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Monogenic Obesity via the SIM1 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
15199 SIM1 81479 81479,81479 $640 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
15199SIM181479 81479(x2) $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.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

Turnaround Time

18 days on average for standard orders or 13 days on average for STAT orders.

Please note: Once the testing process begins, an Estimated Report Date (ERD) range will be displayed in the portal. This is the most accurate prediction of when your report will be complete and may differ from the average TAT published on our website. About 85% of our tests will be reported within or before the ERD range. We will notify you of significant delays or holds which will impact the ERD. Learn more about turnaround times here.

Targeted Testing

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

EMAIL CONTACTS

Genetic Counselors

Geneticist

  • Eric Bend, PhD

Clinical Features and Genetics

Clinical Features

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, adults with a body-mass index (BMI) greater than 30 kg/m2 are considered obese. BMI is a multifactorial trait that is usually influenced by multiple genes (Gusev et al. 2014. PubMed ID: 25439723), as well as environmental and lifestyle factors. However, in some cases obesity is inherited by a monogenetic mechanism due to pathogenic variants in a single gene. Monogenic obesity can be non-syndromic, occurring as an isolated feature. Alternatively, it may be syndromic, occurring with a pattern of recurrent clinical phenotypes.

Pathogenic SIM1 variants may cause isolated obesity (Ramachandrappa et al. 2013. PubMed ID: 23778139) or obesity with neurodevelopmental co-morbidities (Bonnefond et al. 2013. PubMed ID: 23778136). The latter resembles an interstitial deletion syndrome at 6q16 that includes the SIM1 gene and is frequently referred to as Prader-Willi-like syndrome (El Khattabi et al. 2015. PubMed ID: 25351778). These patients present with global developmental delay, hypotonia, and feeding problems in infancy followed by hyperphagia, obesity, autonomic dysfunction and facial dysmorphism later in life. Phenotypes resulting from single nucleotide variants in SIM1 or the contiguous gene deletion at 6q16 have variable expressivity (El Khattabi et al. 2015. PubMed ID: 25351778; Bonnefond et al. 2013. PubMed ID: 23778136). Moreover, familial single nucleotide variants have been attributed to both isolated obesity and Prader-Willi-like syndrome within a single family (Bonnefond et al. 2013. PubMed ID: 23778136).

To date, pathogenic variants in eleven genes have been 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). In contrast, variants in approximately forty genes are known to cause syndromic obesity. However, only four of these genes are associated with phenotypes resembling Prader-Willi syndrome (SNRPN, MAGEL2, VPS13B, and ZDHHC15).

Genetics

Pathogenic SIM1 variants cause autosomal dominant obesity in humans and mice. The SIM1 gene encodes a basic helix-loop-helix transcription factor. In the absence of Sim1, mice fail to develop the paraventricular nucleus (PVN) of the hypothalamus and die perinatally (Michaud et al. 1998. PubMed ID: 9784500). Haploinsufficiency results in hyperphagic obesity (Michaud et al. 1998. PubMed ID: 9784500) and conditional knock-out experiments suggest that normally developing mice require Sim1 for regulating the leptin-melanocortin-oxytocin signaling pathway (Tolson et al. 2010. PubMed ID: 20220015). Collectively, these data suggest that the SIM1 gene is required for development of the hypothalamus and maintenance of post-natal food intake behaviors in mice and humans.

Human pathogenic SIM1 variants include the 6q16 interstitial deletion, missense variants, small frameshift deletions, and in one case a de novo balanced translocation (Holder et al. 2000. PubMed ID: 10587584). One de novo missense variant in SIM1 has also been described (Bonnefond et al. 2013. PubMed ID: 23778136). To date, no founder variants have been identified.

Clinical Sensitivity - Sequencing with CNV PG-Select

Given the small number of individuals with pathogenic variants in SIM1, only rough estimates of clinical sensitivity may be inferred from cohort analysis. In a study of 2,100 individuals with isolated severe obesity, 1.3% were found to have rare variants in the SIM1 gene in contrast with 0.8% found in matched controls (Ramachandrappa et al. 2013. PubMed ID: 23778139). These data suggest that roughly 0.5% of individuals with isolated obesity may have a pathogenic variant in SIM1. A smaller study sequenced SIM1 in a cohort of 44 children with Prader-Willi-like features and 568 morbidly obese adults. This study identified candidate variants in four members of the Prader-Willi-like group (9%) and seven members of the morbidly obese adult group (1.2%; Bonnefond et al. 2013. PubMed ID: 23778136).

The analytical sensitivity of this test is expected to be high since Next-Generation sequencing is designed to detect nearly all clinically relevant sequencing variants as well as the documented 6q16 interstitial deletion as part of the CNV analysis. This test will not detect balanced translocations. Since one case of a balanced translocation has been observed, a karyotype may be indicated if sequencing is negative.

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 SIM1 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 or Prader-Willi-like syndrome with global developmental delay, hypotonia, and feeding problems in infancy followed by obesity and facial dysmorphism later in life.

Gene

Official Gene Symbol OMIM ID
SIM1 603128
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Obesity AR, AD 601665

Citations

  • Bonnefond et al. 2013. PubMed ID: 23778136
  • El Khattabi et al. 2015 PubMed ID: 25351778
  • Fontaine et al. 2003. PubMed ID: 12517229
  • Gusev et al. 2014. PubMed ID: 25439723
  • Holder et al. 2000. PubMed ID: 10587584
  • Michaud et al. 1998. PubMed ID: 9784500
  • Pigeyre et al. 2016. PubMed ID: 27154742
  • Ramachandrappa et al. 2013. PubMed ID: 23778139
  • Tolson et al. 2010. PubMed ID: 20220015

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.
  • PGnome sequencing panels can be ordered via the myPrevent portal only at this time.

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

View Ordering Instructions

1) Select Test Method (Backbone)


1) Select Test Type


2) Select Additional Test Options

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

No Additional Test Options are available for this test.

Note: acceptable specimen types are whole blood and DNA from whole blood only.
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