Monogenic Obesity via the MC4R Gene

Summary and Pricing

Test Method

Sequencing and CNV Detection via NextGen Sequencing using PG-Select Capture Probes
Test Code Test Copy GenesPriceCPT Code Copy CPT Codes
8779 MC4R$640 81403,81479 Add to Order

Pricing Comments

This test is also offered via our exome backbone with CNV detection (click here). The exome-based test may be higher priced, but permits reflex to the entire exome or to any other set of clinically relevant genes.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

Turnaround Time

The great majority of tests are completed within 20 days.

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Geneticist

Clinical Features and Genetics

Clinical Features

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 (Vaisse et al. 1998; Yeo et al. 1998). Although less common, recessive inheritance of MC4R-associated obesity can occur (Farooqi et al. 2000). Common features include hyperphagia, increased linear growth, preserved reproductive function and hyperinsulinemia.

Genetics

MC4R-associated monogenic obesity can present with either dominant or recessive patterns of inheritance depending on the specific functional effects of particular mutations on the mutant receptor (Farooqi et al. 2000). The MC4R gene encodes a member of the melanocortin receptor family. So far, documented genetic defects of MC4R include missense, nonsense mutations and small deletion/insertions (Human Gene Mutation Database). A large deletion involving the MC4R gene has been reported (Human Gene Mutation Database).

Testing Strategy

For this Next Generation Sequencing (NGS) test, sequencing is accomplished by capturing specific regions with an optimized solution-based hybridization kit, followed by massively parallel sequencing of the captured DNA fragments. Additional Sanger sequencing is performed for regions not captured or with insufficient number of sequence reads.

For Sanger sequencing, polymerase chain reaction (PCR) is used to amplify targeted regions. After purification of the PCR products, cycle sequencing is carried out using the ABI Big Dye Terminator v.3.0 kit. PCR products are resolved by electrophoresis on an ABI 3730xl capillary sequencer. In nearly all cases, cycle sequencing is performed separately in both the forward and reverse directions.

Copy number variants (CNVs) are also detected from NGS data. We utilize a CNV calling algorithm that compares mean read depth and distribution for each target in the test sample against multiple matched controls. Neighboring target read depth and distribution and zygosity of any variants within each target region are used to reinforce CNV calls. All CNVs are confirmed using another technology such as aCGH, MLPA, or PCR before they are reported.

This test provides full coverage of all coding exons of the MC4R gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.

Clinical Sensitivity - Sequencing and CNV

The frequency of potentially pathogenic MC4R mutations in a cohort of severe early-onset obesity in children before the age of 10 years is 3.3% (Farooqi et al. 2000). In another large cohort study of severely obese adults, the global prevalence of obesity-specific MC4R pathogenic variants was 2.6% (Lubrano-Berthelier et al. 2006).

Indications for Test

Candidates for this test are patients with monogenic obesity. Testing is also indicated for family members of patients who have known mutations in the MC4R gene. This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in MC4R.

Gene

Official Gene Symbol OMIM ID
MC4R 155541
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Obesity 618406

Related Test

Name
Non-Syndromic Monogenic Obesity via the POMC Gene

Citations

  • Farooqi IS, Yeo GS, Keogh JM, Aminian S, Jebb SA, Butler G, Cheetham T, O’Rahilly S. 2000. Dominant and recessive inheritance of morbid obesity associated with melanocortin 4 receptor deficiency. J. Clin. Invest. 106: 271–279. PubMed ID: 10903343
  • Human Gene Mutation Database (Bio-base).
  • Lubrano-Berthelier C, Dubern B, Lacorte J-M, Picard F, Shapiro A, Zhang S, Bertrais S, Hercberg S, Basdevant A, Clement K, Vaisse C. 2006. Melanocortin 4 receptor mutations in a large cohort of severely obese adults: prevalence, functional classification, genotype-phenotype relationship, and lack of association with binge eating. J. Clin. Endocrinol. Metab. 91: 1811–1818. PubMed ID: 16507637
  • Vaisse C, Clement K, Guy-Grand B, Froguel P. 1998. A frameshift mutation in human MC4R is associated with a dominant form of obesity. Nat. Genet. 20: 113–114. PubMed ID: 9771699
  • Yeo GS, Farooqi IS, Aminian S, Halsall DJ, Stanhope RG, O’Rahilly S. 1998. A frameshift mutation in MC4R associated with dominantly inherited human obesity. Nat. Genet. 20: 111–112. PubMed ID: 9771698

Ordering/Specimens

Ordering Options

myPrevent - Online Ordering

  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.

Requisition Form

  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

Specimen Types

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