AUDIOME: a tiered exome sequencing–based comprehensive gene panel for the diagnosis of heterogeneous nonsyndromic sensorineural hearing loss

Qiaoning Guan; Jorune Balciuniene; Kajia Cao; Zhiqian Fan; Sawona Biswas; Alisha Wilkens; Daniel J. Gallo; Emma Bedoukian; Jennifer Tarpinian; Pushkala Jayaraman; Mahdi Sarmady; Matthew Dulik; Avni Santani; Nancy Spinner; Ahmad N. Abou Tayoun; Ian D. Krantz; Laura K. Conlin; Minjie Luo

doi:10.1038/gim.2018.48

AUDIOME: a tiered exome sequencing–based comprehensive gene panel for the diagnosis of heterogeneous nonsyndromic sensorineural hearing loss

Qiaoning Guan, Jorune Balciuniene, Kajia Cao, Zhiqian Fan, Sawona Biswas, Alisha Wilkens, Daniel J. Gallo, Emma Bedoukian, Jennifer Tarpinian, Pushkala Jayaraman, Mahdi Sarmady, Matthew Dulik, Avni Santani, Nancy Spinner, Ahmad N. Abou Tayoun, Ian D. Krantz, Laura K. Conlin, Minjie Luo

Research output: Contribution to journal › Article › peer-review

28 Scopus citations

Abstract

Purpose: Hereditary hearing loss is highly heterogeneous. To keep up with rapidly emerging disease-causing genes, we developed the AUDIOME test for nonsyndromic hearing loss (NSHL) using an exome sequencing (ES) platform and targeted analysis for the curated genes. Methods: A tiered strategy was implemented for this test. Tier 1 includes combined Sanger and targeted deletion analyses of the two most common NSHL genes and two mitochondrial genes. Nondiagnostic tier 1 cases are subjected to ES and array followed by targeted analysis of the remaining AUDIOME genes. Results: ES resulted in good coverage of the selected genes with 98.24% of targeted bases at >15 ×. A fill-in strategy was developed for the poorly covered regions, which generally fell within GC-rich or highly homologous regions. Prospective testing of 33 patients with NSHL revealed a diagnosis in 11 (33%) and a possible diagnosis in 8 cases (24.2%). Among those, 10 individuals had variants in tier 1 genes. The ES data in the remaining nondiagnostic cases are readily available for further analysis. Conclusion: The tiered and ES-based test provides an efficient and cost-effective diagnostic strategy for NSHL, with the potential to reflex to full exome to identify causal changes outside of the AUDIOME test.

Original language	English
Pages (from-to)	1600-1608
Number of pages	9
Journal	Genetics in Medicine
Volume	20
Issue number	12
DOIs	https://doi.org/10.1038/gim.2018.48
State	Published - 1 Dec 2018
Externally published	Yes

Keywords

exome sequencing
hearing loss
next-generation sequencing panel
reflex
tier

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10.1038/gim.2018.48

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Guan, Q., Balciuniene, J., Cao, K., Fan, Z., Biswas, S., Wilkens, A., Gallo, D. J., Bedoukian, E., Tarpinian, J., Jayaraman, P., Sarmady, M., Dulik, M., Santani, A., Spinner, N., Abou Tayoun, A. N., Krantz, I. D., Conlin, L. K., & Luo, M. (2018). AUDIOME: a tiered exome sequencing–based comprehensive gene panel for the diagnosis of heterogeneous nonsyndromic sensorineural hearing loss. Genetics in Medicine, 20(12), 1600-1608. https://doi.org/10.1038/gim.2018.48

@article{eb08289c67a749b18c72acef479354b3,

title = "AUDIOME: a tiered exome sequencing–based comprehensive gene panel for the diagnosis of heterogeneous nonsyndromic sensorineural hearing loss",

abstract = "Purpose: Hereditary hearing loss is highly heterogeneous. To keep up with rapidly emerging disease-causing genes, we developed the AUDIOME test for nonsyndromic hearing loss (NSHL) using an exome sequencing (ES) platform and targeted analysis for the curated genes. Methods: A tiered strategy was implemented for this test. Tier 1 includes combined Sanger and targeted deletion analyses of the two most common NSHL genes and two mitochondrial genes. Nondiagnostic tier 1 cases are subjected to ES and array followed by targeted analysis of the remaining AUDIOME genes. Results: ES resulted in good coverage of the selected genes with 98.24% of targeted bases at >15 ×. A fill-in strategy was developed for the poorly covered regions, which generally fell within GC-rich or highly homologous regions. Prospective testing of 33 patients with NSHL revealed a diagnosis in 11 (33%) and a possible diagnosis in 8 cases (24.2%). Among those, 10 individuals had variants in tier 1 genes. The ES data in the remaining nondiagnostic cases are readily available for further analysis. Conclusion: The tiered and ES-based test provides an efficient and cost-effective diagnostic strategy for NSHL, with the potential to reflex to full exome to identify causal changes outside of the AUDIOME test.",

keywords = "exome sequencing, hearing loss, next-generation sequencing panel, reflex, tier",

author = "Qiaoning Guan and Jorune Balciuniene and Kajia Cao and Zhiqian Fan and Sawona Biswas and Alisha Wilkens and Gallo, {Daniel J.} and Emma Bedoukian and Jennifer Tarpinian and Pushkala Jayaraman and Mahdi Sarmady and Matthew Dulik and Avni Santani and Nancy Spinner and {Abou Tayoun}, {Ahmad N.} and Krantz, {Ian D.} and Conlin, {Laura K.} and Minjie Luo",

note = "Publisher Copyright: {\textcopyright} 2018, American College of Medical Genetics and Genomics.",

year = "2018",

month = dec,

day = "1",

doi = "10.1038/gim.2018.48",

language = "English",

volume = "20",

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Guan, Q, Balciuniene, J, Cao, K, Fan, Z, Biswas, S, Wilkens, A, Gallo, DJ, Bedoukian, E, Tarpinian, J, Jayaraman, P, Sarmady, M, Dulik, M, Santani, A, Spinner, N, Abou Tayoun, AN, Krantz, ID, Conlin, LK & Luo, M 2018, 'AUDIOME: a tiered exome sequencing–based comprehensive gene panel for the diagnosis of heterogeneous nonsyndromic sensorineural hearing loss', Genetics in Medicine, vol. 20, no. 12, pp. 1600-1608. https://doi.org/10.1038/gim.2018.48

TY - JOUR

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T2 - a tiered exome sequencing–based comprehensive gene panel for the diagnosis of heterogeneous nonsyndromic sensorineural hearing loss

AU - Guan, Qiaoning

AU - Balciuniene, Jorune

AU - Cao, Kajia

AU - Fan, Zhiqian

AU - Biswas, Sawona

AU - Wilkens, Alisha

AU - Gallo, Daniel J.

AU - Bedoukian, Emma

AU - Tarpinian, Jennifer

AU - Jayaraman, Pushkala

AU - Sarmady, Mahdi

AU - Dulik, Matthew

AU - Santani, Avni

AU - Spinner, Nancy

AU - Abou Tayoun, Ahmad N.

AU - Krantz, Ian D.

AU - Conlin, Laura K.

AU - Luo, Minjie

PY - 2018/12/1

Y1 - 2018/12/1

N2 - Purpose: Hereditary hearing loss is highly heterogeneous. To keep up with rapidly emerging disease-causing genes, we developed the AUDIOME test for nonsyndromic hearing loss (NSHL) using an exome sequencing (ES) platform and targeted analysis for the curated genes. Methods: A tiered strategy was implemented for this test. Tier 1 includes combined Sanger and targeted deletion analyses of the two most common NSHL genes and two mitochondrial genes. Nondiagnostic tier 1 cases are subjected to ES and array followed by targeted analysis of the remaining AUDIOME genes. Results: ES resulted in good coverage of the selected genes with 98.24% of targeted bases at >15 ×. A fill-in strategy was developed for the poorly covered regions, which generally fell within GC-rich or highly homologous regions. Prospective testing of 33 patients with NSHL revealed a diagnosis in 11 (33%) and a possible diagnosis in 8 cases (24.2%). Among those, 10 individuals had variants in tier 1 genes. The ES data in the remaining nondiagnostic cases are readily available for further analysis. Conclusion: The tiered and ES-based test provides an efficient and cost-effective diagnostic strategy for NSHL, with the potential to reflex to full exome to identify causal changes outside of the AUDIOME test.

AB - Purpose: Hereditary hearing loss is highly heterogeneous. To keep up with rapidly emerging disease-causing genes, we developed the AUDIOME test for nonsyndromic hearing loss (NSHL) using an exome sequencing (ES) platform and targeted analysis for the curated genes. Methods: A tiered strategy was implemented for this test. Tier 1 includes combined Sanger and targeted deletion analyses of the two most common NSHL genes and two mitochondrial genes. Nondiagnostic tier 1 cases are subjected to ES and array followed by targeted analysis of the remaining AUDIOME genes. Results: ES resulted in good coverage of the selected genes with 98.24% of targeted bases at >15 ×. A fill-in strategy was developed for the poorly covered regions, which generally fell within GC-rich or highly homologous regions. Prospective testing of 33 patients with NSHL revealed a diagnosis in 11 (33%) and a possible diagnosis in 8 cases (24.2%). Among those, 10 individuals had variants in tier 1 genes. The ES data in the remaining nondiagnostic cases are readily available for further analysis. Conclusion: The tiered and ES-based test provides an efficient and cost-effective diagnostic strategy for NSHL, with the potential to reflex to full exome to identify causal changes outside of the AUDIOME test.

KW - exome sequencing

KW - hearing loss

KW - next-generation sequencing panel

KW - reflex

KW - tier

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AUDIOME: a tiered exome sequencing–based comprehensive gene panel for the diagnosis of heterogeneous nonsyndromic sensorineural hearing loss

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Keywords

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