Prediction and assessment of splicing alterations: Implications for clinical testing

Amanda B. Spurdle, Fergus J Couch, Frans B L Hogervorst, Paolo Radice, Olga M. Sinilnikova

Research output: Contribution to journalArticle

84 Citations (Scopus)

Abstract

Sequence variants that may result in splicing alterations are a particular class of inherited variants for which consequences can be more readily assessed, using a combination of bioinformatic prediction methods and in vitro assays. There is also a general agreement that a variant would invariably be considered pathogenic on the basis of convincing evidence that it results in transcript(s) carrying a premature stop codon or an in-frame deletion disrupting known functional domain(s). This commentary discusses current practices used to assess the clinical significance of this class of variants, provides suggestions to improve assessment, and highlights the issues involved in routine assessment of potential splicing aberrations. We conclude that classification of sequence variants that may alter splicing is greatly enhanced by supporting in vitro analysis. Additional studies that assess large numbers of variants for induction of splicing aberrations and exon skipping are needed to define the contribution of splicing/exon skipping to cancer and disease. These studies will also provide the impetus for development of algorithms that better predict splicing patterns. To facilitate variant classification and development of more specific bioinformatic tools, we call for the deposition of all laboratory data from splicing analyses into national and international databases.

Original languageEnglish (US)
Pages (from-to)1304-1313
Number of pages10
JournalHuman Mutation
Volume29
Issue number11
DOIs
StatePublished - Nov 2008

Fingerprint

Computational Biology
Exons
Nonsense Codon
Databases
Neoplasms
In Vitro Techniques

Keywords

  • Bioinformatic prediction
  • Cancer
  • Oncology
  • Splicing
  • Unclassified variant

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Spurdle, A. B., Couch, F. J., Hogervorst, F. B. L., Radice, P., & Sinilnikova, O. M. (2008). Prediction and assessment of splicing alterations: Implications for clinical testing. Human Mutation, 29(11), 1304-1313. https://doi.org/10.1002/humu.20901

Prediction and assessment of splicing alterations : Implications for clinical testing. / Spurdle, Amanda B.; Couch, Fergus J; Hogervorst, Frans B L; Radice, Paolo; Sinilnikova, Olga M.

In: Human Mutation, Vol. 29, No. 11, 11.2008, p. 1304-1313.

Research output: Contribution to journalArticle

Spurdle, AB, Couch, FJ, Hogervorst, FBL, Radice, P & Sinilnikova, OM 2008, 'Prediction and assessment of splicing alterations: Implications for clinical testing', Human Mutation, vol. 29, no. 11, pp. 1304-1313. https://doi.org/10.1002/humu.20901
Spurdle, Amanda B. ; Couch, Fergus J ; Hogervorst, Frans B L ; Radice, Paolo ; Sinilnikova, Olga M. / Prediction and assessment of splicing alterations : Implications for clinical testing. In: Human Mutation. 2008 ; Vol. 29, No. 11. pp. 1304-1313.
@article{605af070b19a4979b06b1408835ec964,
title = "Prediction and assessment of splicing alterations: Implications for clinical testing",
abstract = "Sequence variants that may result in splicing alterations are a particular class of inherited variants for which consequences can be more readily assessed, using a combination of bioinformatic prediction methods and in vitro assays. There is also a general agreement that a variant would invariably be considered pathogenic on the basis of convincing evidence that it results in transcript(s) carrying a premature stop codon or an in-frame deletion disrupting known functional domain(s). This commentary discusses current practices used to assess the clinical significance of this class of variants, provides suggestions to improve assessment, and highlights the issues involved in routine assessment of potential splicing aberrations. We conclude that classification of sequence variants that may alter splicing is greatly enhanced by supporting in vitro analysis. Additional studies that assess large numbers of variants for induction of splicing aberrations and exon skipping are needed to define the contribution of splicing/exon skipping to cancer and disease. These studies will also provide the impetus for development of algorithms that better predict splicing patterns. To facilitate variant classification and development of more specific bioinformatic tools, we call for the deposition of all laboratory data from splicing analyses into national and international databases.",
keywords = "Bioinformatic prediction, Cancer, Oncology, Splicing, Unclassified variant",
author = "Spurdle, {Amanda B.} and Couch, {Fergus J} and Hogervorst, {Frans B L} and Paolo Radice and Sinilnikova, {Olga M.}",
year = "2008",
month = "11",
doi = "10.1002/humu.20901",
language = "English (US)",
volume = "29",
pages = "1304--1313",
journal = "Human Mutation",
issn = "1059-7794",
publisher = "Wiley-Liss Inc.",
number = "11",

}

TY - JOUR

T1 - Prediction and assessment of splicing alterations

T2 - Implications for clinical testing

AU - Spurdle, Amanda B.

AU - Couch, Fergus J

AU - Hogervorst, Frans B L

AU - Radice, Paolo

AU - Sinilnikova, Olga M.

PY - 2008/11

Y1 - 2008/11

N2 - Sequence variants that may result in splicing alterations are a particular class of inherited variants for which consequences can be more readily assessed, using a combination of bioinformatic prediction methods and in vitro assays. There is also a general agreement that a variant would invariably be considered pathogenic on the basis of convincing evidence that it results in transcript(s) carrying a premature stop codon or an in-frame deletion disrupting known functional domain(s). This commentary discusses current practices used to assess the clinical significance of this class of variants, provides suggestions to improve assessment, and highlights the issues involved in routine assessment of potential splicing aberrations. We conclude that classification of sequence variants that may alter splicing is greatly enhanced by supporting in vitro analysis. Additional studies that assess large numbers of variants for induction of splicing aberrations and exon skipping are needed to define the contribution of splicing/exon skipping to cancer and disease. These studies will also provide the impetus for development of algorithms that better predict splicing patterns. To facilitate variant classification and development of more specific bioinformatic tools, we call for the deposition of all laboratory data from splicing analyses into national and international databases.

AB - Sequence variants that may result in splicing alterations are a particular class of inherited variants for which consequences can be more readily assessed, using a combination of bioinformatic prediction methods and in vitro assays. There is also a general agreement that a variant would invariably be considered pathogenic on the basis of convincing evidence that it results in transcript(s) carrying a premature stop codon or an in-frame deletion disrupting known functional domain(s). This commentary discusses current practices used to assess the clinical significance of this class of variants, provides suggestions to improve assessment, and highlights the issues involved in routine assessment of potential splicing aberrations. We conclude that classification of sequence variants that may alter splicing is greatly enhanced by supporting in vitro analysis. Additional studies that assess large numbers of variants for induction of splicing aberrations and exon skipping are needed to define the contribution of splicing/exon skipping to cancer and disease. These studies will also provide the impetus for development of algorithms that better predict splicing patterns. To facilitate variant classification and development of more specific bioinformatic tools, we call for the deposition of all laboratory data from splicing analyses into national and international databases.

KW - Bioinformatic prediction

KW - Cancer

KW - Oncology

KW - Splicing

KW - Unclassified variant

UR - http://www.scopus.com/inward/record.url?scp=55549124905&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=55549124905&partnerID=8YFLogxK

U2 - 10.1002/humu.20901

DO - 10.1002/humu.20901

M3 - Article

C2 - 18951448

AN - SCOPUS:55549124905

VL - 29

SP - 1304

EP - 1313

JO - Human Mutation

JF - Human Mutation

SN - 1059-7794

IS - 11

ER -