Monogenic obesity: MC4R

What is monogenic obesity?

Obesity is defined as abnormal or excessive fat accumulation that presents a risk to health, which occurs when abnormal amounts of triglycerides are stored in adipocytes and released as free fatty acids. In addition to dietary and lifestyle factors, epigenetic modifications play a role in excess fat accumulation. Obesity is correlated with an increased risk of type 2 diabetes, cardiovascular disease, cancer and mortality. The heritability of obesity and body weight in general is high.

Monogenic obesity is a group of single gene disorders with obesity as an isolated or predominant feature. Severe early-onset obesity caused by heterozygous mutations in the melanocortin-4 receptor gene (MC4R) is typically dominantly inherited. Although less common, recessive inheritance of MC4R-associated obesity can occur.

The clinical features of monogenic obesity can vary significantly. However, some common features are listed below:

• Early onset obesity: Individuals with monogenic obesity often develop obesity before the age of five, so early onset symptoms are key when deciding whether to consider genomic testing.
• Severe obesity: Children and adults whose obesity is severe, such as a child whose BMI is more than three standard deviations (3SD) above the mean or an adult whose BMI is higher than 40, is a common feature of monogenic obesity.
• Excessive appetite: Individuals with monogenic obesity often have significant hyperphagia and may report having very large appetites and/or disordered eating behaviors.
• Reduced energy expenditure: Individuals with monogenic obesity may have a reduced energy expenditure, with a weight trajectory not apparently explained by dietary intake.
• Other health problems: Affected individuals are at an increased risk of several health problems, including type 2 diabetes, heart disease and sleep apnea.
• Family history: Further questioning may reveal a significant family history of early onset obesity or parental consanguinity.

Associated genes

MC4R is the most common cause of non-syndromic severe early onset obesity. It can be inherited in an autosomal dominant or an autosomal recessive pattern. An increased severity can be seen in association with biallelic pathogenic variants. In childhood, accelerated linear growth and additional lean mass is typically seen.

Why should you test?

This test may be appropriate for individuals with hyperphagia and endocrine dysfunction and individuals with obesity and phenotypic changes consistent with a syndromic etiology. Genetic testing may confirm a suspected diagnosis and help guide treatment and management decisions.