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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 - Ann Lab Med (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

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.

No MeSH data available.


Related in: MedlinePlus

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.
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Figure 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.

Mentions: The p.Arg74Gly variant was likely pathogenic because the affected residue is strictly conserved from zebrafish to human (Fig. 1), and the variant was predicted to be deleterious by in silico analysis by using SIFT and PolyPhen-2. The p.Arg74Gly variant was absent in the dbSNP and was not found in 11,906 chromosomes in the National Heart, Lung, and Blood Institute (NHLBI) Exome Sequencing Project database. In addition, the variant was not observed in in-house control exomes of individuals of Korean descent. We regarded this variant as the best candidate and subsequently validated it by Sanger sequencing.


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 - Ann Lab Med (2015)

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.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4390707&req=5

Figure 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.
Mentions: The p.Arg74Gly variant was likely pathogenic because the affected residue is strictly conserved from zebrafish to human (Fig. 1), and the variant was predicted to be deleterious by in silico analysis by using SIFT and PolyPhen-2. The p.Arg74Gly variant was absent in the dbSNP and was not found in 11,906 chromosomes in the National Heart, Lung, and Blood Institute (NHLBI) Exome Sequencing Project database. In addition, the variant was not observed in in-house control exomes of individuals of Korean descent. We regarded this variant as the best candidate and subsequently validated it by Sanger sequencing.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

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.

No MeSH data available.


Related in: MedlinePlus