Rhythm Pharmaceuticals

Clinical Features

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. Monogenic obesity can be non-syndromic, occurring as an isolated feature, or syndromic, occurring as a co-morbidity of a complex phenotype.

The phenotype of non-syndromic monogenic obesity 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).

Syndromic obesity includes a heterogeneous group of disorders where excessive weight gain is accompanied by intellectual disability, developmental delays, and/or congenital anomalies (Albuquerque et al. 2015. PubMed ID: 25749980; Pigeyre et al. 2016. PubMed ID: 27154742). Examples include Bardet Biedl, Alstrom, and Borjeson-Forssman-Lehmann syndromes. This panel is designed to sequence all genes for which obesity is a common feature (please see Genes and Diseases tables below).


Monogenic non-syndromic obesity can be sporadic or inherited by autosomal dominant or recessive modes. The largest genetic contributors to this phenotype include genes controlling energy balance via the leptin-melanocortin signaling pathway (LEP, LEPR, POMC, PCSK1, MC4R, and SIM1). Additional genes are involved in cell proliferation and differentiation via tyrosine kinase signaling cascades (BDNF, NTRK2, SH2B1, and KSR2; Pigeyre et al. 2016. PubMed ID: 27154742).

Monogenic syndromic obesity is frequently sporadic but can also be inherited by x-linked, autosomal recessive, and autosomal dominant patterns. Approximately forty genes are known to cause syndromic obesity. Nearly half of the genes are associated with Bardet-Biedl syndrome and other ciliopathies.

Testing Strategy

This panel typically provides ≥98% coverage of all coding exons of the genes listed, plus ~10 bases of flanking noncoding DNA. We define coverage as ≥20X NGS reads or Sanger sequencing.

Clinical Sensitivity

It is difficult to estimate the clinical sensitivity of this test given the heterogeneous phenotypes represented and 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. This test will not detect imprinting defects, uniparental disomy, or balanced translocations. If those mechanisms are suspected, additional testing may be indicated.

Indication For Test

Candidates for this test are patients with early onset non-syndromic obesity or patients suspected to have a syndrome with obesity as a predominant feature.

Patients of all ages with severe obesity could be eligible for the Rhythm-sponsored genetic testing program.  To be eligible for testing, patients must meet one of the following criteria*:

  • ≤18 years of age, BMI ≥97th percentile or
  • ≥19 years of age, BMI ≥40, and a history of childhood obesity before age 10

 Call us at 844-513-3994 or visit Rhythm’s website for more information about the program.

 *Testing available only for patients located in the United States and its territories. Select family members of patients who were previously tested may also be eligible for testing.