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Updates on Rare Genetic Variants, Genetic Testing, and Gene Therapy in Individuals With Obesity

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Abstract

Purpose of Review

The goal of this paper is to aggregate information on monogenic contributions to obesity in the past five years and to provide guidance for genetic testing in clinical care.

Recent Findings

Advances in sequencing technologies, increasing awareness, access to testing, and new treatments have increased the utilization of genetics in clinical care. There is increasing recognition of the prevalence of rare genetic obesity from variants with mean allele frequency < 5% –new variants in known genes as well as identification of novel genes– causing monogenic obesity. While most of these genes are in the leptin melanocortin pathway, those in adipocytes may also contribute. Common variants may contribute either to higher lifetime tendency for weight gain or provide protection from monogenic obesity.

Summary

While specific genetic mutations are rare, these segregate in individuals with early-onset severe obesity; thus, collectively genetic etiologies are not as rare. Some genetic conditions are amenable to targeted treatment. Research into the discovery of novel genetic causes as well as targeted treatment is growing over time. The utility of therapeutic strategies based on the genetic risk of obesity is an advancing frontier.

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Funding

This work is supported in part by NIH-NIDDK K23 DK110539, Pilot and Feasibility Grant, the New York Obesity and Nutrition Research Center, NIH-NIDDK P30 DK26687, and Louis V. Gerstner Scholar Program at Columbia University Irving Medical Center to VVT. CAL is supported in part by funding from the NIH-NIDDK R01 DK52431 and ASPIRE Pfizer Obesity Research Grant.

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Authors and Affiliations

  1. Division of Genetics and Genomics, Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, MA, 02115, United States

    Michael V. Zuccaro

  2. Division of Molecular Genetics, Department of Pediatrics, Columbia University Irving Medical Center, 1150, St. Nicholas Avenue, NY 10032, United States

    Charles A. LeDuc & Vidhu V. Thaker

  3. Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, 10032, United States

    Charles A. LeDuc & Vidhu V. Thaker

  4. Division of Pediatric Endocrinology, Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, 10032, United States

    Vidhu V. Thaker

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M.V. Z., C.A.L. and V.V.T wrote the main manuscript text. M.V. Z. prepared the figure, V.V.T prepared the tables. All authors reviewed and approved the manuscript.

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Correspondence to Vidhu V. Thaker.

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VVT participates in clinical trials for genetic obesity sponsored by Rhythm Pharmaceuticals. MVZ and CAL have nothing to disclose.

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Zuccaro, M.V., LeDuc, C.A. & Thaker, V.V. Updates on Rare Genetic Variants, Genetic Testing, and Gene Therapy in Individuals With Obesity. Curr Obes Rep (2024). https://doi.org/10.1007/s13679-024-00567-y

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