Smith-Magenis and Potocki-Lupski syndromes via the RAI1 Gene

  • Summary and Pricing
  • Clinical Features and Genetics
  • Citations
  • Methods
  • Ordering/Specimens
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Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
1519 RAI1$1020.00 81405 Add to Order
Targeted Testing

For ordering targeted known variants, please proceed to our Targeted Variants landing page.

Turnaround Time

The great majority of tests are completed within 18 days.

Clinical Sensitivity
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).

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Deletion/Duplication Testing via aCGH

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
600 RAI1$690.00 81479 Add to Order
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Turnaround Time

The great majority of tests are completed within 28 days.

Clinical Sensitivity
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).

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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).
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.
Testing Strategy
Testing involves PCR amplification from genomic DNA and bidirectional Sanger sequencing of the coding exons and ~10bp of adjacent noncoding sequences. This testing strategy will reveal coding sequence changes, splice site mutations and small insertions or deletions in the RAI1 gene, but will not detect large deletions, insertions or rearrangements in the RAI1 locus. We will also sequence any single exon (Test #100) in family members of patients with a known mutation or to confirm research results.
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).


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


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

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Genetic Counselors
  • 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
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Bi-Directional Sanger Sequencing

Test Procedure

Nomenclature for sequence variants was from the Human Genome Variation Society (  As required, DNA is extracted from the patient specimen.  PCR is used to amplify the indicated exons plus additional flanking non-coding sequence.  After cleaning of the PCR products, cycle sequencing is carried out using the ABI Big Dye Terminator v.3.0 kit.  Products are resolved by electrophoresis on an ABI 3730xl capillary sequencer.  In most cases, sequencing is performed in both forward and reverse directions; in some cases, sequencing is performed twice in either the forward or reverse directions.  In nearly all cases, the full coding region of each exon as well as 10 bases of non-coding DNA flanking the exon are sequenced.

Analytical Validity

As of February 2018, we compared 26.8 Mb of Sanger DNA sequence generated at PreventionGenetics to NextGen sequence generated in other labs. We detected only 4 errors in our Sanger sequences, and these were all due to allele dropout during PCR. For Proficiency Testing, both external and internal, in the 14 years of our lab operation we have Sanger sequenced roughly 14,300 PCR amplicons. Only one error has been identified, and this was an error in analysis of sequence data.

Our Sanger sequencing is capable of detecting virtually all nucleotide substitutions within the PCR amplicons. Similarly, we detect essentially all heterozygous or homozygous deletions within the amplicons. Homozygous deletions which overlap one or more PCR primer annealing sites are detectable as PCR failure. Heterozygous deletions which overlap one or more PCR primer annealing sites are usually not detected (see Analytical Limitations). All heterozygous insertions within the amplicons up to about 100 nucleotides in length appear to be detectable. Larger heterozygous insertions may not be detected. All homozygous insertions within the amplicons up to about 300 nucleotides in length appear to be detectable. Larger homozygous insertions may masquerade as homozygous deletions (PCR failure).

Analytical Limitations

In exons where our sequencing did not reveal any variation between the two alleles, we cannot be certain that we were able to PCR amplify both of the patient’s alleles. Occasionally, a patient may carry an allele which does not amplify, due for example to a deletion or a large insertion. In these cases, the report contains no information about the second allele.

Similarly, our sequencing tests have almost no power to detect duplications, triplications, etc. of the gene sequences.

In most cases, only the indicated exons and roughly 10 bp of flanking non-coding sequence on each side are analyzed. Test reports contain little or no information about other portions of the gene, including many regulatory regions.

In nearly all cases, we are unable to determine the phase of sequence variants. In particular, when we find two likely causative mutations for recessive disorders, we cannot be certain that the mutations are on different alleles.

Our ability to detect minor sequence variants, due for example to somatic mosaicism is limited. Sequence variants that are present in less than 50% of the patient’s nucleated cells may not be detected.

Runs of mononucleotide repeats (eg (A)n or (T)n) with n >8 in the reference sequence are generally not analyzed because of strand slippage during PCR and cycle sequencing.

Unless otherwise indicated, the sequence data that we report are based on DNA isolated from a specific tissue (usually leukocytes). Test reports contain no information about gene sequences in other tissues.

Deletion/Duplication Testing via Array Comparative Genomic Hybridization

Test Procedure

Equal amounts of genomic DNA from the patient and a gender matched reference sample are amplified and labeled with Cy3 and Cy5 dyes, respectively. To prevent any sample cross contamination, a unique sample tracking control is added into each patient sample. Each labeled patient product is then purified, quantified, and combined with the same amount of reference product. The combined sample is loaded onto the designed array and hybridized for at least 22-42 hours at 65°C. Arrays are then washed and scanned immediately with 2.5 µM resolution. Only data for the gene(s) of interest for each patient are extracted and analyzed.

Analytical Validity

PreventionGenetics' high density gene-centric custom designed aCGH enables the detection of relatively small deletions and duplications within a single exon of a given gene or deletions and duplications encompassing the entire gene. PreventionGenetics has established and verified this test's accuracy and precision.

Analytical Limitations

Our dense probe coverage may allow detection of deletions/duplications down to 100 bp; however due to limitations and probe spacing this cannot be guaranteed across all exons of all genes. Therefore, some copy number changes smaller than 100-300 bp within a targeted large exon may not be detected by our array.

This array may not detect deletions and duplications present at low levels of mosaicism or those present in genes that have pseudogene copies or repeats elsewhere in the genome.

aCGH will not detect balanced translocations, inversions, or point mutations that may be responsible for the clinical phenotype.

Breakpoints, if occurring outside the targeted gene, may be hard to define.

The sensitivity of this assay may be reduced when DNA is extracted by an outside laboratory.

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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.
  • 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.


(Delivery accepted Monday - Saturday)

  • Collect 3 ml -5 ml (5 ml preferred) of whole blood in EDTA (purple top tube) or ACD (yellow top tube). For Test #500-DNA Banking only, collect 10 ml -20 ml of whole blood.
  • For small babies, we require a minimum of 1 ml of blood.
  • Only one blood tube is required for multiple tests.
  • Ship blood tubes at room temperature in an insulated container. Do not freeze blood.
  • During hot weather, include a frozen ice pack in the shipping container. Place a paper towel or other thin material between the ice pack and the blood tube.
  • In cold weather, include an unfrozen ice pack in the shipping container as insulation.
  • At room temperature, blood specimen is stable for up to 48 hours.
  • If refrigerated, blood specimen is stable for up to one week.
  • Label the tube with the patient name, date of birth and/or ID number.


(Delivery accepted Monday - Saturday)

  • Send in screw cap tube at least 5 µg -10 µg of purified DNA at a concentration of at least 20 µg/ml for NGS and Sanger tests and at least 5 µg of purified DNA at a concentration of at least 100 µg/ml for gene-centric aCGH, MLPA, and CMA tests, minimum 2 µg for limited specimens.
  • For requests requiring more than one test, send an additional 5 µg DNA per test ordered when possible.
  • DNA may be shipped at room temperature.
  • Label the tube with the composition of the solute, DNA concentration as well as the patient’s name, date of birth, and/or ID number.
  • We only accept genomic DNA for testing. We do NOT accept products of whole genome amplification reactions or other amplification reactions.


(Delivery preferred Monday - Thursday)

  • PreventionGenetics should be notified in advance of arrival of a cell culture.
  • Culture and send at least two T25 flasks of confluent cells.
  • Some panels may require additional flasks (dependent on size of genes, amount of Sanger sequencing required, etc.). Multiple test requests may also require additional flasks. Please contact us for details.
  • Send specimens in insulated, shatterproof container overnight.
  • Cell cultures may be shipped at room temperature or refrigerated.
  • Label the flasks with the patient name, date of birth, and/or ID number.
  • We strongly recommend maintaining a local back-up culture. We do not culture cells.
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