An evidence-based approach to establish the functional and clinical significance of copy number variants in intellectual and developmental disabilities

Erin B. Kaminsky, Vineith Kaul, Justin Paschall, Deanna M. Church, Brian Bunke, Dawn Kunig, Daniel Moreno-De-Luca, Andres Moreno-De-Luca, Jennifer G. Mulle, Stephen T. Warren, Gabriele Richard, John G. Compton, Amy E. Fuller, Troy J. Gliem, Shuwen Huang, Morag N. Collinson, Sarah J. Beal, Todd Ackley, Diane L. Pickering, Denae M. Golden & 14 others Emily Aston, Heidi Whitby, Shashirekha Shetty, Michael R. Rossi, M. Katharine Rudd, Sarah T. South, Arthur R. Brothman, Warren G. Sanger, Ramaswamy K. Iyer, John A. Crolla, Erik C Thorland, Swaroop Aradhya, David H. Ledbetter, Christa L. Martin

Research output: Contribution to journalArticle

245 Citations (Scopus)

Abstract

PURPOSE: Copy number variants have emerged as a major cause of human disease such as autism and intellectual disabilities. Because copy number variants are common in normal individuals, determining the functional and clinical significance of rare copy number variants in patients remains challenging. The adoption of whole-genome chromosomal microarray analysis as a first-tier diagnostic test for individuals with unexplained developmental disabilities provides a unique opportunity to obtain large copy number variant datasets generated through routine patient care. METHODS: A consortium of diagnostic laboratories was established (the International Standards for Cytogenomic Arrays consortium) to share copy number variant and phenotypic data in a central, public database. We present the largest copy number variant case-control study to date comprising 15,749 International Standards for Cytogenomic Arrays cases and 10,118 published controls, focusing our initial analysis on recurrent deletions and duplications involving 14 copy number variant regions. RESULTS: Compared with controls, 14 deletions and seven duplications were significantly overrepresented in cases, providing a clinical diagnosis as pathogenic. CONCLUSION: Given the rapid expansion of clinical chromosomal microarray analysis testing, very large datasets will be available to determine the functional significance of increasingly rare copy number variants. This data will provide an evidence-based guide to clinicians across many disciplines involved in the diagnosis, management, and care of these patients and their families.

Original languageEnglish (US)
Pages (from-to)777-784
Number of pages8
JournalGenetics in Medicine
Volume13
Issue number9
DOIs
StatePublished - Sep 2011

Fingerprint

Developmental Disabilities
Microarray Analysis
Intellectual Disability
Patient Care Management
Autistic Disorder
Routine Diagnostic Tests
Case-Control Studies
Patient Care
Genome
Databases
Datasets

Keywords

  • clinical significance
  • CNVs
  • consortium
  • evidence-based approach
  • ID/DD

ASJC Scopus subject areas

  • Genetics(clinical)

Cite this

An evidence-based approach to establish the functional and clinical significance of copy number variants in intellectual and developmental disabilities. / Kaminsky, Erin B.; Kaul, Vineith; Paschall, Justin; Church, Deanna M.; Bunke, Brian; Kunig, Dawn; Moreno-De-Luca, Daniel; Moreno-De-Luca, Andres; Mulle, Jennifer G.; Warren, Stephen T.; Richard, Gabriele; Compton, John G.; Fuller, Amy E.; Gliem, Troy J.; Huang, Shuwen; Collinson, Morag N.; Beal, Sarah J.; Ackley, Todd; Pickering, Diane L.; Golden, Denae M.; Aston, Emily; Whitby, Heidi; Shetty, Shashirekha; Rossi, Michael R.; Rudd, M. Katharine; South, Sarah T.; Brothman, Arthur R.; Sanger, Warren G.; Iyer, Ramaswamy K.; Crolla, John A.; Thorland, Erik C; Aradhya, Swaroop; Ledbetter, David H.; Martin, Christa L.

In: Genetics in Medicine, Vol. 13, No. 9, 09.2011, p. 777-784.

Research output: Contribution to journalArticle

Kaminsky, EB, Kaul, V, Paschall, J, Church, DM, Bunke, B, Kunig, D, Moreno-De-Luca, D, Moreno-De-Luca, A, Mulle, JG, Warren, ST, Richard, G, Compton, JG, Fuller, AE, Gliem, TJ, Huang, S, Collinson, MN, Beal, SJ, Ackley, T, Pickering, DL, Golden, DM, Aston, E, Whitby, H, Shetty, S, Rossi, MR, Rudd, MK, South, ST, Brothman, AR, Sanger, WG, Iyer, RK, Crolla, JA, Thorland, EC, Aradhya, S, Ledbetter, DH & Martin, CL 2011, 'An evidence-based approach to establish the functional and clinical significance of copy number variants in intellectual and developmental disabilities', Genetics in Medicine, vol. 13, no. 9, pp. 777-784. https://doi.org/10.1097/GIM.0b013e31822c79f9
Kaminsky, Erin B. ; Kaul, Vineith ; Paschall, Justin ; Church, Deanna M. ; Bunke, Brian ; Kunig, Dawn ; Moreno-De-Luca, Daniel ; Moreno-De-Luca, Andres ; Mulle, Jennifer G. ; Warren, Stephen T. ; Richard, Gabriele ; Compton, John G. ; Fuller, Amy E. ; Gliem, Troy J. ; Huang, Shuwen ; Collinson, Morag N. ; Beal, Sarah J. ; Ackley, Todd ; Pickering, Diane L. ; Golden, Denae M. ; Aston, Emily ; Whitby, Heidi ; Shetty, Shashirekha ; Rossi, Michael R. ; Rudd, M. Katharine ; South, Sarah T. ; Brothman, Arthur R. ; Sanger, Warren G. ; Iyer, Ramaswamy K. ; Crolla, John A. ; Thorland, Erik C ; Aradhya, Swaroop ; Ledbetter, David H. ; Martin, Christa L. / An evidence-based approach to establish the functional and clinical significance of copy number variants in intellectual and developmental disabilities. In: Genetics in Medicine. 2011 ; Vol. 13, No. 9. pp. 777-784.
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AU - Kaminsky, Erin B.

AU - Kaul, Vineith

AU - Paschall, Justin

AU - Church, Deanna M.

AU - Bunke, Brian

AU - Kunig, Dawn

AU - Moreno-De-Luca, Daniel

AU - Moreno-De-Luca, Andres

AU - Mulle, Jennifer G.

AU - Warren, Stephen T.

AU - Richard, Gabriele

AU - Compton, John G.

AU - Fuller, Amy E.

AU - Gliem, Troy J.

AU - Huang, Shuwen

AU - Collinson, Morag N.

AU - Beal, Sarah J.

AU - Ackley, Todd

AU - Pickering, Diane L.

AU - Golden, Denae M.

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AU - Whitby, Heidi

AU - Shetty, Shashirekha

AU - Rossi, Michael R.

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AU - South, Sarah T.

AU - Brothman, Arthur R.

AU - Sanger, Warren G.

AU - Iyer, Ramaswamy K.

AU - Crolla, John A.

AU - Thorland, Erik C

AU - Aradhya, Swaroop

AU - Ledbetter, David H.

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