NGS-based diagnostic DNA analysis in syndromal and nonsyndromal obesity.

In the past few decades, there has been an exploding prevalence of obesity with its subsequent morbidity and mortality forming a major threat to public health. Although generally considered to be generated by environmental factors, it is remarkable that despite sharing the same ‘obesogenic’ environment not all Westernized people are obese. A number of genes have indeed been identified that, when mutated, can cause obesity in humans. Nevertheless, mutations in these genes (e.g. MC4R, POMC, LEP, LEPR, PCSK1) , combined with chromosomal aberrations (e.g. deletion 16p11.2, 15q11-q13) explain no more than ~6% of the heritability shown by twin studies. Next generation sequencing techniques now provide a time- and cost-efficient method to identify mutations in large panels of known disease genes and to additionally screen a large number of candidate genes involved in or associated with a trait. We developed a custom NGS enrichment kit (the ‘Obesitome’) aimed at enrichment of 255 either known obesity genes or putative obesity candidate genes. Analysis of 53 obesity related genes is offered as a diagnostic analysis through our genome-diagnostics laboratory. The remaining 202 candidate genes can be analyzed in a research setting, to identify novel obesity-related genes. We present the results of diagnostic analysis in (syndromal) morbidly obese patients (N>900). A clear molecular diagnosis can be made in up to ~6% of the patients and possible pathogenic mutations needing further follow-up were detected in an additional ~8% of patients. These results prove the validity of genetic testing in obesity and open new avenues to providing genotype-based personalized treatment in this population.