How to Access Genetic Testing
When to consider Genetic Testing
A number of genes have been shown to cause monogenic obesity, and whilst the clinical features can vary depending on which gene is affected, the below clinical features are indications that genetic testing should be considered:
- Early onset obesity – current clinical guidelines recommend that patients with severe obesity of early onset (before 5 years of age) are offered genetic testing (Styne et al. JCEM 2017)
- Severe Obesity – In children this is a BMI sds>3 and in adults a BMI>40
- Family History – A significant family history of early onset obesity or consanguinity
Although some forms of monogenic obesity are associated with developmental delay and behavioural problems (see SIM1 and SH2B1 below), this is not the case in all forms of monogenic obesity, so testing should not be discounted if these are not present. Key clinical features are:
Recessive Causes of Monogenic Obesity:
Leptin deficiency and Leptin Receptor deficiency: extreme hyperphagia and rapid weight gain from birth, frequent infections, hypogonadotropic hypogonadism and mild hypothyroidism.
POMC and PCSK1 deficiency: early onset obesity and ACTH deficiency (hypoglycaemia in infancy). Patients with POMC deficiency often have pale skin and red hair, whilst those with PCSK1 deficiency may also have small bowel enteropathy, postprandial hypoglycemia and diabetes insipidus.
Bardet-Biedl syndrome: Patients with Bardet-Biedl syndrome have dysmorphic extremities, such as polydactyly, hypogonadism, renal abnormalities and retinal dystrophy or pigmentary retinopathy.
Dominant Causes of Monogenic Obesity:
MC4R deficiency: This is the commonest cause of early onset obesity. Patients with MC4R pathogenic variants have hyperphagia and accelerated linear growth. Where patients carry a homozygous variant the obesity is more severe than in those who carry heterozygous variants. More information can be found at www.mc4r.org.uk
SIM1 deficiency: hyperphagia, speech and language delay and neurobehavioral abnormalities including autistic behaviours and emotional lability.
SH2B1 deficiency including 16p11.2 deletions containing SH2B1: hyperphagia, disproportionate insulin resistance and early type 2 diabetes, speech and language delay and behavioural problems
Accessing Genetic Testing in the UK
Two options for testing are currently available in the UK (detailed below).
If your patient is found to have a pathogenic, likely pathogenic or variant of unknown significance in an obesity gene please review our Clinical Trials and Treatment page for up-to-date information on treatments and clinical trials in the UK your patient may be eligible for.
NHS Severe Early-Onset Obesity panel test
Paediatricians, Endocrinologists and Geneticists can arrange genetic testing through the NHS for children and adults whose obesity is severe (BMI sds >3; BMI >40kg/m2) and started before the age of 5 years. As genetic testing is nationally commissioned there is no cost to NHS Trusts.
The test is called ‘Severe Early-Onset Obesity (code R149.1)’ and currently includes 30 genes and 3 chromosomal regions. The panel is reviewed on an annual basis and details of the genes included in the current panel can be found on the NHS Genomic Medicine Service website.
The test is carried by the East Genomics Laboratory Hub in Cambridge and details on how to request the test here.
ROAD genetic testing
Rhythm Pharmaceuticals have partnered with Unilabs/CGC Genetics in Portugal to offer genetic screening via the Rare Obesity Advanced Diagnosis (ROAD)
This is a GLP accredited commercial laboratory which runs a panel of 79 obesity genes and 1 chromosome region. There is no cost involved for the test and it is available for patients under 18 years of age who have a BMI ≥ 97th percentile and for patients over 18 years of age who have a BMI≥40 kg/m2 and a history of childhood obesity.
Patients have to be consented for this test by a Physician. This service has been available in the US for some time through Prevention Genetics; their website has some useful information for Physicians and patients
UK Physicians may wish to discuss the use of this test with their local Research Board or Ethics Committee (it is a commercial test). When consenting to this diagnostic ROAD test, patients/carers will be asked if they consent to being approached to participate in ongoing and future clinical trials based on their genotype. As the samples are anonymized, only the Physician can contact the patient about clinical trials.
Genetic results are returned to the referring Physician and reported in line with internationally accepted criteria (pathogenic, likely pathogenic, variant of unknown significance (VUS), benign). The ACMG criteria can be found here.
Accessing Genetic Testing outside the UK
Genetic testing for monogenic obesity via gene panels or whole exome sequencing is now readily available in most countries. Rhythm Pharmaceuticals also offers free genetic testing via the ROAD programme in Europe ROAD programme in Europe or in partnership with Prevention genetics in the US If you have problems accessing genetic testing please contact us at This email address is being protected from spambots. You need JavaScript enabled to view it. for further advice.
