SAT-686 Genetic Screening Yields Positive Results In 75% Of Patients With Early-onset Morbid Obesity And Identified Patients Who Can Benefit From A Personalized Approach To Treatment

Abstract Disclosure: B. Labib: None. M. Berra: None. E. Volcotrub: None. L. Musmanno: None. A. Bayoumy: None. P. Rizzuto: None. M. Gangat: None. E. Iofel: None. I. Marshall: None. A. Khattab: None. A.S. Bhangoo: None. S.B. Ten: None. Knowing the genetic background of patients with morbid obesity can provide individualized treatment. The FDA approved Setmelanotide for the treatment of morbid obesity secondary to variants in with POMC, PCSK1, LEPR, and Bardet-Beidl syndrome (BBS). The study aimed to screen for genetic predisposition in cases of morbid obesity in the MCR 4 pathway. Methodology: 533 patients (16.4 ± 7.7 yrs., 281 females) with morbid obesity, BMI of 39.0 ± 8.7 kg/m2 underwent genetic testing. Results: Out of 533 cases, 134 (25 %) had negative results, and 399 (75%) had positive results.25 cases carried two heterozygous BBS gene variants, 5 cases carried three heterozygous BBS gene variants, 5 cases carried two POMC heterozygous variants, and 1 case carried two PCSK1 heterozygous variants. All these 36 cases (9% of positive and 6.7 % of total) were eligible for treatment with Setmelanotide.In 138 cases, only 1 gene was involved; in 101 cases, 2 genes were involved; in 32 cases, 3 genes were involved; in 23 cases, 4 genes were involved; in 6 cases, 5 genes were involved, and in 4 cases, 6 genes were involved.Cases were divided into 3 groups: Group 1: Genes involved in the leptin-melanocortin signaling pathway were positive in 134 cases, 25 % of the total and 33.5 % of the positive cases.The following genes showed heterozygous polymorphism: LEP -1, LEPR -12, SH2B1 -13, POMC - 19 (5 cases had 2 genes), PCSK1- 22 (1 case had 2 genes), NCOA1 -12, MC4R - 14, MRAP2 - 4, GNAS -16, MCR3 - 4, NCOA in 17 cases. Group- 2. Genes involved in developing neurons responsible for energy homeostasis were positive in 220 cases, 41 % of the total, and 55 % of the positive cases.The following genes showed heterozygous polymorphism: PLXNA1 - 13, PLXNA2 - 5, PLXNA3 -11, PLXNA4 - 14, , PPARG 0 , RAI1 -13, RPS6KA3 0 , SEMA3A- 3, SEMA3B - 3, SEMA3C - 7, SEMA3D - 7, SEMA3E - 4, SEMA3F - 4, SEMA3G - 10, SIM1 - 5, ADCY3 - 9 , BDNF4 - 3, CPE2 - 0 , CREBBP - 2, CUL4B - 0, DNMT3A- 1 , DYRK1B - 7, EP300 - 3, HTR2C, ISL1, KIDINS220 - 10, KSR2-16, MAGEL2 - 6, MECP2 - 6, NPR1 - 4, NPR2 - 5, AFF4 - 9, VPS13B - 16, TRAIP - 1 , NR0B2 - 3, NTRK2 - 5, PHF6 - 1, TBX3 - 1, TRPC5 - 2, TUB - 7, UCP3 in 9 cases. Group 3: Genes involved in cilia signaling function were positive in 321 cases, 60 % of the total and 80% of positive cases. ALMS1 - 43, BBS1- 7, BBS2 - 9, BBS3(ARL6) -3, BBS4 6, BBS5 - 8, BBS6 (MKKS) - 5 , BBS7 6, BBS8 (TTC8 )-4, BBS9 (PTHB1)-14, BBS10 -13, BBS11 (TRIM32)-9, BBS12 -15, BBS13 (MKS1) -24, BBS14 (CEP290) -18, BBS15 (WDPCP ) -10, BBS16 (SDCCAG8)- 10, BBS17 (LZTFL1)-2, BBS18 (BBIP1)- 4,, BBS19 (IFT27) -8, BBS20 (IFT172)-23, BBS21 (CFAP418, C8orf37) - 6, BBS22 (IFT74) -5, INPP5E - 8, PCNT -36, RPGRIP1L - 13, NRP1 - 4, NRP2 in 8 cases. Conclusion: Genetic screening revealed positive results in 75 % of cases. According to the FDA guidelines, 9% of positive cases and 6.7 % of total cases were eligible for treatment with Setmelanotide. Genes involved in cilia signaling play a significant role in obesity, and they were found to be positive in 80% of 399 cases. Presentation: Saturday, July 12, 2025