310-7]

9. Poudyel P, Sharma S. Relationship of body mass index and waist-hip ratio among dental interns, residents and dental practitioners. Journal of Chitwan Medical College. 2021;11(2):54-7. [DOI:10.54530/jcmc.422]

10. Zhang W, He K, Zhao H, Hu X, Yin C, Zhao X, et al. Association of body mass index and waist circumference with high blood pressure in older adults. BMC geriatrics. 2021;21(1):1-0. [DOI:10.1186/s12877-021-02154-5]

11. Behera S, Mishra A, Esther Sr A, Sahoo A. Tailoring Body Mass Index for Prediction of Obesity in Young Adults: A Multi-Centric Study on MBBS Students of Southeast India. Cureus. 2021;13(1): e12579. [DOI:10.7759/cureus.12579]

12. African Health Organization. World Obesity Day. 2021.https://aho.org/events/world-obesity-day/

13. Fox A, Feng W, Asal V. What is driving global obesity trends? Globalization or "modernization"?. Globalization and health. 2019 ;15(1):1-6. [DOI:10.1186/s12992-019-0457-y]

14. Shekar M, Popkin B, editors. Obesity: health and economic consequences of an impending global challenge. World Bank Publications; 2020. [DOI:10.1596/978-1-4648-1491-4]

15. Ford ND, Patel SA, Narayan KV. Obesity in low-and middle-income countries: burden, drivers, and emerging challenges. Annual review of public health. 2017;38:145-64. [DOI:10.1146/annurev-publhealth-031816-044604]

16. Adeloye D, Ige-Elegbede JO, Ezejimofor M, Owolabi EO, Ezeigwe N, Omoyele C, et al. Estimating the prevalence of overweight and obesity in Nigeria in 2020: a systematic review and meta-analysis. Annals of medicine. 2021;53(1):495-507. [DOI:10.1080/07853890.2021.1897665]

17. National Health Services. Overview: Obesity. https://www.nhs.uk/conditions/obesity/.

18. Bhaskaran K, Douglas I, Forbes H, dos-Santos-Silva I, Leon DA, Smeeth L. Body-mass index and risk of 22 specific cancers: a population-based cohort study of 5• 24 million UK adults. The Lancet. 2014;384(9945):755-65. [DOI:10.1016/S0140-6736(14)60892-8]

19. Wu J, Xu H, He X, Yuan Y, Wang C, Sun J, et al. Six-year changes in the prevalence of obesity and obesity-related diseases in Northeastern China from 2007 to 2013. Scientific Reports. 2017;7(1):1-8. [DOI:10.1038/srep41518]

20. GBD 2015 Obesity Collaborators. Health effects of overweight and obesity in 195 countries over 25 years. New England journal of medicine. 2017;377(1):13-27. [DOI:10.1056/NEJMoa1614362]

21. Organization for Economic Cooperation and Development 2019. Heavy Burden of Obesity: The Economics of Prevention. https://www.oecd.org /health/health-systems/Heavy-burden-of-obesity-Policy-Brief-2019.pdf

22. Okunogbe A, Nugent R, Spencer G, Ralston J, Wilding J. Economic impacts of overweight and obesity: current and future estimates for eight countries. BMJ Global Health. 2021;6(10):e006351. http://dx.doi.org/10.1136 /bmjgh-2021-006351. [DOI:10.1136/bmjgh-2021-006351]

23. Abubakar MB, Fatola AO, Sanusi KO, Ibrahim KG. The Burden of Obesity in Nigeria. Nigerian Journal of Basic and Applied Medical Sciences. 2021;1(1):23-6.https://www.sciencegate.app/ document/10.53994/njbams.202111.6. [DOI:10.53994/NJBAMS.202111.6]

24. Umar MU, Sanusi A, Garba MR. Comparison of health-care expenditure of obese and non-obese patients attending a tertiary health-care institution in Northwest, Nigeria. Sahel Medical Journal. 2016;19(3):125. [DOI:10.4103/1118-8561.192391]

25. Cleveland Clinic. 2022. Obesity. https://my.clevelandclinic.org/health/diseases/11209-weight-control-and-obesity

26. Sicat J. Obesity and Genetics: Nature and Nurture. Obesity Medicine Association. 2018. https://obesitymedicine.org/obesity-and-genetics/

27. Hill JO, Wyatt HR, Peters JC. Energy balance and obesity. Circulation. 2012;126(1):126-32. [DOI:10.1161/CIRCULATIONAHA.111.087213]

28. Bosy-Westphal A, Hägele FA, Müller MJ. What is the impact of energy expenditure on energy intake?. Nutrients. 2021;13(10):3508. [DOI:10.3390/nu13103508]

29. Basolo A, Bechi Genzano S, Piaggi P, Krakoff J, Santini F. Energy balance and control of body weight: Possible effects of meal timing and circadian rhythm dysregulation. Nutrients. 2021;13(9):3276. [DOI:10.3390/nu13093276]

30. Luo L, Liu M. Adipose tissue in control of metabolism. Journal of endocrinology. 2016;231(3):R77-99. [DOI:10.1530/JOE-16-0211]

31. Sikaris KA. The clinical biochemistry of obesity. The Clinical Biochemist Reviews. 2004;25(3):165.

32. Lee Fist SJ, Shin SW. Mechanisms, Pathophysiology, and Management of Obesity.The New England Journal of Medicine.2017; 376(15):1490-2. [DOI:10.1056/NEJMc1701944]

33. Romieu I, Dossus L, Barquera S, Blottière HM, Franks PW, Gunter M, et al. Energy balance and obesity: what are the main drivers?. Cancer Causes & Control. 2017;28(3):247-58. [DOI:10.1007/s10552-017-0869-z]

34. Sacks FM, Bray GA, Carey VJ, Smith SR, Ryan DH, Anton SD, et al. Comparison of weight-loss diets with different compositions of fat, protein, and carbohydrates. New England Journal of Medicine. 2009;360(9):859-73. [DOI:10.1056/NEJMoa0804748]

35. Center for Disease Control and Prevention. Genes and obesity. 2013. https://www.cdc.gov/ genomics/resources/diseases/obesity/obesedit.htm

36. Kim KS, Seeley RJ, Sandoval DA. Signalling from the periphery to the brain that regulates energy homeostasis. Nature Reviews Neuroscience. 2018;19(4):185-96. [DOI:10.1038/nrn.2018.8]

37. Herrera BM, Lindgren CM. The genetics of obesity. Current diabetes reports. 2010;10(6):498-505. [DOI:10.1007/s11892-010-0153-z]

38. Albuquerque D, Nóbrega C, Manco L, Padez C. The contribution of genetics and environment to obesity. British medical bulletin. 2017;123(1):159-73. [DOI:10.1093/bmb/ldx022]

39. Thaker VV. Genetic and epigenetic causes of obesity. Adolescent medicine: state of the art reviews. 2017;28(2):379. [DOI:10.1542/9781581109405-genetic]

40. Niazi RK, Gjesing AP, Hollensted M, Have CT, Borisevich D, Grarup N, et al. Screening of 31 genes involved in monogenic forms of obesity in 23 Pakistani probands with early-onset childhood obesity: a case report. BMC medical genetics. 2019;20(1):1-8. [DOI:10.1186/s12881-019-0886-8]

41. Elena G, Bruna C, Benedetta M, Stefania DC, Giuseppe C. Prader-Willi syndrome: clinical aspects. Journal of obesity. 2012;2012. [DOI:10.1155/2012/473941]

42. Flores-Dorantes MT, Díaz-López YE, Gutiérrez-Aguilar R. Environment and gene association with obesity and their impact on neurodegenerative and neurodevelopmental diseases. Frontiers in Neuroscience. 2020;14:863. [DOI:10.3389/fnins.2020.00863]

43. National Center for Biotechnology Information. Obesity, hyperphagia, and developmental delay (OBHD). 2021. https://www.ncbi.nlm.nih.gov /medgen/462653

44. Doulla M, McIntyre AD, Hegele RA, Gallego PH. A novel MC4R mutation associated with childhood-onset obesity: A case report. Paediatrics & Child Health. 2014;19(10):515-8. [DOI:10.1093/pch/19.10.515]

45. Namjou B, Stanaway IB, Lingren T, Mentch FD, Benoit B, Dikilitas O, et al. Evaluation of the MC4R gene across eMERGE network identifies many unreported obesity-associated variants. International Journal of Obesity. 2021;45(1):155-69. [DOI:10.1038/s41366-020-00675-4]

46. MedlinePlus. LEP gene: leptin. 2020. https://medlineplus.gov/genetics/gene/lep/#

47. MedlinePlus. LEPR gene: leptin receptor. 2020. https://medlineplus.gov/genetics/gene/lepr/

48. Ramos-Molina B, Martin MG, Lindberg I. PCSK1 variants and human obesity. Progress in molecular biology and translational science. 2016;140:47-74. [DOI:10.1016/bs.pmbts.2015.12.001]

49. Rui L. SH2B1 regulation of energy balance, body weight, and glucose metabolism. World journal of diabetes. 2014;5(4):511. [DOI:10.4239/wjd.v5.i4.511]

50. MalaCards. Severe Early-Onset Obesity-Insulin Resistance Syndrome Due to Sh2b1 Deficiency.2021.https://www.malacards.org/card/severe_early_onset_obesity_insulin_resistance_syndrome_due_to_sh2b1_deficiency

51. Lee YS, Challis BG, Thompson DA, Yeo GS, Keogh JM, Madonna ME, et al. A POMC variant implicates β-melanocyte-stimulating hormone in the control of human energy balance. Cell metabolism. 2006;3(2):135-40. https://doi.org/10.1016/j.metabol.2005.08.005 [DOI:10.1016/j.cmet.2006.01.006]

52. Stanikova D, Buzga M, Krumpolec P, Skopkova M, Surova M, Ukropcova B, et al. Genetic analysis of single-minded 1 gene in early-onset severely obese children and adolescents. PloS one. 2017;12(5):e0177222. [DOI:10.1371/journal.pone.0177222]

53. Ramachandrappa S, Raimondo A, Cali AM, Keogh JM, Henning E, Saeed S, Thompson A, Garg S, Bochukova EG, Brage S, Trowse V. Rare variants in single-minded 1 (SIM1) are associated with severe obesity. The Journal of clinical investigation. 2013;123(7):3042-50. [DOI:10.1172/JCI68016]

54. Bonnefond A, Raimondo A, Stutzmann F, Ghoussaini M, Ramachandrappa S, Bersten DC, et al. Loss-of-function mutations in SIM1 contribute to obesity and Prader-Willi-like features. The Journal of clinical investigation. 2013;123(7):3037-41. [DOI:10.1172/JCI68035]

55. Fawcett KA, Barroso I. The genetics of obesity: FTO leads the way. Trends in genetics. 2010;26(6):266-74. [DOI:10.1016/j.tig.2010.02.006]

56. Xu Z, Ying Y, BaoFa S, YongLiang Z, YunGui Y. FTO and obesity: mechanisms of association. Current Diabetes Reports. 2014;14(5). [DOI:10.1007/s11892-014-0486-0]

57. MedlinePlus. ANK2 gene. 2020. https://medlineplus.gov/genetics/gene/ank2/

58. Lorenzo DN, Healy JA, Hostettler J, Davis J, Yang J, Wang C, et al. Ankyrin-B metabolic syndrome combines age-dependent adiposity with pancreatic β cell insufficiency. The Journal of clinical investigation. 2015;125(8):3087-102. [DOI:10.1172/JCI81317]

59. Wei FY, Nagashima K, Ohshima T, Saheki Y, Lu YF, Matsushita M, et al. Cdk5-dependent regulation of glucose-stimulated insulin secretion. Nature medicine. 2005;11(10):1104-8. [DOI:10.1038/nm1299]

60. Daval M, Gurlo T, Costes S, Huang CJ, Butler PC. Cyclin-dependent kinase 5 promotes pancreatic β-cell survival via Fak-Akt signaling pathways. Diabetes. 2011;60(4):1186-97. [DOI:10.2337/db10-1048]

61. Palmer CJ, Bruckner RJ, Paulo JA, Kazak L, Long JZ, Mina AI, et al. Cdkal1, a type 2 diabetes susceptibility gene, regulates mitochondrial function in adipose tissue. Molecular metabolism. 2017;6(10):1212-25. [DOI:10.1016/j.molmet.2017.07.013]

62. Larsen LH. Obesity: Underlying Mechanisms and the Evolving Influence of Diet. Current Nutrition Reports. 2012;1(4):205-14. [DOI:10.1007/s13668-012-0028-9]

63. National Center for Biotechnology Information. TNNI3K TNNI3 interacting kinase. 2021. https://www.ncbi.nlm.nih.gov/gene/51086

64. Sauber J, Grothe J, Behm M, Scherag A, Grallert H, Illig T, et al. Association of variants in gastric inhibitory polypeptide receptor gene with impaired glucose homeostasis in obese children and adolescents from Berlin. European journal of endocrinology. 2010;163(2):259-64. [DOI:10.1530/EJE-10-0444]

65. Skuratovskaia DA, Vulf MA, Kirienkova EV, Mironyuk NI, Zatolokin PA, Litvinova LS. The role of single nucleotide polymorphisms in GIPR gene in the changes of secretion in hormones and adipokines in patients with obesity with type 2 diabetes. Biomeditsinskaia Khimiia. 2018;64(2):208-16. [DOI:10.18097/PBMC20186402208]

66. Wang T, Ma X, Tang T, Higuchi K, Peng D, Zhang R, et al. The effect of glucose-dependent insulinotropic polypeptide (GIP) variants on visceral fat accumulation in Han Chinese populations. Nutrition & diabetes. 2017;7(5):e278. [DOI:10.1038/nutd.2017.28]

67. MedlinePlus. NPC1 gene (NPC intracellular cholesterol transporter 1). 2020. https://medlineplus.gov/genetics/gene/npc1/

68. Carstea ED, Morris JA, Coleman KG, Loftus SK, Zhang D, Cummings C, et al. Niemann-Pick C1 disease gene: homology to mediators of cholesterol homeostasis. Science. 1997;277(5323):228-31. [DOI:10.1126/science.277.5323.228]

69. National Center for Biotechnology Information. ADIPOQ adiponectin, C1Q and collagen domain containing [Homo sapiens (human)]. 2021. https://www.ncbi.nlm.nih.gov/gene/9370

70. Wu J, Liu Z, Meng K, Zhang L. Association of adiponectin gene (ADIPOQ) rs2241766 polymorphism with obesity in adults: a meta-analysis. PLoS One. 2014;9(4):e95270. [DOI:10.1371/journal.pone.0095270]

71. Talbert ME, Langefeld CD, Ziegler JT, Haffner SM, Norris JM, Bowden DW. INSIG2 SNPs associated with obesity and glucose homeostasis traits in Hispanics: the IRAS Family Study. Obesity. 2009;17(8):1554-62. [DOI:10.1038/oby.2009.94]

72. Orkunoglu-Suer FE, Gordish-Dressman H, Clarkson PM, Thompson PD, Angelopoulos TJ, Gordon PM, et al. INSIG2 gene polymorphism is associated with increased subcutaneous fat in women and poor response to resistance training in men. BMC medical genetics. 2008;9(1):1-8. [DOI:10.1186/1471-2350-9-117]

73. Celi FS, Shuldiner AR. The role of peroxisome proliferator-activated receptor gamma in diabetes and obesity. Current diabetes reports. 2002;2(2):179-85. [DOI:10.1007/s11892-002-0078-2]

74. Barak Y, Kim S. Genetic manipulations of PPARs: effects on obesity and metabolic disease. PPAR research. 2007;2007. [DOI:10.1155/2007/12781]

75. Ahmadian M, Suh JM, Hah N, Liddle C, Atkins AR, Downes M, et al. PPARγ signaling and metabolism: the good, the bad and the future. Nature medicine. 2013;19(5):557-66. [DOI:10.1038/nm.3159]

76. Boender AJ, van Gestel MA, Garner KM, Luijendijk MC, Adan RA. The obesity‐associated gene Negr1 regulates aspects of energy balance in rat hypothalamic areas. Physiological reports. 2014;2(7):e12083. [DOI:10.14814/phy2.12083]

77. GeneCards. NEGR1 Gene (Protein Coding): Neuronal Growth Regulator 1. 2021. https://www.genecards.org/cgi-bin/carddisp.pl? gene=NEGR1

78. Yuan Q, Yang W, Zhang S, Li T, Zuo M, Zhou X, et al. Inhibition of mitochondrial carrier homolog 2 (MTCH2) suppresses tumor invasion and enhances sensitivity to temozolomide in malignant glioma. Molecular Medicine. 2021;27(1):1-3. [DOI:10.1186/s10020-020-00261-4]

79. Bar-Lev Y, Moshitch-Moshkovitz S, Tsarfaty G, Kaufman D, Horev J, Resau JH, et al. Mimp/Mtch2, an obesity susceptibility gene, induces alteration of fatty acid metabolism in transgenic mice. PLoS One. 2016;11(6):e0157850. [DOI:10.1371/journal.pone.0157850]

80. Buzaglo-Azriel L, Kuperman Y, Tsoory M, Zaltsman Y, Shachnai L, Zaidman SL, et al. Loss of muscle MTCH2 increases whole-body energy utilization and protects from diet-induced obesity. Cell reports. 2016;14(7):1602-10. [DOI:10.1016/j.celrep.2016.01.046]

81. Sun C, Kovacs P, Guiu-Jurado E. Genetics of obesity in East Asians. Frontiers in Genetics. 2020;11:575049. [DOI:10.3389/fgene.2020.575049]

82. Kang HC, Kim JI, Chang HK, Woodard G, Choi YS, Ku JL, et al. FAIM2, as a novel diagnostic maker and a potential therapeutic target for small-cell lung cancer and atypical carcinoid. Scientific reports. 2016;6(1):1-9. [DOI:10.1038/srep34022]

83. Li S, Zhao JH, Luan JA, Luben RN, Rodwell SA, Khaw KT, et al. Cumulative effects and predictive value of common obesity-susceptibility variants identified by genome-wide association studies. The American journal of clinical nutrition. 2010;91(1):184-90. [DOI:10.3945/ajcn.2009.28403]

84. González-Soltero R, de Valderrama MJ, González-Soltero E, Larrosa M. Can study of the ADRB3 gene help improve weight loss programs in obese individuals?. Endocrinología, Diabetes y Nutrición (English ed.). 2021;68(1):66-73. [DOI:10.1016/j.endien.2021.02.003]

85. Benzinou M, Chevre JC, Ward KJ, Lecoeur C, Dina C, Lobbens S, et al. Endocannabinoid receptor 1 gene variations increase risk for obesity and modulate body mass index in European populations. Human molecular genetics. 2008;17(13):1916-21. [DOI:10.1093/hmg/ddn089]

86. Sidibeh CO, Pereira MJ, Lau Börjesson J, Kamble PG, Skrtic S, Katsogiannos P, et al. Role of cannabinoid receptor 1 in human adipose tissue for lipolysis regulation and insulin resistance. Endocrine. 2017;55(3):839-52. [DOI:10.1007/s12020-016-1172-6]

87. Baye TM, Zhang Y, Smith E, Hillard CJ, Gunnell J, Myklebust J, et al. Genetic variation in cannabinoid receptor 1 (CNR1) is associated with derangements in lipid homeostasis, independent of body mass index. Pharmacogenomics. 2008; 9(11):1647-56. [DOI:10.2217/14622416.9.11.1647]

88. Suviolahti E, Oksanen LJ, Öhman M, Cantor RM, Ridderstrale M, Tuomi T, et al. The SLC6A14 gene shows evidence of association with obesity. The Journal of clinical investigation. 2003;112(11):1762-72. [DOI:10.1172/JCI200317491]

89. Sivaprakasam S, Sikder MO, Ramalingam L, Kaur G, Dufour JM, Moustaid-Moussa N, et al. SLC6A14 deficiency is linked to obesity, fatty liver, and metabolic syndrome but only under conditions of a high-fat diet. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease. 2021;1867(5):166087. [DOI:10.1016/j.bbadis.2021.166087]

90. Pearce LR, Atanassova N, Banton MC, Bottomley B, van der Klaauw AA, Revelli JP, et al. KSR2 mutations are associated with obesity, insulin resistance, and impaired cellular fuel oxidation. Cell. 2013;155(4):765-77. [DOI:10.1016/j.cell.2013.09.058]

91. Körber I, Sowada N, Schirmer M, Herrmann G, Nunziata A, Bald M, et al. Pathogenic mutations and variants in KSR2 in a cohort of obese children. ESPE Abstracts. 2019;92.

92. Alsters SI, Goldstone AP, Buxton JL, Zekavati A, Sosinsky A, Yiorkas AM, et al. Truncating homozygous mutation of carboxypeptidase E (CPE) in a morbidly obese female with type 2 diabetes mellitus, intellectual disability and hypogonadotrophic hypogonadism. PloS one. 2015;10(6):e0131417. [DOI:10.1371/journal.pone.0131417]

93. van Vliet-Ostaptchouk JV, Onland-Moret NC, Shiri-Sverdlov R, Van Gorp PJ, Custers A, Peeters PH, et al. Polymorphisms of the TUB gene are associated with body composition and eating behavior in middle-aged women. PLoS One. 2008;3(1):e1405. [DOI:10.1371/journal.pone.0001405]

94. Nies VJ, Struik D, Wolfs MG, Rensen SS, Szalowska E, Unmehopa UA, et al. TUB gene expression in hypothalamus and adipose tissue and its association with obesity in humans. International Journal of Obesity. 2018;42(3):376-83. [DOI:10.1038/ijo.2017.214]

95. Borman AD, Pearce LR, Mackay DS, Nagel‐Wolfrum K, Davidson AE, Henderson R, et al. A homozygous mutation in the TUB gene associated with retinal dystrophy and obesity. Human mutation. 2014;35(3):289-93. [DOI:10.1002/humu.22482]

96. National Biotechnology Center for Information. RAI1 retinoic acid induced 1 [Homo sapiens (human)]. 2021.https://www.ncbi.nlm.nih.gov /gene/10743

97. Carmona-Mora P, Encina CA, Canales CP, Cao L, Molina J, Kairath P, et al. Functional and cellular characterization of human Retinoic Acid Induced 1 (RAI1) mutations associated with Smith-Magenis Syndrome. BMC molecular biology. 2010;11(1):1-2. [DOI:10.1186/1471-2199-11-63]

98. Andreasen CH, Mogensen MS, Borch-Johnsen K, Sandbæk A, Lauritzen T, Almind K, et al. Studies of CTNNBL1 and FDFT1variants and measures of obesity: analyses of quantitative traits and case-control studies in 18,014 Danes. BMC medical genetics. 2009;10(1):1-9. [DOI:10.1186/1471-2350-10-17]

99. Chen M, Lu P, Ma Q, Cao Y, Chen N, Li W, et al. CTNNB1/β-catenin dysfunction contributes to adiposity by regulating the cross-talk of mature adipocytes and preadipocytes. Science advances. 2020;6(2):eaax9605. [DOI:10.1126/sciadv.aax9605]

100. Yin Y, Liu L, Yang C, Lin C, Veith GM, Wang C, et al. Cell autonomous and nonautonomous function of CUL4B in mouse spermatogenesis. Journal of Biological Chemistry. 2016;291(13):6923-35. [DOI:10.1074/jbc.M115.699660]

101. Londin ER, Adijanto J, Philp N, Novelli A, Vitale E, Perria C, et al. Donor splice‐site mutation in CUL4B is likely cause of X‐linked intellectual disability. American Journal of Medical Genetics Part A. 2014;164(9):2294-9. [DOI:10.1002/ajmg.a.36629]

102. Bruinsma CF, Savelberg SM, Kool MJ, Jolfaei MA, Van Woerden GM, Baarends WM, et al. An essential role for UBE2A/HR6A in learning and memory and mGLUR-dependent long-term depression. Human molecular genetics. 2016;25(1):1-8. [DOI:10.1093/hmg/ddv436]

103. Budny B, Badura‐Stronka M, Materna‐Kiryluk A, Tzschach A, Raynaud M, Latos‐Bielenska A, et al. Novel missense mutations in the ubiquitination‐related gene UBE2A cause a recognizable X‐linked mental retardation syndrome. Clinical genetics. 2010;77(6):541-51. [DOI:10.1111/j.1399-0004.2010.01429.x]

104. MedlinePlus. ALMS1 gene. 2020. https://medlineplus.gov/genetics/gene/alms1/ [DOI:10.1007/978-3-319-69892-2_450-2]

105. Yang L, Li Z, Mei M, Fan X, Zhan G, Wang H, et al. Whole genome sequencing identifies a novel ALMS1 gene mutation in two Chinese siblings with Alström syndrome. BMC medical genetics. 2017;18(1):1-6. [DOI:10.1186/s12881-017-0418-3]

106. Orphanet. Ulnar-mammary syndrome. 2021. Available at https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=3138

107. Quarta C, Fisette A, Xu Y, Colldén G, Legutko B, Tseng YT, et al. Functional identity of hypothalamic melanocortin neurons depends on Tbx3. Nature metabolism. 2019;1(2):222-35. [DOI:10.1038/s42255-018-0028-1]

108. Honarmand H, Bonyadi M, Rafat A, Mahdavi R, Aliasghari F. Association study of the BDNF gene polymorphism (G196A) with overweight/obesity among women from Northwest of Iran. Egyptian Journal of Medical Human Genetics. 2021;22(1):1-5. [DOI:10.1186/s43042-020-00130-z]

109. MedlinePlus. WAGR syndrome. 2020. https://medlineplus.gov/genetics/condition/wagr-syndrome/#

110. Mariani M, Decimi V, Bettini LR, Maitz S, Gervasini C, Masciadri M, et al. Adolescents and adults affected by Cornelia de Lange syndrome: A report of 73 Italian patients. InAmerican Journal of Medical Genetics Part C: Seminars in Medical Genetics. 2016; 172(2):206-13. [DOI:10.1002/ajmg.c.31502]

111. Krawczynska N, Wierzba J, Jasiecki J, Wasag B. Molecular characterization of two novel intronic variants of NIPBL gene detected in unrelated Cornelia de Lange syndrome patients. BMC medical genetics. 2019;20(1):1-6. [DOI:10.1186/s12881-018-0738-y]

112. MedlinePlus. NIPBL gene. 2020. https://medlineplus.gov/genetics/gene/nipbl/

113. Plagge A, Kelsey G, Germain-Lee EL. Physiological functions of the imprinted Gnas locus and its protein variants Galpha (s) and XLalpha (s) in human and mouse. The Journal of endocrinology. 2008;196(2):193-214. [DOI:10.1677/JOE-07-0544]

114. Ong KK, Amin R, Dunger DB. Pseudohypoparathyroidism-another monogenic obesity syndrome. Clinical endocrinology. 2000;52(3):389-91. [DOI:10.1046/j.1365-2265.2000.00911.x]

115. Kayemba-Kay's S, Tripon C, Heron A, Hindmarsh P. Pseudohypoparathyroidism type 1A-subclinical hypothyroidism and rapid weight gain as early clinical signs: a clinical review of 10 cases. Journal of Clinical Research in Pediatric Endocrinology. 2016;8(4):432. [DOI:10.4274/jcrpe.2743]

116. Falco M, Amabile S, Acquaviva F. RAI1 gene mutations: mechanisms of Smith-Magenis syndrome. The application of clinical genetics. 2017;10:85-94. [DOI:10.2147/TACG.S128455]

117. Smith ACM, Boyd KE, Brennan C. Smith-Magenis Syndrome. [Updated 2019 Sep 5]. In: Adam MP, Ardinger HH, Pagon RA editors. Seattle (WA): University of Washington, Seattle; 1993-2021.https://www.ncbi.nlm.nih.gov/books/NBK1310/

118. Abad C, Cook MM, Cao L, Jones JR, Rao NR, Dukes-Rimsky L, et al. A rare de novo RAI1 gene mutation affecting BDNF-enhancer-driven transcription activity associated with autism and atypical Smith-Magenis syndrome presentation. Biology. 2018;7(2):31. [DOI:10.3390/biology7020031]

119. Tsend‐Ayush E, O'Sullivan LA, Grützner FS, Onnebo SM, Lewis RS, Delbridge ML, et al. RBMX gene is essential for brain development in zebrafish. Developmental Dynamics. 2005;234(3):682-8. [DOI:10.1002/dvdy.20432]

120. Shashi V, Xie P, Schoch K, Goldstein DB, Howard TD, Berry MN, et al. The RBMX gene as a candidate for the Shashi X‐linked intellectual disability syndrome. Clinical genetics. 2015;88(4):386-90. [DOI:10.1111/cge.12511]

121. National Biotechnology Center for Information. Syndromic X-linked intellectual disability Shashi type. 2021. https://www.ncbi.nlm.nih.gov/ medgen/335348

122. MedlinePlus. CREBBP gene. 2020. https://medlineplus.gov/genetics/gene/crebbp/

123. Bentivegna A, Milani D, Gervasini C, Castronovo P, Mottadelli F, Manzini S, Colapietro P, et al. Rubinstein-Taybi Syndrome: spectrum of CREBBP mutations in Italian patients. BMC medical genetics. 2006;7(1):1-3. [DOI:10.1186/1471-2350-7-77]

124. MedlinePlus. Rubinstein-Taybi syndrome. 2020. https://medlineplus.gov/genetics/condition/rubinstein-taybi-syndrome/

125. Yellapragada V, Liu X, Lund C, Känsäkoski J, Pulli K, Vuoristo S, et al. MKRN3 interacts with several proteins implicated in puberty timing but does not influence GNRH1 expression. Frontiers in endocrinology. 2019;10:48. [DOI:10.3389/fendo.2019.00048]

126. O'neill MA, Farooqi IS, Wevrick R. Evaluation of Prader‐Willi Syndrome Gene MAGEL2 in Severe Childhood‐Onset Obesity. Obesity research. 2005;13(10):1841-2. [DOI:10.1038/oby.2005.224]

127. Wijesuriya TM, De Ceuninck L, Masschaele D, Sanderson MR, Carias KV, Tavernier J, et al. The Prader-Willi syndrome proteins MAGEL2 and necdin regulate leptin receptor cell surface abundance through ubiquitination pathways. Human molecular genetics. 2017;26(21):4215-30. [DOI:10.1093/hmg/ddx311]

128. Luo N, Lu J, Sun Y. Evidence of a role of inositol polyphosphate 5-phosphatase INPP5E in cilia formation in zebrafish. Vision research. 2012;75:98-107. [DOI:10.1016/j.visres.2012.09.011]

129. Hampshire DJ, Ayub M, Springell K, Roberts E, Jafri H, Rashid Y, et al. MORM syndrome (mental retardation, truncal obesity, retinal dystrophy and micropenis), a new autosomal recessive disorder, links to 9q34. European journal of human genetics. 2006;14(5):543-8. [DOI:10.1038/sj.ejhg.5201577]

130. Torga AP, Hodax J, Mori M, Schwab J, Quintos JB. Hypogonadotropic hypogonadism and Kleefstra Syndrome due to a pathogenic variant in the EHMT1 gene: an underrecognized association. Case Reports in Endocrinology. 2018;2018. [DOI:10.1155/2018/4283267]

131. MedlinePlus. KLeestra syndrome. 2020. https://medlineplus.gov/genetics/condition/kleefstra-syndrome/#

132. White SM, Thompson EM, Kidd A, Savarirayan R, Turner A, Amor D, et al. Growth, behavior, and clinical findings in 27 patients with Kabuki (Niikawa-Kuroki) syndrome. American Journal of Medical Genetics Part A. 2004;127(2):118-27. [DOI:10.1002/ajmg.a.20674]

133. MedlinePlus. KMT2D gene. 2020. https://medlineplus.gov/genetics/gene/kmt2d/

134. Moon JE, Lee SJ, Ko CW. A de novo KMT2D mutation in a girl with Kabuki syndrome associated with endocrine symptoms: a case report. BMC medical genetics. 2018;19(1):1-4. [DOI:10.1186/s12881-018-0606-9]

135. Cuvertino S, Hartill V, Colyer A. A restricted spectrum of missense KMT2D variants cause a multiple malformations disorder distinct fromKabuki syndrome.Genetics in Medicine. 2020;22(5): 867-77. https://doi.org/ 10.1038/s41436-019-0743-3 [DOI:10.1038/s41436-019-0743-3]

136. MedlinePlus. AFF4 gene. 2020. https://medlineplus.gov/genetics/gene/aff4/

137. MedlinePlus. CHOPS syndrome. 2020. https://medlineplus.gov/genetics/condition/chops-syndrome/

138. Ben-Salem S, Begum MA, Ali BR, Al-Gazali L. A novel aberrant splice site mutation in RAB23 leads to an eight nucleotide deletion in the mRNA and is responsible for carpenter syndrome in a consanguineous emirati family. Molecular syndromology. 2012;3(6):255-61. [DOI:10.1159/000345653]

139. Haye D, Collet C, Sembely‐Taveau C, Haddad G, Denis C, Soulé N, et al. Prenatal findings in carpenter syndrome and a novel mutation in RAB23. American Journal of Medical Genetics Part A. 2014;164(11):2926-30. [DOI:10.1002/ajmg.a.36726]

140. National Center for Biotechnology Information. MEGF8-related Carpenter syndrome. 2021. https://www.ncbi.nlm.nih.gov/medgen/767161

141. Zheng LQ, Chi SM, Li CX. Rab23's genetic structure, function and related diseases: A review. Bioscience Reports. 2017;37(2). [DOI:10.1042/BSR20160410]

142. MedlinePlus. RAB23 gene. 2020. https://medlineplus.gov/genetics/gene/rab23/

143. National Center for Biotechnology Information.PHF6 PHD finger protein 6 [Homo sapiens (human)]. 2021. https://www.ncbi.nlm.nih.gov/gene/84295

144. Baumstark A, Lower KM, Sinkus A, Andriuškevičiūtė I, Jurkėnienė L, Gécz J, et al. Novel PHF6 mutation p. D333del causes Börjeson-Forssman-Lehmann syndrome. Journal of medical genetics. 2003;40(4):e50. [DOI:10.1136/jmg.40.4.e50]

145. National Institute of Health. Borjeson-Forssman-Lehmann syndrome. 2011.https://rarediseases.info.nih.gov/diseases/936/borjeson-forssman-lehmann syndrome#

146. Ernst A, Le VQ, Højland AT, Pedersen IS, Sørensen TH, Bjerregaard LL, et al. The PHF6 mutation c. 1A> G; PM1V causes Börjeson-Forsman-Lehmann syndrome in a family with four affected young boys. Molecular Syndromology. 2015;6(4):181-6. [DOI:10.1159/000441047]

147. Bellad A, Bandari AK, Pandey A, Girimaji SC, Muthusamy B. A Novel Missense Variant in PHF6 Gene Causing Börjeson-Forssman-Lehman Syndrome. Journal of Molecular Neuroscience. 2020;70(9):1403-9. [DOI:10.1007/s12031-020-01560-5]

148. National Center for Biotechnology Information. BBS2 Bardet-Biedl syndrome 2. 2021. https://www.ncbi.nlm.nih.gov/gene/583

149. Ohto T, Enokizono T, Tanaka R, Tanaka M, Suzuki H, Sakai A, et al. A novel BBS10 mutation identified in a patient with Bardet-Biedl syndrome with a violent emotional outbreak. Human Genome Variation. 2017;4(1):1-3. [DOI:10.1038/hgv.2017.33]

150. Manara E, Paolacci S, D'Esposito F, Abeshi A, Ziccardi L, Falsini B, et al. Mutation profile of BBS genes in patients with Bardet-Biedl syndrome: An Italian study. Italian journal of pediatrics. 2019;45(1):1-8. [DOI:10.1186/s13052-019-0659-1]

151. BBS Foundation. What is BBS? 2020. https://www.bardetbiedl.org/what-is-bbs

152. MedlinePlus. VPS13B gene. 2020. https://medlineplus.gov/genetics/gene/vps13b/

153. Rodrigues JM, Fernandes HD, Caruthers C, Braddock SR, Knutsen AP. Cohen Syndrome: Review of the Literature. Cureus. 2018; 10 (9): e3330. [DOI:10.7759/cureus.3330]

154. Zhao S, Luo Z, Xiao Z, Li L, Zhao R, Yang Y, et al. Case report: two novel VPS13B mutations in a Chinese family with Cohen syndrome and hyperlinear palms. BMC medical genetics. 2019;20(1):1-5. [DOI:10.1186/s12881-019-0920-x]

155. Koehler K, Schuelke M, Hell AK, Schittkowski M, Huebner A, Brockmann K. A novel homozygous nonsense mutation of VPS13B associated with previously unreported features of Cohen syndrome. American Journal of Medical Genetics Part A. 2020;182(3):570-5. [DOI:10.1002/ajmg.a.61435]

156. Kaushik P, Mahajan N, Girimaji SC, Kumar A. Whole exome sequencing identifies a novel homozygous duplication mutation in the VPS13B gene in an Indian family with Cohen syndrome. Journal of Molecular Neuroscience. 2020;70(8):1225-8. [DOI:10.1007/s12031-020-01530-x]

157. MedlinePlus. ATRX gene. 2020. https://medlineplus.gov/genetics/gene/atrx/

158. Abidi FE, Cardoso C, Lossi AM, Lowry RB, Depetris D, Mattéi MG, et al. Mutation in the 5′ alternatively spliced region of the XNP/ATR-X gene causes Chudley-Lowry syndrome. European Journal of Human Genetics. 2005;13(2):176-83. [DOI:10.1038/sj.ejhg.5201303]

159. Loos RJ, Yeo GS. The genetics of obesity: from discovery to biology. Nature Reviews Genetics. 2022;23(2):120-33. [DOI:10.1038/s41576-021-00414-z]

160. Sequencing.com. DNA Testing for Weight Loss Diets. 2021.https://sequencing.com/education-center/genetic-testing-weight-loss/dna-testing-weight-loss-diets

161. Farr OM, Gavrieli A, Mantzoros CS. Leptin applications in 2015: what have we learned about leptin and obesity?. Current opinion in endocrinology, diabetes, and obesity. 2015;22(5):353. [DOI:10.1097/MED.0000000000000184]

162. European Medicines Agency. New treatment for obesity caused by rare genetic disorders. 2021. https://www.ema.europa.eu/en/news/new-treatment-obesity-caused-rare-genetic-disorders

163. Ng MC, Bowden DW. Is genetic testing of value in predicting and treating obesity?. North Carolina medical journal. 2013;74(6):530-3. [DOI:10.18043/ncm.74.6.530]

164. MedlinePlus. What is the cost of genetic testing, and how long does it take to get the results? 2021. https://medlineplus.gov/genetics/understanding/testing/costresults/

165. Personaldiagnostic. Fat and Health DNA Test Kit. 2022. https://www.personaldiagnostics.co.uk/fat-and-health-dna-test.html

166. pwnhealth. Rhythm Offers Free Genetic Testing in U.S. to People Suspected of Genetic Obesity. 2022. https://www.pwnhealth.com/news-and-insights/ rhythm-offers-free-genetic-testing-in-u s-to-people-suspected-of-genetic-obesity/