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Identification and Clinical Implications of Novel MYO15A Mutations in a Non-consanguineous Korean Family by Targeted Exome Sequencing.

Chang MY, Kim AR, Kim NK, Lee C, Lee KY, Jeon WS, Koo JW, Oh SH, Park WY, Kim D, Choi BY - Mol. Cells (2015)

Bottom Line: Mutations of MYO15A are generally known to cause severe to profound hearing loss throughout all frequencies.From the literature analysis, mutations in the N-terminal domain were more frequently associated with residual hearing at low frequencies than mutations in the other regions of this gene.Therefore we suggest a hypothetical genotype-phenotype correlation whereby MYO15A mutations that affect domains other than the N-terminal domain, lead to profound SNHL throughout all frequencies and mutations that affect the N-terminal domain, result in residual hearing at low frequencies.

View Article: PubMed Central - PubMed

Affiliation: Department of Otorhinolaryngology, Seoul National University Hospital, Seoul national University College of Medicine, Seoul 110-744, Korea.

ABSTRACT
Mutations of MYO15A are generally known to cause severe to profound hearing loss throughout all frequencies. Here, we found two novel MYO15A mutations, c.3871C>T (p.L1291F) and c.5835T>G (p.Y1945X) in an affected individual carrying congenital profound sensorineural hearing loss (SNHL) through targeted resequencing of 134 known deafness genes. The variant, p.L1291F and p.Y1945X, resided in the myosin motor and IQ2 domains, respectively. The p.L1291F variant was predicted to affect the structure of the actin-binding site from three-dimensional protein modeling, thereby interfering with the correct interaction between actin and myosin. From the literature analysis, mutations in the N-terminal domain were more frequently associated with residual hearing at low frequencies than mutations in the other regions of this gene. Therefore we suggest a hypothetical genotype-phenotype correlation whereby MYO15A mutations that affect domains other than the N-terminal domain, lead to profound SNHL throughout all frequencies and mutations that affect the N-terminal domain, result in residual hearing at low frequencies. This genotype-phenotype correlation suggests that preservation of residual hearing during auditory rehabilitation like cochlear implantation should be intended for those who carry mutations in the N-terminal domain and that individuals with mutations elsewhere in MYO15A require early cochlear implantation to timely initiate speech development.

No MeSH data available.


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Schematic flow chart of the filtering of causative variants in this study
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f2-molce-38-9-781: Schematic flow chart of the filtering of causative variants in this study

Mentions: Targeted resequencing and bioinformatics analyses were performed as described previously (Choi et al., 2013). DNA samples from SB156-272 were subjected to targeted resequencing of 134 known deafness genes (TRS-134) by Otogenetics (USA) (Supplementary Table S1). The acquired reads were mapped onto the UCSC hg19 reference genome. Further bioinformatics analyses were performed to identify variants. As a basic filtering step, non-synonymous single nucleotide polymorphisms (SNPs) with read depths >40 were chosen. These non-synonymous SNPs were compared against an in-house database, an independent cohort consisting of 54 normal Korean individuals and the Single Nucleotide Polymorphism Database (dbSNP build 138). Only novel SNPs or known disease-causing SNPs remained. Inheritance patterns were checked and SNPs that did not coincide with an autosomal recessive pattern were excluded. The remaining SNPs were validated in other family members (SB156-327 and SB156-328) by Sanger sequencing. The SNPs were also checked against an additional 426 unrelated Korean control chromosomes (Fig. 2).


Identification and Clinical Implications of Novel MYO15A Mutations in a Non-consanguineous Korean Family by Targeted Exome Sequencing.

Chang MY, Kim AR, Kim NK, Lee C, Lee KY, Jeon WS, Koo JW, Oh SH, Park WY, Kim D, Choi BY - Mol. Cells (2015)

Schematic flow chart of the filtering of causative variants in this study
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4588721&req=5

f2-molce-38-9-781: Schematic flow chart of the filtering of causative variants in this study
Mentions: Targeted resequencing and bioinformatics analyses were performed as described previously (Choi et al., 2013). DNA samples from SB156-272 were subjected to targeted resequencing of 134 known deafness genes (TRS-134) by Otogenetics (USA) (Supplementary Table S1). The acquired reads were mapped onto the UCSC hg19 reference genome. Further bioinformatics analyses were performed to identify variants. As a basic filtering step, non-synonymous single nucleotide polymorphisms (SNPs) with read depths >40 were chosen. These non-synonymous SNPs were compared against an in-house database, an independent cohort consisting of 54 normal Korean individuals and the Single Nucleotide Polymorphism Database (dbSNP build 138). Only novel SNPs or known disease-causing SNPs remained. Inheritance patterns were checked and SNPs that did not coincide with an autosomal recessive pattern were excluded. The remaining SNPs were validated in other family members (SB156-327 and SB156-328) by Sanger sequencing. The SNPs were also checked against an additional 426 unrelated Korean control chromosomes (Fig. 2).

Bottom Line: Mutations of MYO15A are generally known to cause severe to profound hearing loss throughout all frequencies.From the literature analysis, mutations in the N-terminal domain were more frequently associated with residual hearing at low frequencies than mutations in the other regions of this gene.Therefore we suggest a hypothetical genotype-phenotype correlation whereby MYO15A mutations that affect domains other than the N-terminal domain, lead to profound SNHL throughout all frequencies and mutations that affect the N-terminal domain, result in residual hearing at low frequencies.

View Article: PubMed Central - PubMed

Affiliation: Department of Otorhinolaryngology, Seoul National University Hospital, Seoul national University College of Medicine, Seoul 110-744, Korea.

ABSTRACT
Mutations of MYO15A are generally known to cause severe to profound hearing loss throughout all frequencies. Here, we found two novel MYO15A mutations, c.3871C>T (p.L1291F) and c.5835T>G (p.Y1945X) in an affected individual carrying congenital profound sensorineural hearing loss (SNHL) through targeted resequencing of 134 known deafness genes. The variant, p.L1291F and p.Y1945X, resided in the myosin motor and IQ2 domains, respectively. The p.L1291F variant was predicted to affect the structure of the actin-binding site from three-dimensional protein modeling, thereby interfering with the correct interaction between actin and myosin. From the literature analysis, mutations in the N-terminal domain were more frequently associated with residual hearing at low frequencies than mutations in the other regions of this gene. Therefore we suggest a hypothetical genotype-phenotype correlation whereby MYO15A mutations that affect domains other than the N-terminal domain, lead to profound SNHL throughout all frequencies and mutations that affect the N-terminal domain, result in residual hearing at low frequencies. This genotype-phenotype correlation suggests that preservation of residual hearing during auditory rehabilitation like cochlear implantation should be intended for those who carry mutations in the N-terminal domain and that individuals with mutations elsewhere in MYO15A require early cochlear implantation to timely initiate speech development.

No MeSH data available.


Related in: MedlinePlus