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Risk Factors Correlating With MC4R Pathway Variants on Genetic Testing

Clinical Genetics and Therapeutics
  • Primary Categories:
    • Clinical Genetics
  • Secondary Categories:
    • Clinical Genetics
Introduction:
Genetic variants in the melanocortin-4 receptor (MC4R) pathway can contribute to obesity. The Uncovering Rare Obesity® (URO) program aims to increase genetic testing access and identify individuals with obesity caused by rare genetic variants.

Methods:
Eligible consented patients are tested per physician order for gene variants in a panel of 79 genes and a chromosomal region known to be associated with obesity as part of the URO program. Using deidentified data, correlations between detected genetic variants and characteristics of patient obesity, hyperphagia, and family history were assessed using linear regression for continuous variables or chi-square tests for categorical values.

Results:
At the time of this analysis, 43,014 individuals had been tested in the URO program. Of these individuals, 68% were aged <18 years, 32% were aged ≥18 years, 49% were male, and 51% were female. Overall, there was a 2.6% positive result rate based on detected variants. The reported presence of hyperphagia as well as an earlier age of onset (vs later) of both obesity and hyperphagia were significantly correlated with a positive test result for a variant (P=0.0010, P<0.0001, and P<0.0001, respectively). This was also reflected by the positive result rate, which increased to 6.6% in patients with obesity onset <2 years of age who also reported hyperphagia. Family history of genetic disease was also significantly associated with the likelihood of a positive test result (P<0.0001), with 15.7% of patients with a positive test result having a family history of genetic disease vs only 5.3% in patients with no genetic finding.

 

Conclusion:
Early-onset obesity, hyperphagia, and family history of genetic disease are clinical characteristics strongly associated with the presence of variants in the MC4R pathway. As shown by the URO testing experience in >40,000 patients, genetic testing can assist in diagnosing patients to improve management of their condition.

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