title: The value of MLPA in Waardenburg syndrome.
abstract: Waardenburg syndrome (WS) is an autosomal-dominant neurocristopathy characterized by sensorineural hearing loss, pigmentary abnormalities of the iris, hair, and skin, and is responsible for about 3% of congenital hearing loss. Point mutations in PAX3 have been identified in more than 90% of affected individuals with WS Type 1/WS Type 3. MITF point mutations have been identified in 10-15% of individuals affected with WS Type 2 (lacking dystopia canthorum). Multiplex ligation-dependent probe amplification (MLPA) is now a standard technology in the molecular genetics laboratory to detect copy number changes in targeted genes. We employed MLPA for PAX3 and MITF in a cohort of patients submitted with a diagnosis of WS1, 2 or 3 who were sequence negative for PAX3 and/or MITF. All coding exons of PAX3 and exons 1, 2, 3, and 10 of MITF were included in the MLPA assay. MLPA on 48 patients with WS 1 or 3 revealed 3 PAX3 whole gene deletions (2 WS1; 1 WS3), 2 PAX3 partial gene deletions [WS1, exon 1 and promoter (1st report); WS1, exons 5-9], and 1 partial MITF deletion ("WS1", exons 3-10) (6/48 approximately 12.5%). MLPA on 41 patients with WS2 and 20 patients submitted with a diagnosis of either WS1 or WS2 revealed no copy number changes. The detection of both partial and whole gene deletions of PAX3/MITF in this clinical cohort increases the mutation detection yield by at least 6% and supports integrating MLPA into clinical molecular testing primarily for patients with WS1 and 3.
authors.affiliation: Center for Human Genetics, Boston University School of Medicine, Boston, Massachusetts 02118-2526, USA. jmilunsk@bu.edu
authors.forename: J M
authors.initials: JM
authors.lastname: Milunsky
authors.forename: T A
authors.initials: TA
authors.lastname: Maher
authors.forename: M
authors.initials: M
authors.lastname: Ito
authors.forename: A
authors.initials: A
authors.lastname: Milunsky
mesh_terms: D004247:DNA / Q000097:blood / Q000235:genetics / Q000302:isolation & purification; D005260:Female; D005784:Gene Amplification; D017353:Gene Deletion; D006801:Humans; D008297:Male; D051739:Microphthalmia-Associated Transcription Factor / Q000235:genetics*; D009154:Mutation; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics*; D010375:Pedigree; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D014849:Waardenburg Syndrome / Q000235:genetics*
chemical_list: C497234:MITF protein, human; D051739:Microphthalmia-Associated Transcription Factor; D000072041:PAX3 Transcription Factor; C489409:PAX3 protein, human; D051761:Paired Box Transcription Factors; D004247:DNA