ESPE Abstracts

Aim of the study: Correlate genetic data of patients heterozygous of PCSK1 gene variations with the clinical phenotype.

Introduction: Heterozygous variants of the PCSK1 gene have been described in cases of early onset of morbid obesity in childhood. This gene encodes prohormone convertase 1/3 enzyme, a serine endoprotease expressed in neuroendocrine cells that converts inactive prohormones into functional hormones important in regulation of energy metabolism.

Methods: 293 cases of morbid obesity underwent genetic testing at Prevention Genetics after obtaining consent.

Results: All cases presented with early weight gain from 3-5 years of age, hyperphagia, acanthosis nigricans. 35 (12 %) cases had heterozygous PCSK1 gene variations. 22 were females and 13 males: 15 Caucasian, 9 Hispanic, 6 Asian, and 5 African American. The age at diagnosis was 16.7 ± 9.4 (from 3 to 42 yrs.), BMI was extremely high 40.7 ± 4.6 kg/m2. 24 cases of 35 (68.5 %) carried the heterozygous polymorphism c.661A>G, which is predicted to result in an amino acid substitution p.Asn221Asp (rs6232). In other cases different PCSK1 variants were found: 2 cases c.818_820del, p.Asp273del; 2 cases c.1381G>A, p.Val461Met; 2 cases c.1918A>G, p.Thr640Ala; 2 cases c.28T>G, p.Cys10Gly; 1 case c.2099_2101del, p.Phe700del; 1 case c.1387G>A, p.Glu463Lys; 1 case c.760A>G, p.Ile254Val. 11 cases were only heterozygous for one PCSK1 gene variant, 14 cases in a combination of PCSK1 and one additional gene, 3 cases in combination with 2 additional genes, 5 cases in combination with 3 additional genes, 1 case each of 4 and 5 additional genes. There were no cases of diabetes type 2. Intellectual development was normal in all patients, no evidence of autism, learning disability or mental retardation. Only 2 patients had fatty liver, 2 had hypertension and another 2 had borderline elevated HbA1c of 5.9 and 6.2%. As a group the average Insulin was 24.91± 16.82 mcIU/mL; TG of 133.3 ± 53.6 mg/dl, HDL of 43.5 ± 7.6 mg/dl. They had low-normal Leptin levels of 25.73± 14.5 ng/mL.

Conclusion: Genetic screening of early onset of obesity can identify patients with PCSK1 heterozygous gene polymorphisms. PCSK1 rs6232 is a frequent gene polymorphism associated with morbid obesity. Insulin resistance was not severe as expected for the degree of morbid obesity and leptin levels were relatively low. This information can help in the understanding of the natural history of PCSK1 gene carriers in diverse ethnic groups.