Smith-Magenis Syndrome: RAI1 Gene Sequencing

Create a PDF of this page

Condition Description

Smith-Magenis syndrome (SMS) is characterized by behavioral abnormalities, including the “self-hug” and “lick and flip” behaviors, significant sleep disturbances, and self-injurious behaviors; distinctive facial features that progress with age, mild to moderate intellectual disability, and developmental delay.  Additionally, individuals with SMS have mild to moderate infantile hypotonia with feeding difficulties and failure to thrive, minor skeletal anomalies, short stature, eye abnormalities, otolaryngologic abnormalities, early speech delays with or without hearing loss, and peripheral neuropathy.  SMS is caused by deletions or mutations of the RAI1 (17p11.2) gene.

For patients with suspected SMS, deletion/duplication analysis is recommended as the first step in mutation identification. For patients in whom mutations are not identified by deletion/duplication analysis, full gene sequencing is appropriate.

References:

Deletion/Duplication testing should be ordered as the first tier test.

Genes (1)

Indications

This test is indicated for:
  • Confirmation of a clinical diagnosis of Smith-Magenis syndrome in an individual in whom deletion/duplication analysis was negative.
  • Carrier testing in adults with a family history of autosomal recessive Smith-Magenis syndrome in whom deletion/duplication analysis was negative.

Methodology

Next Generation Sequencing: In-solution hybridization of all coding exons is performed on the patient's genomic DNA. Although some deep intronic regions may also be analyzed, this assay is not meant to interrogate most promoter regions, deep intronic regions, or other regulatory elements, and does not detect single or multi-exon deletions or duplications. Direct sequencing of the captured regions is performed using next generation sequencing. The patient's gene sequences are then compared to a standard reference sequence. Potentially causative variants and areas of low coverage are Sanger-sequenced. Sequence variations are classified as pathogenic, likely pathogenic, benign, likely benign, or variants of unknown significance. Variants of unknown significance may require further studies of the patient and/or family members.

Detection

5-10% of SMS mutations are detected by sequencing. Mutations in the promoter region, some mutations in the introns and other regulatory element mutations cannot be detected by this analysis. Large deletions will not be detected by this analysis. Results of molecular analysis should be interpreted in the context of the patient's clinical and/or biochemical phenotype.

Analytical Sensitivity: ~99%

Specimen Requirements

Submit only 1 of the following specimen types

Preferred specimen type: Whole Blood

Type: Whole Blood

Specimen Requirements:

In EDTA (purple top) or ACD (yellow top) tube:
Infants (<2 years): 2-3 ml
Children (>2 years): 3-5 ml
Older Children & Adults: 5-10 ml

Specimen Collection and Shipping: Refrigerate until time of shipment. Ship sample within 5 days of collection at room temperature with overnight delivery.

Type: Saliva

Specimen Requirements:

OrageneTM Saliva Collection kit (available through EGL) used according to manufacturer instructions.

Specimen Collection and Shipping: Store sample at room temperature. Ship sample within 5 days of collection at room temperature with overnight delivery.

  • Deletion/duplication analysis of the RAI1 gene is available and is required before sequencing analysis.
  • Custom diagnostic mutation analysis (KM) is available to family members if mutations are identified by targeted mutation testing or sequencing analysis.
  • Prenatal testing is available only for known familial mutations to individuals who are confirmed carriers of mutations. Please contact the laboratory genetic counselor to discuss appropriate testing prior to collecting a prenatal specimen.

How to Order