Waardenburg Syndrome Panel (6 Genes) Test Details
Waardenburg syndrome (WS) is characterized by pigmentation abnormalities of the eyes, hair, and skin and hearing loss. Up to 90% of individuals have sensorineural hearing loss, and its severity can be variable. Inner ear malformations such as enlarged vestibular aqueducts or abnormalities of the semicircular canals can be present (Pingault 2010 PMID: 20127975).
Other features such as dystopia canthorum (a displacement of the inner corners of the eyes), limb or musucloskeletal abnormalities, Hirschsprung disease, or neurological abnormalities may be present. WS has been traditionally divided into the four subtypes, based on the presence or absence of additional features. Waardenburg syndrome Type 1 and Type 2 are the most common, with types 3 and 4 being more rare. Six genes have been associated to Waardenburg syndrome. The subtypes and associated genes are shown below.Read More...
|Type 1||Dystopia canthorum||PAX3|
|Type 2||No additional features||MITF, SOX10, SNAI2|
|Type 3||Dystopia canthorum, limb/musculoskeletal abnormalities||PAX3|
|Type 4||Hirschsprung disease||SOX10, EDN3, EDNRB|
|PAX3||Paired Box Protein PAX-3||606597||2q36.1|
|SOX10||Transcription Factor SOX-10||602229||22q13.1|
|MITF||Microphthalmia-Associated Transcription Factor||156845||3p14-p13|
|EDNRB||Endothelin B receptor||131244||13q22.3|
|SNAI2||Zinc Finger Protein SNAI2||602150||8q11.21|
The Waardenburg Syndrome Panel is recommended for individuals with a clinical diagnosis or suspicion of Waardenburg syndrome. Testing affected individuals is the most informative strategy in identifying a genetic cause of this condition.
This test is performed by next generation sequencing using Agilent SureSelect capture followed by sequencing of the coding regions and splice sites using Illumina sequencing technologies. Variant calls are generated using the Burrows-Wheeler Aligner followed by Genomic Analysis Tool Kit (GATK) analysis. Detection of copy number variants (CNVs) encompassing 1 or more exons is performed using VisCap™ analysis. Sanger sequencing is used to fill in regions with insufficient coverage. All clinically significant variants are confirmed by Sanger sequencing or droplet digital PCR. Variants classified as likely benign or benign are not confirmed. This test does not detect variants in non-coding regions that could affect gene expression, aside from the splice junctions, and a few exons have been excluded due to technical difficulties. CNV analysis is only performed when data meets necessary quality standards and may not be available for all cases.
Analytical and Clinical Sensitivity
This test is 100.00% sensitive (525/525 variants tested; 95% CI = 99.27-100.00% ) to detect variants changing a single base and 100.00% sensitive to detect insertion/deletions 1-21 bp in size (17/17 variants tested; 95% CI = 81.57-100.00%). Regions with high sequence homology are included in this test if a unique Sanger sequencing assay can be designed to rule out false positive calls. Analytical sensitivity in these regions may be reduced.
Approximately 90% of individuals with a diagnosis of WS1 will have pathogenic variants in the PAX3 gene. Pathogenic variants in MITF and SOX10 are seen in 10-20% and 15% of WS2, respectively. The detection rates for the remaining genes and subtypes of WS are not well understood (Milunsky 2011 PMID: 20301703).