FRI047 Clinical Characteristics Of Patients With Morbid Obesity With Semaphorines (SEMA3D,E,G) And PLXNA3&4 Gene Variants

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Abstract Disclosure: M. Berra: None. A. Khattab: None. S.B. Ten: None. A.S. Bhangoo: None. Aim of the study: To describe the clinical characteristics of patients with morbid obesity with SEMA3D,E,G and PLXNA3&4 gene variants. Introduction: Heterozygous variants of SEMA3s and their receptors PLXNA3 and 4 were described in cases of morbid obesity (Ref1). SEMA3 genes encodes a member of the semaphorin III family of secreted signaling proteins that are involved in axon guidance during neuronal development. SEMA3s signaling pathway is important for POMC neurons projections from the arcuate to the paraventricular nucleus. Methods: Patients with morbid obesity underwent genetic testing at the Prevention Genetics after obtaining consent. Results: Heterozygous gene variants were found in 8 cases, 3 males, 5 females, from 2 to 22 yrs., average BMI 33.3±8.6 kg/m2, 5 Hispanics, 2 Caucasians, 1 Asian. All cases presented with early morbid obesity from 2-4 yrs. of age, hyperphagia. Leptin was measured in 4 cases and was low for the degree of obesity (5.8-7.8 ng/ml). They had fatty liver, elevated triglycerides 168±33; had HDL 41.7±6.9 (data presented as avg±SDS).16 yrs. old female, BMI 31.2, PLXN3, c.1556G>A, p.Arg519His variant. Father had morbid obesity, treated with bariatric surgery lap band procedure.8 yrs. old girl, BMI 28.7, PLXN3, c.1733C>T, p.Ala578Val variant. Maternal aunt had bariatric surgery.22 yrs. old female, BMI 53, PLXNA4, c.1982C>T, p.Ser661Leu variant. She had impaired glucose tolerance, PCOS, a nodular goiter, impaired glucose tolerance, 2 sisters and a brother had bariatric surgery.16 yrs. old boy, BMI 35.5, SEMA3D, c.1048T>C, p.Ser350Pro variant. He had anxiety, panic attacks, depression. His PGF and paternal uncle has morbid obesity. 16 yrs. old girl, BMI 30.9, SEMA3G, c.2305>G variant. She had impaired fasting glucose, elevated prolactin and amenorrhea. Mother and MGM had morbid obesity. 2 year old male with BMI of 30.1, SEMA3E, c.1443A>T, p.Glu481Asp variant. Mother had morbid obesity.4 year old female with BMI of 23.7, SEMA3G, c.2086GA, p.Gly696Arg variant. She has autism, epilepsy and motor delay. Mother and maternal aunt had morbid obesity.11 year old male, BMI 33.6, PLXNA4, c.4896CA, p.Asp1632Glu variant. MGF had morbid obesity. Conclusion: Clinical phenotype of patients with heterozygous variants of Semaphorins and its receptors shows presence of severe obesity from a young age of 2-4 yrs. All had a very strong family history of morbid obesity. These children developed insulin resistance with elevated TG and fatty liver from a young age. Leptin levels in few were low for the degree of obesity. Ref1. van der Klaauw AA, Farooqi IS et.al. Human Semaphorin 3 Variants Link Melanocortin Circuit Development and Energy Balance. Cell. 2019 Feb 7;176(4):729-742.e18. doi: 10.1016/j.cell.2018.12.009. PMID: 30661757. Presentation: Friday, June 16, 2023