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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 sequences genes with clinical and/or molecular evidence suggesting a role in human obesity.


Monogenic obesity can be sporadic (de novo) or inherited by dominant or recessive modes. Most obesity-associated genes are autosomal, but some reside on the X-chromosome. All variant-types have been reported including missense, nonsense, frameshift, splicing, and copy number variants (CNVs). This panel will detect all these variant types. Notably, the vast majority of CNVs, including 16p11.2 deletion syndrome and Smith-Magenis syndrome (17p11.2) will be detected. This panel is not designed to diagnose Prader Willi syndrome.

This panel sequences a comprehensive list of genes associated with obesity, including those with definitive evidence establishing the gene-disease relationship and several with only supporting evidence.

The largest genetic contributors to non-syndromic obesity control energy balance via the leptin-melanocortin signaling pathway (LEP, LEPR, POMC, PCSK1, and MC4R). Several cell-signaling genes interact with this pathway peripherally or influence the development of neurons responsible for energy homeostasis (ADCY3, BDNF, CPE, CREBBP, CUL4B, DNMT3A, EP300, GNAS, HTR2C, ISL1, KIDINS220, KSR2, MAGEL2, MECP2, MRAP2, NCOA1, NPR1, NPR2, NR0B2, NTRK2, PHF6, PLXNA1, PLXNA2, PLXNA3, PLXNA4, PPARG, RAI1, RPS6KA3, SEMA3A, SEMA3B, SEMA3C, SEMA3D, SEMA3E, SEMA3F, SEMA3G, SH2B1, SIM1, TBX3, TRPC5, TUB, and UCP3). This group of genes has diverse functions, and not surprisingly, the associated phenotypes vary considerably. Several of the conditions have significant pleiotropy and obesity may be a minor feature.

The largest phenotypic series associated with syndromic obesity includes Bardet-Biedl syndrome and related ciliopathies (ALMS1, ARL6, BBIP1, BBS1, BBS10, BBS12, BBS2, BBS4, BBS5, BBS7, BBS9, CFAP418/C8orf37, CEP290, IFT172, IFT27, IFT74, INPP5E, LZTFL1, MKKS, MKS1, PCNT, RPGRIP1L, SDCCAG8, TRIM32, TTC8, WDPCP). See individual gene summaries for more information about molecular biology of gene products and spectra of pathogenic variants.

Testing Strategy

This panel typically provides 99.92% 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.

Clinical Sensitivity

Pathogenic variants in the MC4R gene are the most common monogenic cause of obesity. 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. Historic testing data at PreventionGenetics suggests that this test will be diagnostic in approximately 5% of cases. 

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 or uniparental disomy (e.g. Prader-Willi syndrome). 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

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, its territories, and Canada. Select family members of patients who were previously tested may also be eligible for testing.