A novel mutation in the PAX3 gene causes Waardenburg syndrome type I in an Iranian family.
OBJECTIVE
Sensorineural hearing impairment (HI) is one of the most frequent congenital defects, with a prevalence of 1 in 500 among neonates. Although there are over 400 syndromes involving HI, most cases of HI are nonsyndromic (70%), 20% of which follow autosomal dominant mode of inheritance. Waardenburg syndrome (WS) ranks first among autosomal dominant syndromic forms of HI. WS is characterized by sensorineural hearing impairment, pigmentation abnormalities of hair and skin and hypoplastic blue eyes or heterochromia iridis. WS is subdivided into four major types, WS1-WS4. WS1 is diagnosed by the presence of dystopia canthorum and PAX3 is the only gene involved. This study aims to determine the pathogenic mutation in a large Iranian pedigree affected with WS1 in order to further confirm the clinical diagnosis.


METHODS
In the present study, a family segregating HI was ascertained in a genetic counseling center. Upon clinical inspection, white forelock, dystopia canthorum, broad high nasal root and synophrys, characteristic of WS1 were evident. In order to clarify the genetic etiology and confirm the clinical data, primers were designed to amplify exons and exon-intron boundaries of the responsible gene, PAX3 with 10 exons, followed by the Sanger DNA sequencing method.


RESULTS
Genetic analysis of PAX3 revealed a novel mutation in PAX3 (c.1024_1040 del AGCACGATTCCTTCCAA). Our data provide genotype-phenotype correlation for the mutation in PAX3 and WS1 in the studied family, with implications for genetic counseling, which necessitates detailed clinical inspection of HI patients to distinguish syndromic HI from the more common non-syndromic cases.


CONCLUSIONS
Our results reveal the value of phenotype-directed genetic analysis and could further expand the spectrum of PAX3 mutations.
Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
Nazanin
N
Jalilian
Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran; Pediatric Inherited Diseases Research Center, Research Institute for Primordial Prevention of Non-communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran.
Mohammad Amin
MA
Tabatabaiefar
Department and Research Center of Otolaryngology, Head and Neck Surgery, Hazrat Rasoul Akram Hospital, Iran University of Medical Sciences, Tehran, Iran.
Mohammad
M
Farhadi
Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
Tayyeb
T
Bahrami
Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. Electronic address: nooridaloii@tums.ac.ir.
Mohammad Reza
MR
Noori-Daloii
D004252:DNA Mutational Analysis; D005091:Exons; D005260:Female; D005838:Genotype; D006801:Humans; D007492:Iran; D008297:Male; D009154:Mutation; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D014849:Waardenburg Syndrome / Q000235:genetics*
D000072041:PAX3 Transcription Factor; C489409:PAX3 protein, human; D051761:Paired Box Transcription Factors
Iran; Novel mutation; PAX3; Waardenburg syndrome type 1