Ann Lab Med.  2015 May;35(3):362-365. 10.3343/alm.2015.35.3.362.

Identification of a Novel De Novo Variant in the PAX3 Gene in Waardenburg Syndrome by Diagnostic Exome Sequencing: The First Molecular Diagnosis in Korea

• Jang MA
• Lee T
• Lee J
• Cho EH
• Ki CS

• KMID: 2363211
• DOI: http://doi.org/10.3343/alm.2015.35.3.362

Abstract

Waardenburg syndrome (WS) is a clinically and genetically heterogeneous hereditary auditory pigmentary disorder characterized by congenital sensorineural hearing loss and iris discoloration. Many genes have been linked to WS, including PAX3, MITF, SNAI2, EDNRB, EDN3, and SOX10, and many additional genes have been associated with disorders with phenotypic overlap with WS. To screen all possible genes associated with WS and congenital deafness simultaneously, we performed diagnostic exome sequencing (DES) in a male patient with clinical features consistent with WS. Using DES, we identified a novel missense variant (c.220C>G; p.Arg74Gly) in exon 2 of the PAX3 gene in the patient. Further analysis by Sanger sequencing of the patient and his parents revealed a de novo occurrence of the variant. Our findings show that DES can be a useful tool for the identification of pathogenic gene variants in WS patients and for differentiation between WS and similar disorders. To the best of our knowledge, this is the first report of genetically confirmed WS in Korea.

Keyword

Exome; PAX3; Waardenburg syndrome

MeSH Terms

Adult
Amino Acid Sequence
Asian Continental Ancestry Group/genetics
Base Sequence
DNA/chemistry/genetics/metabolism
Exons
Humans
Male
Mutation, Missense
PAX3 Transcription Factor/*genetics
Phenotype
Polymorphism, Single Nucleotide
Republic of Korea
Sequence Analysis, DNA
Waardenburg Syndrome/*diagnosis/genetics
DNA
PAX3 Transcription Factor

Figure

• 

  Fig. 1 Ortholog conservation of a novel PAX3 variant. Schematic representation of the PAX3 variant relative to the protein domain. Protein sequence alignment of PAX3 in vertebrate species. The region of alignment corresponding to the missense variant is shown. Arg (R) at codon 74 is highly conserved across all species (indicated by the open box). The Ensembl IDs for the aligned PAX3 amino acid sequences are as follows: human, ENSP 00000343052; chimpanzee, ENSPTRT00000024032; orangutan, ENSPPYT00000015369; mouse, ENSMUSP00000004994; rat, ENSRNOT00000018652; dog, ENSCAFT00000025445; horse, ENSECAT00000015993; cow, ENSBTAT00000013131; and zebrafish, ENSDART00000014350.Abbreviations: PD, paired domain; HD, homeodomain.

• 

  Fig. 2 Validation of a novel PAX3 variant by Sanger sequencing. The patient had a nonsynonymous substitution (c.220C>G; p.Arg74Gly, arrow) in PAX3. The patient's father and mother did not have this variant.

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