Non-Syndromic Monogenic Obesity via the KSR2 Gene

Summary and Pricing

Test Method

Sequencing and CNV Detection via NextGen Sequencing using PG-Select Capture Probes
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
15173 KSR2 81479 81479,81479 $640 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
15173KSR281479 81479 $640 Order Options and Pricing

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.

A 25% additional charge will be applied to STAT orders. View STAT turnaround times here.

Targeted Testing

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

Turnaround Time

18 days on average

EMAIL CONTACTS

Genetic Counselors

Geneticist

Clinical Features and Genetics

Clinical Features

Non-syndromic monogenic obesity is a group of single-gene disorders with obesity as an isolated or predominant feature. Obesity is defined as an increase in fat mass that is sufficient to adversely affect health and reduce longevity (Fontaine et al. 2003. PubMed ID: 12517229). Clinically, body-mass index (BMI) is the accepted measure of adipose mass. For adults, a BMI greater than 30 is typically used to diagnose a person as obese. BMI is a multifactorial trait that is frequently influenced by multiple genes as well as environmental and lifestyle factors (Gusev et al. 2014. PubMed ID: 25439723). However, to date, eleven genes have been specifically implicated in non-syndromic monogenic obesity: LEP, LEPR, SH2B1, POMC, PCSK1, MC4R, NTRK2, BDNF, SIM1, KSR2, and TUB (Pigeyre et al. 2016. PubMed ID: 27154742).

KSR2-related obesity is characterized by severe early-onset obesity (<10 years of age), hyperphagia in childhood, low heart rate, reduced basal metabolic rate, and severe insulin resistance (Pearce et al. 2013. PubMed ID: 24209692). Importantly, the Pearce et al. study provided anecdotal evidence that carriers of suspected pathogenic KSR2 variants respond well to the common anti-diabetes medication Metformin. Therefore, this molecular diagnosis may provide information that would guide treatment decisions for patients.

Genetics

Pathogenic variants in KSR2 cause autosomal dominant non-syndromic obesity. The KSR2 gene encodes the kinase suppressor of Ras2 (KSR2) protein which regulates energy consumption, metabolic expenditure, and substrate utilization via the Ras/Raf/MEK/ERK signaling pathway. KSR2 is an intracellular scaffolding protein. In response to growth factor signaling, it translocates to the plasma membrane where it catalyzes MEK phosphorylation by scaffolding Ras, Raf, and MEK in a complex (Michaud et al. 1997. PubMed ID: 9371754; Roy et al. 2002. PubMed ID: 11850406). Through this process KSR2 activates gene expression by coordinating the ERK signaling cascade in both time and space.

Functional studies in cell culture have determined that pathogenic variants in the KSR2 gene disrupt Raf-MEK-ERK signaling causing decreases in fatty acid oxidation and glucose oxidation. These defects are attenuated by the application of the diabetes drug metformin (Pearce et al. 2013. PubMed ID: 24209692).

The predominant inheritance of KSR2-related obesity is autosomal dominant; however, one severely obese individual has been described with compound heterozygous rare variants, and recessive inheritance has not been ruled out (Pearce et al. 2013. PubMed ID: 24209692). Incomplete penetrance and variable expressivity was also noted in this study, so some carriers may be unaffected or mildly affected. The causative variants include missense, nonsense, and frameshift alterations, the majority of which cluster to the C-terminal kinase domain. To date, no founder variants, large gene rearrangements, or de novo variants have been described.

Clinical Sensitivity - Sequencing with CNV PG-Select

In a study of 2,101 severely obese individuals of mixed European ancestry, 2.1% were found to have rare variants in the KSR2 gene in contrast with 1.0% of matched controls (Pearce et al. 2013. PubMed ID: 24209692). These data provide a rough estimate of clinical sensitivity at approximately 1%. Analytical sensitivity is expected to be high because all reported causative variants are detectable by sequencing.

Testing Strategy

This test is performed using Next-Generation sequencing with additional Sanger sequencing as necessary.

This test provides full coverage of all coding exons of the KSR2 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.

Indications for Test

Candidates for this test are patients with isolated obesity and other features which may include childhood hyperphagia, low heart rate, and insulin resistance.

Gene

Official Gene Symbol OMIM ID
KSR2 610737
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID

Citations

  • Fontaine et al. 2003. PubMed ID: 12517229
  • Gusev et al. 2014. PubMed ID: 25439723
  • Michaud et al. 1997. PubMed ID: 9371754
  • Pearce et al. 2013. PubMed ID: 24209692
  • Pigeyre et al. 2016. PubMed ID: 27154742
  • Roy et al. 2002. PubMed ID: 11850406

Ordering/Specimens

Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

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.

For Requisition Forms, visit our Forms page


Specimen Types

Specimen Requirements and Shipping Details

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ORDER OPTIONS

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2) Select Additional Test Options

STAT and Prenatal Test Options are not available with Patient Plus.

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