Endocrine Abstracts

Introduction: There have been more than 130 genes described in relation with the development of obesity, which condition hyperphagia and early obesity. The aim of this study is to determine the prevalence of genetic alterations in a cohort of patients with morbid obesity.

Materials and Methods: We designed a descriptive cross-sectional study for a cohort of subjects with obesity grade III or higher (BMI ≥40 kg/m²), treated at endocrinologist consultations of Hospital Puerta del Mar. In order to determine cases of genetic obesity, an obesity panel has been designed based on exome sequencing of 80 genes.

Results: Preliminarily, we recruited 80 patients, 54 (67.5%) female with a median age of 50 (42-56) years. The maximum weight recorded was 137 (118-158.7) kg. and the maximum BMI was 50.8 (46-56) kg/m². Regarding metabolic comorbidities, 39 patients (48.8%) had arterial hypertension, 49 (61.3%) hepatic steatosis, 22 (27.5%) obstructive sleep apnea syndrome, 24 (30%) type 2 diabetes mellitus and 7 (8.8%) impaired fasting blood glucose. A total of 11 (13.6%) patients were diagnosed of hypothyroidism and 6 (7.5%) had history of cardiovascular events. Genetic variants were detected in 48 patients (60%), 33 of them (68.8%) were considered uncertain significance variants, 4 (8.3%) were probably pathogenic variants and 11 (22.9%) were considered pathogenic variants. Regarding the probably pathogenic variants, only a POMC variant [NM_001035256.2:c.638C>T p.(Ala213Val)] with autosomal dominant inheritance could justify the patient’s symptoms. The other three probably pathogenic variants (one in ALSM1, another one in BBS10 and another one in IFT4), all of them with autosomal recessive inheritance, should be considered as carrier patients. Regarding pathogenic variants, a variant in MCR4 [NM_005912.3(MC4R):c.27G>A p.(Met9Ile)] with autosomal dominant inheritance could justify the patient’s symptoms, whereas the other variants (one in BBS1, one in CEP290, one in IFT74 and seven in PSCK1) with autosomal recessive inheritance should be considered as carrier patients.

Conclusions: In our cohort, we detected a high incidence of variants, although most of them are uncertain significance variables whereas those that are pathogenic or probably pathogenic should be considered as a carrier status in many cases. Only 2 variants could be considered as a definitive diagnosis of non-syndromic genetic obesity: a variant in POMC [NM_001035256.2:c.638C>T p.(Ala213Val)] and another in MCR4 [NM_005912.3:c.380C>T p. (Ser127Leu)].