Accuracy of next-generation sequencing for molecular diagnosis in patients with infantile nystagmus syndrome

John Hoon Rim, Seung Tae Lee, Heon Yung Gee, Byung Joo Lee, Jong Rak Choi, Hye Won Park, Sueng Han Han, Jinu Han

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

IMPORTANCE Infantile nystagmus syndrome (INS) is a group of disorders presenting with genetic and clinical heterogeneities that have challenged the genetic and clinical diagnoses of INS. Precise molecular diagnosis in early infancymay result in more accurate genetic counseling and improved patient management. OBJECTIVE To assess the accuracy of genomic data from next-generation sequencing (NGS) and phenotypic data to enhance the definitive diagnosis of INS. DESIGN, SETTING, AND PARTICIPANTS A single-center retrospective case serieswas conducted in 48 unrelated, consecutive patients with INS, with or without associated ocular or systemic conditions, who underwent genetic testing between June 1, 2015, and January 31, 2017. Next-generation sequencing analysis was performed using a target panel that included 113 genes associated with INS (n = 47) or a TruSight One sequencing panel that included 4813 genes associated with known human phenotypes (n = 1). Variants were filtered and prioritized by in-depth clinical review, and finally classified according to the American College of Medical Genetics and Genomics guidelines. Patients underwent a detailed ophthalmic examination, including electroretinography and optical coherence tomography, if feasible. MAIN OUTCOMES AND MEASURES Diagnostic yield of targeted NGS testing. RESULTS Among the 48 patients (21 female and 27 male; mean [SD] age at genetic testing, 9.2 [10.3] years), 8 had a family history of nystagmus and 40 were simplex. All patients were of a single ethnicity (Korean). Genetic variants that were highly likely to be causative were identified in 28 of the 48 patients, corresponding to a molecular diagnostic yield of 58.3% (95%CI, 44.4%-72.2%). FRMD7, GPR143, and PAX6 mutations appeared to be the major genetic causes of familial INS. A total of 10 patients (21%) were reclassified to a different diagnosis based on results of NGS testing, enabling accurate clinical management. CONCLUSIONS AND RELEVANCE These findings suggest that NGS is an accurate diagnostic tool to differentiate causes of INS because diagnostic tests, such as electroretinography and optical coherence tomography, are not easily applicable in young infants. Accurate application of NGS using a standardized, stepwise, team-based approach in early childhood not only facilitated early molecular diagnosis but also led to improved personalized management in patients with INS.

Original languageEnglish
Pages (from-to)1376-1385
Number of pages10
JournalJAMA Ophthalmology
Volume135
Issue number12
DOIs
Publication statusPublished - 2017 Dec 1

Fingerprint

Electroretinography
Optical Coherence Tomography
Genetic Testing
Genetic Heterogeneity
Molecular Pathology
Genetic Counseling
Genomics
Routine Diagnostic Tests
Genes
Early Diagnosis
Guidelines
Phenotype
Mutation
Data Accuracy

All Science Journal Classification (ASJC) codes

  • Ophthalmology

Cite this

Rim, John Hoon ; Lee, Seung Tae ; Gee, Heon Yung ; Lee, Byung Joo ; Choi, Jong Rak ; Park, Hye Won ; Han, Sueng Han ; Han, Jinu. / Accuracy of next-generation sequencing for molecular diagnosis in patients with infantile nystagmus syndrome. In: JAMA Ophthalmology. 2017 ; Vol. 135, No. 12. pp. 1376-1385.
@article{34f4d394df374f269de7611958371564,
title = "Accuracy of next-generation sequencing for molecular diagnosis in patients with infantile nystagmus syndrome",
abstract = "IMPORTANCE Infantile nystagmus syndrome (INS) is a group of disorders presenting with genetic and clinical heterogeneities that have challenged the genetic and clinical diagnoses of INS. Precise molecular diagnosis in early infancymay result in more accurate genetic counseling and improved patient management. OBJECTIVE To assess the accuracy of genomic data from next-generation sequencing (NGS) and phenotypic data to enhance the definitive diagnosis of INS. DESIGN, SETTING, AND PARTICIPANTS A single-center retrospective case serieswas conducted in 48 unrelated, consecutive patients with INS, with or without associated ocular or systemic conditions, who underwent genetic testing between June 1, 2015, and January 31, 2017. Next-generation sequencing analysis was performed using a target panel that included 113 genes associated with INS (n = 47) or a TruSight One sequencing panel that included 4813 genes associated with known human phenotypes (n = 1). Variants were filtered and prioritized by in-depth clinical review, and finally classified according to the American College of Medical Genetics and Genomics guidelines. Patients underwent a detailed ophthalmic examination, including electroretinography and optical coherence tomography, if feasible. MAIN OUTCOMES AND MEASURES Diagnostic yield of targeted NGS testing. RESULTS Among the 48 patients (21 female and 27 male; mean [SD] age at genetic testing, 9.2 [10.3] years), 8 had a family history of nystagmus and 40 were simplex. All patients were of a single ethnicity (Korean). Genetic variants that were highly likely to be causative were identified in 28 of the 48 patients, corresponding to a molecular diagnostic yield of 58.3{\%} (95{\%}CI, 44.4{\%}-72.2{\%}). FRMD7, GPR143, and PAX6 mutations appeared to be the major genetic causes of familial INS. A total of 10 patients (21{\%}) were reclassified to a different diagnosis based on results of NGS testing, enabling accurate clinical management. CONCLUSIONS AND RELEVANCE These findings suggest that NGS is an accurate diagnostic tool to differentiate causes of INS because diagnostic tests, such as electroretinography and optical coherence tomography, are not easily applicable in young infants. Accurate application of NGS using a standardized, stepwise, team-based approach in early childhood not only facilitated early molecular diagnosis but also led to improved personalized management in patients with INS.",
author = "Rim, {John Hoon} and Lee, {Seung Tae} and Gee, {Heon Yung} and Lee, {Byung Joo} and Choi, {Jong Rak} and Park, {Hye Won} and Han, {Sueng Han} and Jinu Han",
year = "2017",
month = "12",
day = "1",
doi = "10.1001/jamaophthalmol.2017.4859",
language = "English",
volume = "135",
pages = "1376--1385",
journal = "JAMA Ophthalmology",
issn = "2168-6165",
publisher = "American Medical Association",
number = "12",

}

Accuracy of next-generation sequencing for molecular diagnosis in patients with infantile nystagmus syndrome. / Rim, John Hoon; Lee, Seung Tae; Gee, Heon Yung; Lee, Byung Joo; Choi, Jong Rak; Park, Hye Won; Han, Sueng Han; Han, Jinu.

In: JAMA Ophthalmology, Vol. 135, No. 12, 01.12.2017, p. 1376-1385.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Accuracy of next-generation sequencing for molecular diagnosis in patients with infantile nystagmus syndrome

AU - Rim, John Hoon

AU - Lee, Seung Tae

AU - Gee, Heon Yung

AU - Lee, Byung Joo

AU - Choi, Jong Rak

AU - Park, Hye Won

AU - Han, Sueng Han

AU - Han, Jinu

PY - 2017/12/1

Y1 - 2017/12/1

N2 - IMPORTANCE Infantile nystagmus syndrome (INS) is a group of disorders presenting with genetic and clinical heterogeneities that have challenged the genetic and clinical diagnoses of INS. Precise molecular diagnosis in early infancymay result in more accurate genetic counseling and improved patient management. OBJECTIVE To assess the accuracy of genomic data from next-generation sequencing (NGS) and phenotypic data to enhance the definitive diagnosis of INS. DESIGN, SETTING, AND PARTICIPANTS A single-center retrospective case serieswas conducted in 48 unrelated, consecutive patients with INS, with or without associated ocular or systemic conditions, who underwent genetic testing between June 1, 2015, and January 31, 2017. Next-generation sequencing analysis was performed using a target panel that included 113 genes associated with INS (n = 47) or a TruSight One sequencing panel that included 4813 genes associated with known human phenotypes (n = 1). Variants were filtered and prioritized by in-depth clinical review, and finally classified according to the American College of Medical Genetics and Genomics guidelines. Patients underwent a detailed ophthalmic examination, including electroretinography and optical coherence tomography, if feasible. MAIN OUTCOMES AND MEASURES Diagnostic yield of targeted NGS testing. RESULTS Among the 48 patients (21 female and 27 male; mean [SD] age at genetic testing, 9.2 [10.3] years), 8 had a family history of nystagmus and 40 were simplex. All patients were of a single ethnicity (Korean). Genetic variants that were highly likely to be causative were identified in 28 of the 48 patients, corresponding to a molecular diagnostic yield of 58.3% (95%CI, 44.4%-72.2%). FRMD7, GPR143, and PAX6 mutations appeared to be the major genetic causes of familial INS. A total of 10 patients (21%) were reclassified to a different diagnosis based on results of NGS testing, enabling accurate clinical management. CONCLUSIONS AND RELEVANCE These findings suggest that NGS is an accurate diagnostic tool to differentiate causes of INS because diagnostic tests, such as electroretinography and optical coherence tomography, are not easily applicable in young infants. Accurate application of NGS using a standardized, stepwise, team-based approach in early childhood not only facilitated early molecular diagnosis but also led to improved personalized management in patients with INS.

AB - IMPORTANCE Infantile nystagmus syndrome (INS) is a group of disorders presenting with genetic and clinical heterogeneities that have challenged the genetic and clinical diagnoses of INS. Precise molecular diagnosis in early infancymay result in more accurate genetic counseling and improved patient management. OBJECTIVE To assess the accuracy of genomic data from next-generation sequencing (NGS) and phenotypic data to enhance the definitive diagnosis of INS. DESIGN, SETTING, AND PARTICIPANTS A single-center retrospective case serieswas conducted in 48 unrelated, consecutive patients with INS, with or without associated ocular or systemic conditions, who underwent genetic testing between June 1, 2015, and January 31, 2017. Next-generation sequencing analysis was performed using a target panel that included 113 genes associated with INS (n = 47) or a TruSight One sequencing panel that included 4813 genes associated with known human phenotypes (n = 1). Variants were filtered and prioritized by in-depth clinical review, and finally classified according to the American College of Medical Genetics and Genomics guidelines. Patients underwent a detailed ophthalmic examination, including electroretinography and optical coherence tomography, if feasible. MAIN OUTCOMES AND MEASURES Diagnostic yield of targeted NGS testing. RESULTS Among the 48 patients (21 female and 27 male; mean [SD] age at genetic testing, 9.2 [10.3] years), 8 had a family history of nystagmus and 40 were simplex. All patients were of a single ethnicity (Korean). Genetic variants that were highly likely to be causative were identified in 28 of the 48 patients, corresponding to a molecular diagnostic yield of 58.3% (95%CI, 44.4%-72.2%). FRMD7, GPR143, and PAX6 mutations appeared to be the major genetic causes of familial INS. A total of 10 patients (21%) were reclassified to a different diagnosis based on results of NGS testing, enabling accurate clinical management. CONCLUSIONS AND RELEVANCE These findings suggest that NGS is an accurate diagnostic tool to differentiate causes of INS because diagnostic tests, such as electroretinography and optical coherence tomography, are not easily applicable in young infants. Accurate application of NGS using a standardized, stepwise, team-based approach in early childhood not only facilitated early molecular diagnosis but also led to improved personalized management in patients with INS.

UR - http://www.scopus.com/inward/record.url?scp=85039928740&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85039928740&partnerID=8YFLogxK

U2 - 10.1001/jamaophthalmol.2017.4859

DO - 10.1001/jamaophthalmol.2017.4859

M3 - Article

VL - 135

SP - 1376

EP - 1385

JO - JAMA Ophthalmology

JF - JAMA Ophthalmology

SN - 2168-6165

IS - 12

ER -