# Monogenic obesity due to MC4R deficiency: lessons from a multigenerational case

## TL;DR

A four-generation family with MC4R deficiency highlights the importance of early genetic testing for effective obesity treatment.

## Contribution

Demonstrates the clinical utility of genetic testing in identifying MC4R deficiency and guiding targeted therapies in multigenerational cases.

## Key findings

- A rare MC4R variant (c.913C > T; p.Arg305Trp) was identified in four family members with early-onset obesity.
- Liraglutide treatment significantly reduced BMI in the index patient.
- The MC4R variant segregated with obesity in the family, supporting its pathogenic role.

## Abstract

Melanocortin 4 receptor (MC4R) deficiency is the most common monogenic cause of obesity, yet remains underdiagnosed. Patients with monogenic obesity often undergo a frustrating diagnostic and therapeutic odyssey of years of ineffective lifestyle interventions before a causal diagnosis is made. We report a four-generation family where genetic testing in a child identified a likely pathogenic MC4R variant also carried by three ancestors.

The studied family included a 7-year-old index patient, her mother, grandmother, and great-grandmother with a history of early-onset obesity. Panel sequencing of monogenic obesity genes was performed in the index patient whereas in the relatives targeted analysis of the familial MC4R variant was performed by Sanger sequencing.

The index patient developed severe obesity by age 2 years, with hyperphagia, tall stature, and dyslipidemia. Despite lifestyle interventions, her body mass index (BMI) continued to increase. At the age of 7 years, genetic panel testing identified a rare monoallelic variant in the MC4R gene c.913C > T; p.Arg305Trp, previously shown to impair receptor function. Treatment with liraglutide (3.0 mg/day) was initiated at age 8 years, resulting in marked reduction in BMI during the first year of treatment. Subsequent genetic testing of family members identified the same variant in her mother, grandmother, and great-grandmother, all of whom had a history of early-onset obesity and related comorbidities, consistent with segregation of the variant within the family.

This case underscores the importance of early genetic testing in severe childhood obesity to avoid ineffective treatments and enable targeted therapies (e.g., GLP-1 analogues). Diagnosing (likely) pathogenic MC4R variants can also identify at-risk relatives, providing psychological and clinical benefits across generations.