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Smith-Magenis and Potocki-Lupski syndromes via the RAI1 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
15195 RAI1 81405 81405,81479 $640 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
15195RAI181405 81405,81479 $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.

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

  • Li Fan, MD, PhD, FCCMG, FACMG

Clinical Features and Genetics

Clinical Features

Smith-Magenis syndrome (SMS; OMIM:182290) is a complex neurobehavioral syndrome characterized by mild to severe intellectual disability, distinct craniofacial features and behavioral abnormalities. SMS patients can be recognized by brachycephaly, a broad face with synophrys and a tented upper lip, brachydactyly and a hoarse voice (Girirajan et al. J Med Genet 42(11):820-828, 2005). Behavioral phenotypes of SMS include infantile hypotonia, disrupted sleep, stereotyped self-hugging gesture, tantrums, and self-injurious behaviors such as tearing off fingernails and insertion of objects into the body.

Potocki-Lupski syndrome (PTLS; OMIM: 610883) is a neurological disorder associated with mild intellectual disability and autistic features. The first signs of PTLS occur during infancy as hypotonia, poor feeding and a general failure to thrive. As patients age they display developmental delay, language deficits, hyperactive behavior, abnormal EEG readings, central sleep apnea and cardiac defects (Potocki et al. Am J Hu Genet 80(4):633-649, 2007).

Genetics

SMS is an autosomal dominant microdeletion syndrome resulting from de novo interstitial deletions of the 17p11.2 region. One recurrent 3.5Mb deletion is found in ~75% of SMS patients (Vlangos et al. Mol Genet Metab 79(2):134-141, 2003). The gene RAI1 is contained within the SMS-deletion interval and rare de novo mutations in RAI1 result in an SMS-phenotype. It is believed that loss of RAI1 accounts for the majority of clinical features associated with SMS.

PTLS is caused by reciprocal microduplications of the SMS-17p11.2 region. Recurrent 3.5Mb duplications are found in ~62% of PTLS patients (Potocki et al., 2007). Studies in mice suggest that RAI1 represents the dosage sensitive gene in the duplication interval (Walz et al. J of Clin Invest 116(11):3035-3041, 2006). Most 17p11.2 duplications occur de novo, however, autosomal dominant inheritance has also been reported in one family (Yusupov et al. Am J Med Genet 155A(2):367-371, 2011).

RAI1 encodes the RAI1 protein, a putative transcription factor which localizes to the nucleus (Carmona-Mora et al. BMC Mol Biol 11:63, 2010). The RAI1 transcript is expressed in all fetal and adult tissues, but is enriched in cardiac and neuronal tissues (Toulouse et al. Genomics 82(2):162-171, 2003). One model suggests that disruption of RAI1 gene dosage results in aberrant expression of transcripts in the heart and brain, which results in SMS and PTLS.

Clinical Sensitivity - Sequencing with CNV PG-Select

RAI1 mutations are found in 5-10% of patients with symptoms of SMS but in which no 17p11.2 deletion was detected (Smith et al. GeneReviews. 2012).

Approximately 95% of SMS cases are caused by gross deletions of 17p11.2 encompassing RAI1 (Smith, A.C.M. et al., 2012).

PTLS is defined by the presence of a 17p11.2 duplication; the RAI1 gene is contained within all reported PTLS duplications (Lee et al. Brain Dev 35(7):681-685, 2013).

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 RAI1 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.

Indications for Test

Patients with symptoms of SMS should be tested for RAI1 deletions via aCGH. Candidates for RAI1 sequencing include patients with symptoms of SMS, but for which a deletion of 17p11.2 has not been detected (Vilboux et al. PLoS ONE 6(8): e22861, 2011). Patients with symptoms of PTLS, even if no 17p11.2 duplication was detected by traditional cytogenetic techniques, should consider RAI1 copy number testing via aCGH (Potocki et al., 2007).

Gene

Official Gene Symbol OMIM ID
RAI1 607642
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Diseases

Name Inheritance OMIM ID
Potocki-Lupski syndrome 610883
Smith-Magenis Syndrome AD 182290

Citations

  • Carmona-Mora, P. et al. (2010). "Functional and cellular characaterization of human Retinoic Acid Induced 1 (RAI1) mutations associated with Smith-Megenis Syndrome." BMC Mol Biol 11:63. PubMed ID: 20738874
  • Girirajan, S. et al. (2005). "RAI1 varations in Smith-Magenis syndrome patients without 17p11.2 deletions." J Med Genet 42(11):820-828. PubMed ID: 15788730
  • Lee, C.G. et al. (2013). "Clinical and cytogenetic features of a Potocki-Lupski syndrome with the shortest 0.25Mb microduplication in 17p11.2 including RAI1." Brain Dev 35(7):681-685. PubMed ID: 23078968
  • Potocki, L. et al. (2007). "Characterization of Potocki-Lupski Syndrome (dup(17)(p11.2p11.2)) and Delineation of a Dosage-Sensitive Critical Interval That Can Convey an Autism Phenotype." Am J Hu Genet 80(4):633-649. PubMed ID: 17357070
  • Smith, A.C.M. et al. (2012). "Smith-Magenis Syndrome." GeneReviews. PubMed ID: 20301487
  • Toulouse, A. et al. (2003). "Molecular cloning and characterization of human RAI1, a gene associated with schizophrenia." Genomics 82(2):162-171. PubMed ID: 12837267
  • Vilboux, T. et al. (2011). "Molecular Anlysis of the Retinoic Acid Induced 1 Gene (RAI1) in Patients with Suspected Smith-Magenis Syndrome without the 17p11.2 Deletion." PLoS ONE 6(8): e22861. PubMed ID: 21857958
  • Vlangos, C.N. et al. (2003). "Refinement of the Smith-Magenis syndrome critical region to approximately 950kb and assessment of 17p11.2 deletions. Are all deletions created equally?" Mol Genet Metab 79(2):134-141. PubMed ID: 12809645
  • Walz, K. et al. (2006). "Rai1 duplication causes physical and behavioral phenotypes in a mouse model of dup(17)(p11.2p11.2)" J Clin Invest 116(11):3035-3041. PubMed ID: 17024248
  • Yusupov, R. et al. (2011). "Potocki-Lupski syndrome: an inherited dup(17)(p11.2p11.2) with hypoplastic left heart." Am J Med Genet 155A(2):367-371. PubMed ID: 21271656

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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