Genetic obesity: next-generation sequencing results of 1230 patients with obesity.

BACKGROUND: Obesity is a global and severe health problem. Due to genetic heterogeneity, the identification of genetic defects in patients with obesity can be time consuming and costly. Therefore, we developed a custom diagnostic targeted next-generation sequencing (NGS)-based analysis to simultaneously identify mutations in 52 obesity-related genes. The aim of this study was to assess the diagnostic yield of this approach in patients with suspected genetic obesity. METHODS: DNA of 1230 patients with obesity (median BMI adults 43.6 kg/m2; median body mass index-SD children +3.4 SD) was analysed in the genome diagnostics section of the Department of Genetics of the UMC Utrecht (The Netherlands) by targeted analysis of 52 obesity-related genes. RESULTS: In 48 patients pathogenic mutations confirming the clinical diagnosis were detected. The majority of these were observed in the MC4R gene (18/48). In an additional 67 patients a probable pathogenic mutation was identified, necessitating further analysis to confirm the clinical relevance. CONCLUSIONS: NGS-based gene panel analysis in patients with obesity led to a definitive diagnosis of a genetic obesity disorder in 3.9% of obese probands, and a possible diagnosis in an additional 5.4% of obese probands. The highest yield was achieved in a selected paediatric subgroup, establishing a definitive diagnosis in 12 out of 164 children with severe early onset obesity (7.3%). These findings give a realistic insight in the diagnostic yield of genetic testing for patients with obesity and could help these patients to receive (future) personalised treatment.

[A boy with a cough and shoulder pain]. / Een hoestende jongen met schouderpijn.

A 15-year-old boy reported to the Accident and Emergency Department with excessive coughing, shortness of breath and pain in the area of his left shoulder blade. Methicillin-resistant Staphylococcus aureus (MRSA) was cultured from his sputum. The boy was otherwise healthy, and had no immune deficiency or underlying anatomic abnormality. He probably contracted the MRSA infection at the international school he attends.

Association between increased arterial-wall thickness and impairment in ABCA1-driven cholesterol efflux: an observational study.

BACKGROUND: Decreased concentrations of HDL cholesterol are associated with increased cardiovascular risk. These concentrations are directly related to cholesterol efflux from cells-the first step and a key process in reverse cholesterol transport. Cholesterol efflux is mediated by the ATP-binding cassette A1 transporter (ABCA1), the rate-limiting step in the production of HDL. We aimed to assess the relation between cholesterol efflux, HDL concentrations, and arterial-wall changes in individuals with impaired ABCA1 function. METHODS: We investigated 30 individuals from families with ABCA1 mutations, and 110 controls matched for age, sex, and ethnic origin. We measured concentrations of HDL cholesterol in plasma and intima-media thickness of the carotid arteries by B-mode ultrasonography in all participants. We also measured cholesterol efflux from skin fibroblasts in nine individuals with ABCA1 mutations and in ten controls. FINDINGS: Individuals with ABCA1 mutations had lower amounts of cholesterol efflux, lower HDL cholesterol concentrations, and greater intima-media thicknesses than controls. An intima-media thickness at the upper limit of normal (0.80 mm) was reached by age 55 years in the ABCA1 heterozygotes, and at age 80 years in unaffected controls (p<0.0001). Additionally, strong positive correlations were seen between HDL cholesterol concentrations and cholesterol efflux (r=0.90, p=0.001), and negative correlations between apolipoprotein-AI-mediated (r=-0.61, p=0.030) and HDL-particle-mediated (r=-0.60, p=0.018) efflux and intima-media thickness in the ABCA1 mutation carriers. INTERPRETATION: These results show a direct relation between ABCA1-mediated cellular cholesterol efflux and arterial-wall thickness, and therefore suggest that increasing efflux could inhibit atherosclerosis progression before the manifestation of symptomatic cardiovascular disease.