Development of a genotyping microarray for Usher syndrome

Frans P M Cremers, William J. Kimberling, Maigi Külm, Arjan P. De Brouwer, Erwin Van Wijk, Heleen Te Brinke, Cor W R J Cremers, Lies H. Hoefsloot, Sandro Banfi, Francesca Simonelli, Johannes C. Fleischhauer, Wolfgang Berger, Phil M. Kelley, Elene Haralambous, Maria Bitner-Glindzicz, Andrew R. Webster, Zubin Saihan, Elfride De Baere, Bart P. Leroy, Giuliana Silvestri & 10 others Gareth J. McKay, Robert K. Koenekoop, Jose M. Millan, Thomas Rosenberg, Tarja Joensuu, Eeva Marja Sankila, Dominique Weil, Michael Weston, Bernd Wissinger, Hannie Kremer

Research output: Contribution to journalArticle

84 Citations (Scopus)

Abstract

Background: Usher syndrome, a combination of retinitis pigmentosa (RP) and sensorineural hearing loss with or without vestibular dysfunction, displays a high degree of clinical and genetic heterogeneity. Three clinical subtypes can be distinguished, based on the age of onset and severity of the hearing impairment, and the presence or absence of vestibular abnormalities. Thus far, eight genes have been implicated in the syndrome, together comprising 347 protein-coding exons. Methods: To improve DNA diagnostics for patients with Usher syndrome, we developed a genotyping microarray based on the arrayed primer extension (APEX) method. Allele-specific oligonucleotides corresponding to all 298 Usher syndrome-associated sequence variants known to date, 76 of which are novel, were arrayed. Results: Approximately half of these variants were validated using original patient DNAs, which yielded an accuracy of >98%. The efficiency of the Usher genotyping microarray was tested using DNAs from 370 unrelated European and American patients with Usher syndrome. Sequence variants were identified in 64/140 (46%) patients with Usher syndrome type I, 45/189 (24%) patients with Usher syndrome type II, 6/ 21 (29%) patients with Usher syndrome type III and 6/20 (30%) patients with atypical Usher syndrome. The chip also identified two novel sequence variants, c.400C>T (p.R134X) in PCDH15 and c.1606T>C (p.C536S) in USH2A. Conclusion: The Usher genotyping microarray is a versatile and affordable screening tool for Usher syndrome. Its efficiency will improve with the addition of novel sequence variants with minimal extra costs, making it a very useful first-pass screening tool.

Original languageEnglish
Pages (from-to)153-160
Number of pages8
JournalJournal of Medical Genetics
Volume44
Issue number2
DOIs
StatePublished - Feb 2007

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Usher Syndromes
DNA
Retinitis Pigmentosa
Genetic Heterogeneity
Sensorineural Hearing Loss
Hearing Loss
Age of Onset
Oligonucleotides
Exons
Alleles

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

Cremers, F. P. M., Kimberling, W. J., Külm, M., De Brouwer, A. P., Van Wijk, E., Te Brinke, H., ... Kremer, H. (2007). Development of a genotyping microarray for Usher syndrome. Journal of Medical Genetics, 44(2), 153-160. https://doi.org/10.1136/jmg.2006.044784

Development of a genotyping microarray for Usher syndrome. / Cremers, Frans P M; Kimberling, William J.; Külm, Maigi; De Brouwer, Arjan P.; Van Wijk, Erwin; Te Brinke, Heleen; Cremers, Cor W R J; Hoefsloot, Lies H.; Banfi, Sandro; Simonelli, Francesca; Fleischhauer, Johannes C.; Berger, Wolfgang; Kelley, Phil M.; Haralambous, Elene; Bitner-Glindzicz, Maria; Webster, Andrew R.; Saihan, Zubin; De Baere, Elfride; Leroy, Bart P.; Silvestri, Giuliana; McKay, Gareth J.; Koenekoop, Robert K.; Millan, Jose M.; Rosenberg, Thomas; Joensuu, Tarja; Sankila, Eeva Marja; Weil, Dominique; Weston, Michael; Wissinger, Bernd; Kremer, Hannie.

In: Journal of Medical Genetics, Vol. 44, No. 2, 02.2007, p. 153-160.

Research output: Contribution to journalArticle

Cremers, FPM, Kimberling, WJ, Külm, M, De Brouwer, AP, Van Wijk, E, Te Brinke, H, Cremers, CWRJ, Hoefsloot, LH, Banfi, S, Simonelli, F, Fleischhauer, JC, Berger, W, Kelley, PM, Haralambous, E, Bitner-Glindzicz, M, Webster, AR, Saihan, Z, De Baere, E, Leroy, BP, Silvestri, G, McKay, GJ, Koenekoop, RK, Millan, JM, Rosenberg, T, Joensuu, T, Sankila, EM, Weil, D, Weston, M, Wissinger, B & Kremer, H 2007, 'Development of a genotyping microarray for Usher syndrome', Journal of Medical Genetics, vol. 44, no. 2, pp. 153-160. https://doi.org/10.1136/jmg.2006.044784
Cremers FPM, Kimberling WJ, Külm M, De Brouwer AP, Van Wijk E, Te Brinke H et al. Development of a genotyping microarray for Usher syndrome. Journal of Medical Genetics. 2007 Feb;44(2):153-160. https://doi.org/10.1136/jmg.2006.044784
Cremers, Frans P M ; Kimberling, William J. ; Külm, Maigi ; De Brouwer, Arjan P. ; Van Wijk, Erwin ; Te Brinke, Heleen ; Cremers, Cor W R J ; Hoefsloot, Lies H. ; Banfi, Sandro ; Simonelli, Francesca ; Fleischhauer, Johannes C. ; Berger, Wolfgang ; Kelley, Phil M. ; Haralambous, Elene ; Bitner-Glindzicz, Maria ; Webster, Andrew R. ; Saihan, Zubin ; De Baere, Elfride ; Leroy, Bart P. ; Silvestri, Giuliana ; McKay, Gareth J. ; Koenekoop, Robert K. ; Millan, Jose M. ; Rosenberg, Thomas ; Joensuu, Tarja ; Sankila, Eeva Marja ; Weil, Dominique ; Weston, Michael ; Wissinger, Bernd ; Kremer, Hannie. / Development of a genotyping microarray for Usher syndrome. In: Journal of Medical Genetics. 2007 ; Vol. 44, No. 2. pp. 153-160.
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abstract = "Background: Usher syndrome, a combination of retinitis pigmentosa (RP) and sensorineural hearing loss with or without vestibular dysfunction, displays a high degree of clinical and genetic heterogeneity. Three clinical subtypes can be distinguished, based on the age of onset and severity of the hearing impairment, and the presence or absence of vestibular abnormalities. Thus far, eight genes have been implicated in the syndrome, together comprising 347 protein-coding exons. Methods: To improve DNA diagnostics for patients with Usher syndrome, we developed a genotyping microarray based on the arrayed primer extension (APEX) method. Allele-specific oligonucleotides corresponding to all 298 Usher syndrome-associated sequence variants known to date, 76 of which are novel, were arrayed. Results: Approximately half of these variants were validated using original patient DNAs, which yielded an accuracy of >98{\%}. The efficiency of the Usher genotyping microarray was tested using DNAs from 370 unrelated European and American patients with Usher syndrome. Sequence variants were identified in 64/140 (46{\%}) patients with Usher syndrome type I, 45/189 (24{\%}) patients with Usher syndrome type II, 6/ 21 (29{\%}) patients with Usher syndrome type III and 6/20 (30{\%}) patients with atypical Usher syndrome. The chip also identified two novel sequence variants, c.400C>T (p.R134X) in PCDH15 and c.1606T>C (p.C536S) in USH2A. Conclusion: The Usher genotyping microarray is a versatile and affordable screening tool for Usher syndrome. Its efficiency will improve with the addition of novel sequence variants with minimal extra costs, making it a very useful first-pass screening tool.",
author = "Cremers, {Frans P M} and Kimberling, {William J.} and Maigi K{\"u}lm and {De Brouwer}, {Arjan P.} and {Van Wijk}, Erwin and {Te Brinke}, Heleen and Cremers, {Cor W R J} and Hoefsloot, {Lies H.} and Sandro Banfi and Francesca Simonelli and Fleischhauer, {Johannes C.} and Wolfgang Berger and Kelley, {Phil M.} and Elene Haralambous and Maria Bitner-Glindzicz and Webster, {Andrew R.} and Zubin Saihan and {De Baere}, Elfride and Leroy, {Bart P.} and Giuliana Silvestri and McKay, {Gareth J.} and Koenekoop, {Robert K.} and Millan, {Jose M.} and Thomas Rosenberg and Tarja Joensuu and Sankila, {Eeva Marja} and Dominique Weil and Michael Weston and Bernd Wissinger and Hannie Kremer",
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T1 - Development of a genotyping microarray for Usher syndrome

AU - Cremers, Frans P M

AU - Kimberling, William J.

AU - Külm, Maigi

AU - De Brouwer, Arjan P.

AU - Van Wijk, Erwin

AU - Te Brinke, Heleen

AU - Cremers, Cor W R J

AU - Hoefsloot, Lies H.

AU - Banfi, Sandro

AU - Simonelli, Francesca

AU - Fleischhauer, Johannes C.

AU - Berger, Wolfgang

AU - Kelley, Phil M.

AU - Haralambous, Elene

AU - Bitner-Glindzicz, Maria

AU - Webster, Andrew R.

AU - Saihan, Zubin

AU - De Baere, Elfride

AU - Leroy, Bart P.

AU - Silvestri, Giuliana

AU - McKay, Gareth J.

AU - Koenekoop, Robert K.

AU - Millan, Jose M.

AU - Rosenberg, Thomas

AU - Joensuu, Tarja

AU - Sankila, Eeva Marja

AU - Weil, Dominique

AU - Weston, Michael

AU - Wissinger, Bernd

AU - Kremer, Hannie

PY - 2007/2

Y1 - 2007/2

N2 - Background: Usher syndrome, a combination of retinitis pigmentosa (RP) and sensorineural hearing loss with or without vestibular dysfunction, displays a high degree of clinical and genetic heterogeneity. Three clinical subtypes can be distinguished, based on the age of onset and severity of the hearing impairment, and the presence or absence of vestibular abnormalities. Thus far, eight genes have been implicated in the syndrome, together comprising 347 protein-coding exons. Methods: To improve DNA diagnostics for patients with Usher syndrome, we developed a genotyping microarray based on the arrayed primer extension (APEX) method. Allele-specific oligonucleotides corresponding to all 298 Usher syndrome-associated sequence variants known to date, 76 of which are novel, were arrayed. Results: Approximately half of these variants were validated using original patient DNAs, which yielded an accuracy of >98%. The efficiency of the Usher genotyping microarray was tested using DNAs from 370 unrelated European and American patients with Usher syndrome. Sequence variants were identified in 64/140 (46%) patients with Usher syndrome type I, 45/189 (24%) patients with Usher syndrome type II, 6/ 21 (29%) patients with Usher syndrome type III and 6/20 (30%) patients with atypical Usher syndrome. The chip also identified two novel sequence variants, c.400C>T (p.R134X) in PCDH15 and c.1606T>C (p.C536S) in USH2A. Conclusion: The Usher genotyping microarray is a versatile and affordable screening tool for Usher syndrome. Its efficiency will improve with the addition of novel sequence variants with minimal extra costs, making it a very useful first-pass screening tool.

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