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Whole-exome sequencing identifies a novel genotype-phenotype correlation in the entactin domain of the known deafness gene TECTA.

Choi BY, Kim J, Chung J, Kim AR, Mun SJ, Kang SI, Lee SH, Kim N, Oh SH - PLoS ONE (2014)

Bottom Line: Sanger validation of an additional five family members excluded 20 variants, leaving only one novel variant, TECTA c.710C>T (p.T237I), as the strongest candidate.Based upon what we observed, we propose a novel "genotype to phenotype" correlation in the ENT domain of TECTA.Our results shed light on another important application of whole-exome sequencing: the establishment of a novel genotype-phenotype in the molecular genetic diagnosis of autosomal dominant hearing loss.

View Article: PubMed Central - PubMed

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

ABSTRACT
Postlingual progressive hearing loss, affecting primarily the high frequencies, is the clinical finding in most cases of autosomal dominant nonsyndromic hearing loss (ADNSHL). The molecular genetic etiology of ADNSHL is extremely heterogeneous. We applied whole-exome sequencing to reveal the genetic etiology of high-frequency hearing loss in a mid-sized Korean family without any prior linkage data. Whole-exome sequencing of four family members (two affected and two unaffected), together with our filtering strategy based on comprehensive bioinformatics analyses, identified 21 potential pathogenic candidates. Sanger validation of an additional five family members excluded 20 variants, leaving only one novel variant, TECTA c.710C>T (p.T237I), as the strongest candidate. This variant resides in the entactin (ENT) domain and co-segregated perfectly with non-progressive high-frequency hearing loss in the family. It was absent among 700 ethnically matched control chromosomes, and the T237 residue is conserved among species, which supports its pathogenicity. Interestingly, this finding contrasted with a previously proposed genotype-phenotype correlation in which variants of the ENT domain of TECTA were associated with mid-frequency hearing loss. Based upon what we observed, we propose a novel "genotype to phenotype" correlation in the ENT domain of TECTA. Our results shed light on another important application of whole-exome sequencing: the establishment of a novel genotype-phenotype in the molecular genetic diagnosis of autosomal dominant hearing loss.

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Pedigree and pure tone audiograms of the family SNUBH18.(A) Whole exome sequencing was performed for two affected (III-1 and II-4) and two unaffected individuals (II-5 and II-1) (red diamond). An additional five individuals (two affected and three unaffected) (blue) were recruited for Sanger validation and further filtering. (B) Individuals I-1, II-4, III-1, and III-3 showed typical high frequency hearing loss, while the others showed a normal hearing threshold over all frequencies.
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pone-0097040-g001: Pedigree and pure tone audiograms of the family SNUBH18.(A) Whole exome sequencing was performed for two affected (III-1 and II-4) and two unaffected individuals (II-5 and II-1) (red diamond). An additional five individuals (two affected and three unaffected) (blue) were recruited for Sanger validation and further filtering. (B) Individuals I-1, II-4, III-1, and III-3 showed typical high frequency hearing loss, while the others showed a normal hearing threshold over all frequencies.

Mentions: All procedures in this study were approved by the institutional review boards at Seoul National University Hospital (IRBY-H-0905-041-281) and Seoul National University Bundang Hospital (SNUBH: IRB-B-1007-105-402). Written informed consent was obtained from all individuals or guardians. The pedigree comprised 16 individuals, nine of whom were willing to join the study. Nine members (SB18 I-1, II-1, 2, 3, 4, 5, III-1, 2 and 3) from the SNUBH18 family were identified and evaluated at the Seoul National University Hospital and SNUBH for this study (see Fig. 1). Phenotype evaluations included medical and developmental history interviews, physical examinations, and pure-tone audiometry.


Whole-exome sequencing identifies a novel genotype-phenotype correlation in the entactin domain of the known deafness gene TECTA.

Choi BY, Kim J, Chung J, Kim AR, Mun SJ, Kang SI, Lee SH, Kim N, Oh SH - PLoS ONE (2014)

Pedigree and pure tone audiograms of the family SNUBH18.(A) Whole exome sequencing was performed for two affected (III-1 and II-4) and two unaffected individuals (II-5 and II-1) (red diamond). An additional five individuals (two affected and three unaffected) (blue) were recruited for Sanger validation and further filtering. (B) Individuals I-1, II-4, III-1, and III-3 showed typical high frequency hearing loss, while the others showed a normal hearing threshold over all frequencies.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4016231&req=5

pone-0097040-g001: Pedigree and pure tone audiograms of the family SNUBH18.(A) Whole exome sequencing was performed for two affected (III-1 and II-4) and two unaffected individuals (II-5 and II-1) (red diamond). An additional five individuals (two affected and three unaffected) (blue) were recruited for Sanger validation and further filtering. (B) Individuals I-1, II-4, III-1, and III-3 showed typical high frequency hearing loss, while the others showed a normal hearing threshold over all frequencies.
Mentions: All procedures in this study were approved by the institutional review boards at Seoul National University Hospital (IRBY-H-0905-041-281) and Seoul National University Bundang Hospital (SNUBH: IRB-B-1007-105-402). Written informed consent was obtained from all individuals or guardians. The pedigree comprised 16 individuals, nine of whom were willing to join the study. Nine members (SB18 I-1, II-1, 2, 3, 4, 5, III-1, 2 and 3) from the SNUBH18 family were identified and evaluated at the Seoul National University Hospital and SNUBH for this study (see Fig. 1). Phenotype evaluations included medical and developmental history interviews, physical examinations, and pure-tone audiometry.

Bottom Line: Sanger validation of an additional five family members excluded 20 variants, leaving only one novel variant, TECTA c.710C>T (p.T237I), as the strongest candidate.Based upon what we observed, we propose a novel "genotype to phenotype" correlation in the ENT domain of TECTA.Our results shed light on another important application of whole-exome sequencing: the establishment of a novel genotype-phenotype in the molecular genetic diagnosis of autosomal dominant hearing loss.

View Article: PubMed Central - PubMed

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

ABSTRACT
Postlingual progressive hearing loss, affecting primarily the high frequencies, is the clinical finding in most cases of autosomal dominant nonsyndromic hearing loss (ADNSHL). The molecular genetic etiology of ADNSHL is extremely heterogeneous. We applied whole-exome sequencing to reveal the genetic etiology of high-frequency hearing loss in a mid-sized Korean family without any prior linkage data. Whole-exome sequencing of four family members (two affected and two unaffected), together with our filtering strategy based on comprehensive bioinformatics analyses, identified 21 potential pathogenic candidates. Sanger validation of an additional five family members excluded 20 variants, leaving only one novel variant, TECTA c.710C>T (p.T237I), as the strongest candidate. This variant resides in the entactin (ENT) domain and co-segregated perfectly with non-progressive high-frequency hearing loss in the family. It was absent among 700 ethnically matched control chromosomes, and the T237 residue is conserved among species, which supports its pathogenicity. Interestingly, this finding contrasted with a previously proposed genotype-phenotype correlation in which variants of the ENT domain of TECTA were associated with mid-frequency hearing loss. Based upon what we observed, we propose a novel "genotype to phenotype" correlation in the ENT domain of TECTA. Our results shed light on another important application of whole-exome sequencing: the establishment of a novel genotype-phenotype in the molecular genetic diagnosis of autosomal dominant hearing loss.

Show MeSH
Related in: MedlinePlus