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Diagnostic application of targeted resequencing for familial nonsyndromic hearing loss.

Choi BY, Park G, Gim J, Kim AR, Kim BJ, Kim HS, Park JH, Park T, Oh SH, Han KH, Park WY - PLoS ONE (2013)

Bottom Line: Each proband carried 4.8 variants that were not synonymous and had the occurring frequency of less than three among the 20 probands.These variants were then filtered out with the inheritance pattern of the family, allele frequency in normal hearing 80 control subjects, clinical features.Finally NSHL-causing candidate mutations were identified in 13(65%) of the 20 probands of multiplex families, bringing the total solve rate (or detection rate) in our familial cases to be 78.1% (25/32) Damaging mutations discovered by the targeted resequencing were distributed in nine genes such as WFS1, COCH, EYA4, MYO6, GJB3, COL11A2, OTOF, STRC and MYO3A, most of which were private.

View Article: PubMed Central - PubMed

Affiliation: Department of Otorhinolaryngology, Seoul National University Bundang Hospital, Seongnam, Korea.

ABSTRACT
Identification of causative genes for hereditary nonsyndromic hearing loss (NSHL) is important to decide treatment modalities and to counsel the patients. Due to the genetic heterogeneity in sensorineural genetic disorders, the high-throughput method can be adapted for the efficient diagnosis. To this end, we designed a new diagnostic pipeline to screen all the reported candidate genes for NSHL. For validation of the diagnostic pipeline, we focused upon familial NSHL cases that are most likely to be genetic, rather than to be infectious or environmental. Among the 32 familial NSHL cases, we were able to make a molecular genetic diagnosis from 12 probands (37.5%) in the first stage by their clinical features, characteristic inheritance pattern and further candidate gene sequencing of GJB2, SLC26A4, POU3F4 or mitochondrial DNA. Next we applied targeted resequencing on 80 NSHL genes in the remaining 20 probands. Each proband carried 4.8 variants that were not synonymous and had the occurring frequency of less than three among the 20 probands. These variants were then filtered out with the inheritance pattern of the family, allele frequency in normal hearing 80 control subjects, clinical features. Finally NSHL-causing candidate mutations were identified in 13(65%) of the 20 probands of multiplex families, bringing the total solve rate (or detection rate) in our familial cases to be 78.1% (25/32) Damaging mutations discovered by the targeted resequencing were distributed in nine genes such as WFS1, COCH, EYA4, MYO6, GJB3, COL11A2, OTOF, STRC and MYO3A, most of which were private. Despite the advent of whole genome and whole exome sequencing, we propose targeted resequencing and filtering strategy as a screening and diagnostic tool at least for familial NSHL to find mutations based upon its efficacy and cost-effectiveness.

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Proposed decision procedure for the genetic diagnosis of familial NSHL.We have recruited 145 sensorineural hearing loss patients, Among 115 NSHL cases, we started with 32 familial NSHL because we could check the inheritance patterns in the family. First, we excluded 12 cases with typical clinical features by PCR-Sanger sequencing. In the remaining 20 familial NSHL probands, we found candidate SNVs in 13 probands. In further study, we can find SNVs by whole exome sequencing (WES).
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pone-0068692-g004: Proposed decision procedure for the genetic diagnosis of familial NSHL.We have recruited 145 sensorineural hearing loss patients, Among 115 NSHL cases, we started with 32 familial NSHL because we could check the inheritance patterns in the family. First, we excluded 12 cases with typical clinical features by PCR-Sanger sequencing. In the remaining 20 familial NSHL probands, we found candidate SNVs in 13 probands. In further study, we can find SNVs by whole exome sequencing (WES).

Mentions: Therefore, we propose new diagnostic pipeline with high sensitivity to detect candidate mutations (Fig. 4).


Diagnostic application of targeted resequencing for familial nonsyndromic hearing loss.

Choi BY, Park G, Gim J, Kim AR, Kim BJ, Kim HS, Park JH, Park T, Oh SH, Han KH, Park WY - PLoS ONE (2013)

Proposed decision procedure for the genetic diagnosis of familial NSHL.We have recruited 145 sensorineural hearing loss patients, Among 115 NSHL cases, we started with 32 familial NSHL because we could check the inheritance patterns in the family. First, we excluded 12 cases with typical clinical features by PCR-Sanger sequencing. In the remaining 20 familial NSHL probands, we found candidate SNVs in 13 probands. In further study, we can find SNVs by whole exome sequencing (WES).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3750053&req=5

pone-0068692-g004: Proposed decision procedure for the genetic diagnosis of familial NSHL.We have recruited 145 sensorineural hearing loss patients, Among 115 NSHL cases, we started with 32 familial NSHL because we could check the inheritance patterns in the family. First, we excluded 12 cases with typical clinical features by PCR-Sanger sequencing. In the remaining 20 familial NSHL probands, we found candidate SNVs in 13 probands. In further study, we can find SNVs by whole exome sequencing (WES).
Mentions: Therefore, we propose new diagnostic pipeline with high sensitivity to detect candidate mutations (Fig. 4).

Bottom Line: Each proband carried 4.8 variants that were not synonymous and had the occurring frequency of less than three among the 20 probands.These variants were then filtered out with the inheritance pattern of the family, allele frequency in normal hearing 80 control subjects, clinical features.Finally NSHL-causing candidate mutations were identified in 13(65%) of the 20 probands of multiplex families, bringing the total solve rate (or detection rate) in our familial cases to be 78.1% (25/32) Damaging mutations discovered by the targeted resequencing were distributed in nine genes such as WFS1, COCH, EYA4, MYO6, GJB3, COL11A2, OTOF, STRC and MYO3A, most of which were private.

View Article: PubMed Central - PubMed

Affiliation: Department of Otorhinolaryngology, Seoul National University Bundang Hospital, Seongnam, Korea.

ABSTRACT
Identification of causative genes for hereditary nonsyndromic hearing loss (NSHL) is important to decide treatment modalities and to counsel the patients. Due to the genetic heterogeneity in sensorineural genetic disorders, the high-throughput method can be adapted for the efficient diagnosis. To this end, we designed a new diagnostic pipeline to screen all the reported candidate genes for NSHL. For validation of the diagnostic pipeline, we focused upon familial NSHL cases that are most likely to be genetic, rather than to be infectious or environmental. Among the 32 familial NSHL cases, we were able to make a molecular genetic diagnosis from 12 probands (37.5%) in the first stage by their clinical features, characteristic inheritance pattern and further candidate gene sequencing of GJB2, SLC26A4, POU3F4 or mitochondrial DNA. Next we applied targeted resequencing on 80 NSHL genes in the remaining 20 probands. Each proband carried 4.8 variants that were not synonymous and had the occurring frequency of less than three among the 20 probands. These variants were then filtered out with the inheritance pattern of the family, allele frequency in normal hearing 80 control subjects, clinical features. Finally NSHL-causing candidate mutations were identified in 13(65%) of the 20 probands of multiplex families, bringing the total solve rate (or detection rate) in our familial cases to be 78.1% (25/32) Damaging mutations discovered by the targeted resequencing were distributed in nine genes such as WFS1, COCH, EYA4, MYO6, GJB3, COL11A2, OTOF, STRC and MYO3A, most of which were private. Despite the advent of whole genome and whole exome sequencing, we propose targeted resequencing and filtering strategy as a screening and diagnostic tool at least for familial NSHL to find mutations based upon its efficacy and cost-effectiveness.

Show MeSH
Related in: MedlinePlus