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Conditions

Monogenic obesity

Monogenic obesity is a rare and often severe form of obesity that is caused by a pathogenic variant in one of several different genes.

Overview

Obesity affects more than 26% of adults and more than 23% of 10- to 11-year-old children in the UK. While genomics contributes significantly to obesity, monogenic obesity is comparatively rare and genomic testing should be considered in affected individuals. ​​Many of the monogenic forms of obesity affect the leptin-melanocortin and MC4R pathways and have a role in the regulation of appetite and energy expenditure.

Clinical features

The clinical features of monogenic obesity can vary significantly depending on the gene involved. 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 behaviours.
  • 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 a number of health problems, including type 2 diabetes, heart disease and sleep apnoea. Depending on the genomic aetiology involved, behavioural problems, developmental delay and endocrinopathies may also be present.
  • Family history: Further questioning may reveal a significant family history of early onset obesity or parental consanguinity.

Genomics

Many of the monogenic forms of obesity affect the leptin-melanocortin and MC4R pathways and have a role in the regulation of appetite and energy expenditure.

A number of different genes have been associated with monogenic obesity. Examples of those more frequently encountered include:

  • MC4R: This gene 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.
  • POMC: This gene is inherited in an autosomal recessive pattern. Affected individuals present with neonatal hypoglycaemia, hypocortisolism, hypopigmentation, neonatal hypoglycaemia, seizures and cholestasis.
  • LEP and LEPR: These genes are inherited in an autosomal recessive pattern. There will be rapid weight gain after a normal birth weight. There will be significant metabolic sequelae of obesity and hypogonadal hypogonadism, as well as increased risk of severe bacterial infection.
  • BBS genes: This gene is inherited in an autosomal recessive pattern. Obesity is typically seen with rod cone dystrophy, polydactyly, hypogonadism, renal anomalies and cognitive impairment.

Diagnosis

Testing for severe early-onset obesity should be undertaken after careful consideration, ideally by clinicians working in a dedicated weight management service. The testing criteria includes:

  • a BMI of more than three standard deviations (3SD) above the mean;
  • onset before the age of five; and
  • the absence of significant syndromic features, with no explanation.

The appropriate clinical indication to select within the National Genomic Test Directory is R149 Severe early-onset obesity, which is currently comprised of 33 genes. Individuals with congenital malformations, dysmorphism or other complex or syndromic presentations should be considered for testing under R27 or R89 as appropriate.

For further information about genomic testing, see Patient with possible monogenic obesity.

This condition may be identified before any symptoms appear – for example, through the Generation Study. Confirmation of the diagnosis will require referral to clinical genetics services. Please refer to your regional pathway.

 

Inheritance and genomic counselling

Pre-test genomic counselling should include discussion about the potential finding of a negative test result, the potential of finding variants of uncertain significance, the impact of the test on the patient and their family members and the current limited potential for targeted medical treatment. The possibility of participating in research studies should also be considered.

Post-test genomic counselling should reflect the mode of inheritance which, depending on the causative gene, includes autosomal recessive, autosomal dominant and X-linked patterns.

Management

  • Individualised patient treatment plans should be facilitated by an multidisciplinary team with experience of genomic obesity.
  • Standard pharmacological interventions can be used, as many patients with genomically confirmed severe early-onset obesity do derive metabolic benefit.
  • Setmelanotide can be used to treat obesity and to control hunger in adults and children (aged six years or older) with biallelic constitutional (germline) variants that result in pro-opiomelanocortin deficiency. This includes proprotein convertase subtilisin/kexin type 1 or leptin receptor (LEPR) genes.
    • In the UK, setmelanotide treatment is led by clinicians at Addenbrooke’s Hospital in Cambridge.
  • Bariatric surgery can be considered after careful multidisciplinary team discussion. There is a significant heterogeneity in response, though many patients do derive a significant benefit. Surgery is not recommended for patients with biallelic loss-of-function pathogenic variants in MCR4.

This condition may be identified before any symptoms appear, for example through the Generation Study. Therefore, management of these individuals may differ from those presenting symptomatically.

Resources

For clinicians

References:

For patients

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  • Last reviewed: 18/07/2023
  • Next review due: 18/07/2025
  • Authors: Dr Jonathan Hazlehurst
  • Reviewers: Dr Emile Hendriks, Dr Louise Izatt, Dr Paul Newey