Non-Syndromic Monogenic Obesity Panel

Obesity is defined as an increase in fat mass that is sufficient to adversely affect health and reduce longevity (Fontaine et al. 2003. PubMed ID: 12517229). Clinically, adults with a body-mass index (BMI) greater than 30 kg/m² are considered obese. BMI is a multifactorial trait that is usually influenced by multiple genes (Gusev et al. 2014. PubMed ID: 25439723), as well as environmental and lifestyle factors. However, in some cases obesity is inherited by a monogenetic mechanism due to pathogenic variants in a single gene.

The non-syndromic form of monogenic obesity is a group of single gene disorders with obesity as an isolated or predominant feature. The obesity phenotype in these patients is typically severe and early-onset. Infants experience rapid weight gain in the first year of life and reach a BMI > 3 standard deviations above the mean. Associated features include hyperphagia, increased linear growth, delayed puberty, preserved reproductive function, hypocortisolemia and hyperinsulinemia (Albuquerque et al. 2015. PubMed ID: 25749980; Pigeyre et al. 2016. PubMed ID: 27154742)

The largest genetic contributors to non-syndromic obesity include genes expressed in the hypothalamus that control energy balance via the leptin-melanocortin signaling pathway (LEP, LEPR, MC4R, POMC, PCSK1, SH2B1, and SIM1). MC4R deficiency is the most prevalent of these disorders, affecting up to 1 in 2,000 individuals (Orphanet). Obesity due to pathogenic MC4R variants is inherited by a semidominant mechanism; the phenotype is severe and fully penetrant in homozygotes or compound heterozygotes, and milder with incomplete penetrance in heterozygotes. POMC and PCSK1 have similar inheritance properties. LEP and LEPR cause autosomal recessive obesity; SH2B1 and SIM1 cause obesity with autosomal dominant inheritance.

Additional genes mediate neuron differentiation and proliferation via tyrosine kinase signaling in the brain, apparently unrelated to the leptin pathway (NTRK2 and KSR2; Pigeyre et al. 2016. PubMed ID: 27154742). NTRK2 and KSR2-related obesity is autosomal dominant.

Finally, UCP3 and NR0B2 are involved in energy utilization in peripheral tissues such as skeletal muscle and liver (Millet et al. 1997. PubMed ID: 9389729; Lu et al. 2000. PubMed ID: 11030331). Pathogenic variants in these genes may cause obesity with autosomal dominant or recessive inheritance.

The genes included on this panel account for all known causes of monogenic non-syndromic obesity due to pathogenic sequence alterations. Pathogenic variants include missense and nonsense changes as well as small and large insertions/deletions (Human Gene Mutation Database). In some cases multifactorial inheritance has been proposed, however, at this time the number of cases is too small to clearly define these variants (Pigeyre et al. 2016. PubMed ID: 27154742).

It is difficult to estimate the clinical sensitivity of this test given the significant contribution of environment to obesity. For the MC4R gene alone, the prevalence of pathogenic variants is predicted to be 0.5 - 1% in obese adults and up to 6% in severely obese children (Farooqi and O'Rahilly. 2005. PubMed ID: 15660521; Farooqi et al. 2003. PubMed ID: 12646665). This range in prevalence demonstrates that sensitivity is strongly influenced by the severity and onset of symptoms.

The analytical sensitivity of this test is expected to be high since this Next-Generation sequencing test is designed to detect nearly all clinically relevant sequence and copy number variants in genes that cause monogenic obesity.

Additional Sanger sequencing is performed for any regions not captured or with insufficient number of sequence reads.

This panel provides 100% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing.