Presentation: Patient with possible monogenic obesity

A 26-year-old female patient who is significantly obese attends your clinic (her BMI is over 40). She reports having been significantly overweight since early childhood and having been assessed in the paediatric clinic for obesity and hyperphagia, with no clear cause found. There is no history of developmental delay or other significant childhood illnesses. She reports that a sibling has also been significantly overweight since childhood, and that her mother is also overweight.

Genomic testing should be considered in patients with a BMI more than three standard deviations (3SD) above the mean and an onset of obesity before the age of five, in the absence of significant syndromic features and with no explanation.

• Consult the National Genomic Test Directory. From here you can access the rare and inherited disease eligibility criteria, which provides information about individual tests and their associated eligibility criteria. You can also access a spreadsheet containing details of all available tests.
  • For those working within NHS Wales, please consult the All Wales Medical Genomics Service website for information on how to arrange testing.
• To find out which genes are included on different gene panels, see the NHS Genomic Medicine Service (GMS) Signed Off Panels Resource.
• For patients who meet test directory eligibility criteria and do not have a personal or family history of a genetic variant in a familial hypoparathroid gene, select the following:
  • R149 Severe early-onset obesity (whole exome sequencing or medium panel sequencing). This panel comprises the following genes: ALMS1, ARL6, BBS1, BBS2, BBS4, BBS5, BBS7, BBS9, BBS10, BBS12, CEP19, CPE, GNAS, KIDINS220, LEP, LEPR, MC4R, MKKS, MKS1, MYT1L, NTRK2, PCSK1, PGM2L1, PHF6, PHIP, POM C, SDCCAG8, SIM1, TTC8 and VPS138. Multiplex ligation-dependent probe amplification (MLPA) or equivalent may also be employed to evaluate for loss of genomic material at 15q11q13 (PWS/AS) regions and the 16p11.2 recurrent region (includes SH2B1).
• Similar or overlapping tests include R27 Paediatric disorders and R89 Ultra-rare and atypical monogenic disorders. These panels should be selected for individuals with congenital malformations, dysmorphism or other complex or syndromic presentations.
• For patients presenting with severe monogenic obesity in whom a genetic diagnosis in a relevant predisposition gene has been established in another family member, single gene testing for that specific variant should be considered.
• The above tests do not include whole genome sequencing, so you should use your local Genomic Laboratory Hub test order and consent (record of discussion) forms.
• These tests are DNA based, and an EDTA sample (purple-topped tube) is required. The sample is best stored at four degrees Celsius until it can be posted to the genomic laboratory.
• Information about patient eligibility and test indications was correct at the time of writing. When requesting a test, please refer to the National Genomic Test Directory to confirm the right test for your patient.

For clinicians

• NHS England: National Genomic Test Directory
• University of Cambridge Metabolic Research Laboratories: Genetics of Obesity study
• University of Cambridge Metabolic Research Laboratories: Melanocortin 4 Receptor

For patients

• Genetic Alliance UK
• Obesity UK
• University of Cambridge Metabolic Research Laboratories: Genetics of Obesity study patient information
• University of Cambridge Metabolic Research Laboratories: Melanocortin 4 Receptor