Copy number variation plays an important role in clinical epilepsy

Heather Olson, Yiping Shen, Jennifer Avallone, Beth R. Sheidley, Rebecca Pinsky, Ann M. Bergin, Gerard T. Berry, Frank H. Duffy, Yaman Eksioglu, David J. Harris, Fuki M. Hisama, Eugenia Ho, Mira Irons, Christina M. Jacobsen, Philip James, Sanjeev Kothare, Omar Khwaja, Jonathan Lipton, Tobias Loddenkemper, Jennifer Markowitz & 24 others Kiran Maski, J. Thomas Megerian, Edward Neilan, Peter C. Raffalli, Michael Robbins, Amy Roberts, Eugene Roe, Caitlin Rollins, Mustafa Sahin, Dean Sarco, Alison Schonwald, Sharon E. Smith, Janet Soul, Joan M. Stoler, Masanori Takeoka, Wen Han Tan, Alcy R. Torres, Peter Tsai, David K. Urion, Laura Weissman, Robert Wolff, Bai Lin Wu, David T. Miller, Annapurna Poduri

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Abstract

Objective To evaluate the role of copy number abnormalities detectable using chromosomal microarray (CMA) testing in patients with epilepsy at a tertiary care center. Methods We identified patients with International Classification of Diseases, ninth revision (ICD-9) codes for epilepsy or seizures and clinical CMA testing performed between October 2006 and February 2011 at Boston Children's Hospital. We reviewed medical records and included patients who met criteria for epilepsy. We phenotypically characterized patients with epilepsy-associated abnormalities on CMA. Results Of 973 patients who had CMA and ICD-9 codes for epilepsy or seizures, 805 patients satisfied criteria for epilepsy. We observed 437 copy number variants (CNVs) in 323 patients (1-4 per patient), including 185 (42%) deletions and 252 (58%) duplications. Forty (9%) were confirmed de novo, 186 (43%) were inherited, and parental data were unavailable for 211 (48%). Excluding full chromosome trisomies, CNV size ranged from 18kb to 142Mb, and 34% were >500kb. In at least 40 cases (5%), the epilepsy phenotype was explained by a CNV, including 29 patients with epilepsy-associated syndromes and 11 with likely disease-associated CNVs involving epilepsy genes or "hotspots." We observed numerous recurrent CNVs including 10 involving loss or gain of Xp22.31, a region described in patients with and without epilepsy. Interpretation Copy number abnormalities play an important role in patients with epilepsy. Because the diagnostic yield of CMA for epilepsy patients is similar to the yield in autism spectrum disorders and in prenatal diagnosis, for which published guidelines recommend testing with CMA, we recommend the implementation of CMA in the evaluation of unexplained epilepsy. Ann Neurol 2014;75:943-958

Original languageEnglish (US)
Pages (from-to)943-958
Number of pages16
JournalAnnals of Neurology
Volume75
Issue number6
DOIs
StatePublished - 2014

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Epilepsy
International Classification of Diseases
Seizures
Trisomy
Prenatal Diagnosis
Tertiary Care Centers
Chromosome Aberrations
Medical Records
Chromosomes
Guidelines
Phenotype

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

Olson, H., Shen, Y., Avallone, J., Sheidley, B. R., Pinsky, R., Bergin, A. M., ... Poduri, A. (2014). Copy number variation plays an important role in clinical epilepsy. Annals of Neurology, 75(6), 943-958. https://doi.org/10.1002/ana.24178

Copy number variation plays an important role in clinical epilepsy. / Olson, Heather; Shen, Yiping; Avallone, Jennifer; Sheidley, Beth R.; Pinsky, Rebecca; Bergin, Ann M.; Berry, Gerard T.; Duffy, Frank H.; Eksioglu, Yaman; Harris, David J.; Hisama, Fuki M.; Ho, Eugenia; Irons, Mira; Jacobsen, Christina M.; James, Philip; Kothare, Sanjeev; Khwaja, Omar; Lipton, Jonathan; Loddenkemper, Tobias; Markowitz, Jennifer; Maski, Kiran; Megerian, J. Thomas; Neilan, Edward; Raffalli, Peter C.; Robbins, Michael; Roberts, Amy; Roe, Eugene; Rollins, Caitlin; Sahin, Mustafa; Sarco, Dean; Schonwald, Alison; Smith, Sharon E.; Soul, Janet; Stoler, Joan M.; Takeoka, Masanori; Tan, Wen Han; Torres, Alcy R.; Tsai, Peter; Urion, David K.; Weissman, Laura; Wolff, Robert; Wu, Bai Lin; Miller, David T.; Poduri, Annapurna.

In: Annals of Neurology, Vol. 75, No. 6, 2014, p. 943-958.

Research output: Contribution to journalArticle

Olson, H, Shen, Y, Avallone, J, Sheidley, BR, Pinsky, R, Bergin, AM, Berry, GT, Duffy, FH, Eksioglu, Y, Harris, DJ, Hisama, FM, Ho, E, Irons, M, Jacobsen, CM, James, P, Kothare, S, Khwaja, O, Lipton, J, Loddenkemper, T, Markowitz, J, Maski, K, Megerian, JT, Neilan, E, Raffalli, PC, Robbins, M, Roberts, A, Roe, E, Rollins, C, Sahin, M, Sarco, D, Schonwald, A, Smith, SE, Soul, J, Stoler, JM, Takeoka, M, Tan, WH, Torres, AR, Tsai, P, Urion, DK, Weissman, L, Wolff, R, Wu, BL, Miller, DT & Poduri, A 2014, 'Copy number variation plays an important role in clinical epilepsy', Annals of Neurology, vol. 75, no. 6, pp. 943-958. https://doi.org/10.1002/ana.24178
Olson H, Shen Y, Avallone J, Sheidley BR, Pinsky R, Bergin AM et al. Copy number variation plays an important role in clinical epilepsy. Annals of Neurology. 2014;75(6):943-958. https://doi.org/10.1002/ana.24178
Olson, Heather ; Shen, Yiping ; Avallone, Jennifer ; Sheidley, Beth R. ; Pinsky, Rebecca ; Bergin, Ann M. ; Berry, Gerard T. ; Duffy, Frank H. ; Eksioglu, Yaman ; Harris, David J. ; Hisama, Fuki M. ; Ho, Eugenia ; Irons, Mira ; Jacobsen, Christina M. ; James, Philip ; Kothare, Sanjeev ; Khwaja, Omar ; Lipton, Jonathan ; Loddenkemper, Tobias ; Markowitz, Jennifer ; Maski, Kiran ; Megerian, J. Thomas ; Neilan, Edward ; Raffalli, Peter C. ; Robbins, Michael ; Roberts, Amy ; Roe, Eugene ; Rollins, Caitlin ; Sahin, Mustafa ; Sarco, Dean ; Schonwald, Alison ; Smith, Sharon E. ; Soul, Janet ; Stoler, Joan M. ; Takeoka, Masanori ; Tan, Wen Han ; Torres, Alcy R. ; Tsai, Peter ; Urion, David K. ; Weissman, Laura ; Wolff, Robert ; Wu, Bai Lin ; Miller, David T. ; Poduri, Annapurna. / Copy number variation plays an important role in clinical epilepsy. In: Annals of Neurology. 2014 ; Vol. 75, No. 6. pp. 943-958.
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abstract = "Objective To evaluate the role of copy number abnormalities detectable using chromosomal microarray (CMA) testing in patients with epilepsy at a tertiary care center. Methods We identified patients with International Classification of Diseases, ninth revision (ICD-9) codes for epilepsy or seizures and clinical CMA testing performed between October 2006 and February 2011 at Boston Children's Hospital. We reviewed medical records and included patients who met criteria for epilepsy. We phenotypically characterized patients with epilepsy-associated abnormalities on CMA. Results Of 973 patients who had CMA and ICD-9 codes for epilepsy or seizures, 805 patients satisfied criteria for epilepsy. We observed 437 copy number variants (CNVs) in 323 patients (1-4 per patient), including 185 (42{\%}) deletions and 252 (58{\%}) duplications. Forty (9{\%}) were confirmed de novo, 186 (43{\%}) were inherited, and parental data were unavailable for 211 (48{\%}). Excluding full chromosome trisomies, CNV size ranged from 18kb to 142Mb, and 34{\%} were >500kb. In at least 40 cases (5{\%}), the epilepsy phenotype was explained by a CNV, including 29 patients with epilepsy-associated syndromes and 11 with likely disease-associated CNVs involving epilepsy genes or {"}hotspots.{"} We observed numerous recurrent CNVs including 10 involving loss or gain of Xp22.31, a region described in patients with and without epilepsy. Interpretation Copy number abnormalities play an important role in patients with epilepsy. Because the diagnostic yield of CMA for epilepsy patients is similar to the yield in autism spectrum disorders and in prenatal diagnosis, for which published guidelines recommend testing with CMA, we recommend the implementation of CMA in the evaluation of unexplained epilepsy. Ann Neurol 2014;75:943-958",
author = "Heather Olson and Yiping Shen and Jennifer Avallone and Sheidley, {Beth R.} and Rebecca Pinsky and Bergin, {Ann M.} and Berry, {Gerard T.} and Duffy, {Frank H.} and Yaman Eksioglu and Harris, {David J.} and Hisama, {Fuki M.} and Eugenia Ho and Mira Irons and Jacobsen, {Christina M.} and Philip James and Sanjeev Kothare and Omar Khwaja and Jonathan Lipton and Tobias Loddenkemper and Jennifer Markowitz and Kiran Maski and Megerian, {J. Thomas} and Edward Neilan and Raffalli, {Peter C.} and Michael Robbins and Amy Roberts and Eugene Roe and Caitlin Rollins and Mustafa Sahin and Dean Sarco and Alison Schonwald and Smith, {Sharon E.} and Janet Soul and Stoler, {Joan M.} and Masanori Takeoka and Tan, {Wen Han} and Torres, {Alcy R.} and Peter Tsai and Urion, {David K.} and Laura Weissman and Robert Wolff and Wu, {Bai Lin} and Miller, {David T.} and Annapurna Poduri",
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T1 - Copy number variation plays an important role in clinical epilepsy

AU - Olson, Heather

AU - Shen, Yiping

AU - Avallone, Jennifer

AU - Sheidley, Beth R.

AU - Pinsky, Rebecca

AU - Bergin, Ann M.

AU - Berry, Gerard T.

AU - Duffy, Frank H.

AU - Eksioglu, Yaman

AU - Harris, David J.

AU - Hisama, Fuki M.

AU - Ho, Eugenia

AU - Irons, Mira

AU - Jacobsen, Christina M.

AU - James, Philip

AU - Kothare, Sanjeev

AU - Khwaja, Omar

AU - Lipton, Jonathan

AU - Loddenkemper, Tobias

AU - Markowitz, Jennifer

AU - Maski, Kiran

AU - Megerian, J. Thomas

AU - Neilan, Edward

AU - Raffalli, Peter C.

AU - Robbins, Michael

AU - Roberts, Amy

AU - Roe, Eugene

AU - Rollins, Caitlin

AU - Sahin, Mustafa

AU - Sarco, Dean

AU - Schonwald, Alison

AU - Smith, Sharon E.

AU - Soul, Janet

AU - Stoler, Joan M.

AU - Takeoka, Masanori

AU - Tan, Wen Han

AU - Torres, Alcy R.

AU - Tsai, Peter

AU - Urion, David K.

AU - Weissman, Laura

AU - Wolff, Robert

AU - Wu, Bai Lin

AU - Miller, David T.

AU - Poduri, Annapurna

PY - 2014

Y1 - 2014

N2 - Objective To evaluate the role of copy number abnormalities detectable using chromosomal microarray (CMA) testing in patients with epilepsy at a tertiary care center. Methods We identified patients with International Classification of Diseases, ninth revision (ICD-9) codes for epilepsy or seizures and clinical CMA testing performed between October 2006 and February 2011 at Boston Children's Hospital. We reviewed medical records and included patients who met criteria for epilepsy. We phenotypically characterized patients with epilepsy-associated abnormalities on CMA. Results Of 973 patients who had CMA and ICD-9 codes for epilepsy or seizures, 805 patients satisfied criteria for epilepsy. We observed 437 copy number variants (CNVs) in 323 patients (1-4 per patient), including 185 (42%) deletions and 252 (58%) duplications. Forty (9%) were confirmed de novo, 186 (43%) were inherited, and parental data were unavailable for 211 (48%). Excluding full chromosome trisomies, CNV size ranged from 18kb to 142Mb, and 34% were >500kb. In at least 40 cases (5%), the epilepsy phenotype was explained by a CNV, including 29 patients with epilepsy-associated syndromes and 11 with likely disease-associated CNVs involving epilepsy genes or "hotspots." We observed numerous recurrent CNVs including 10 involving loss or gain of Xp22.31, a region described in patients with and without epilepsy. Interpretation Copy number abnormalities play an important role in patients with epilepsy. Because the diagnostic yield of CMA for epilepsy patients is similar to the yield in autism spectrum disorders and in prenatal diagnosis, for which published guidelines recommend testing with CMA, we recommend the implementation of CMA in the evaluation of unexplained epilepsy. Ann Neurol 2014;75:943-958

AB - Objective To evaluate the role of copy number abnormalities detectable using chromosomal microarray (CMA) testing in patients with epilepsy at a tertiary care center. Methods We identified patients with International Classification of Diseases, ninth revision (ICD-9) codes for epilepsy or seizures and clinical CMA testing performed between October 2006 and February 2011 at Boston Children's Hospital. We reviewed medical records and included patients who met criteria for epilepsy. We phenotypically characterized patients with epilepsy-associated abnormalities on CMA. Results Of 973 patients who had CMA and ICD-9 codes for epilepsy or seizures, 805 patients satisfied criteria for epilepsy. We observed 437 copy number variants (CNVs) in 323 patients (1-4 per patient), including 185 (42%) deletions and 252 (58%) duplications. Forty (9%) were confirmed de novo, 186 (43%) were inherited, and parental data were unavailable for 211 (48%). Excluding full chromosome trisomies, CNV size ranged from 18kb to 142Mb, and 34% were >500kb. In at least 40 cases (5%), the epilepsy phenotype was explained by a CNV, including 29 patients with epilepsy-associated syndromes and 11 with likely disease-associated CNVs involving epilepsy genes or "hotspots." We observed numerous recurrent CNVs including 10 involving loss or gain of Xp22.31, a region described in patients with and without epilepsy. Interpretation Copy number abnormalities play an important role in patients with epilepsy. Because the diagnostic yield of CMA for epilepsy patients is similar to the yield in autism spectrum disorders and in prenatal diagnosis, for which published guidelines recommend testing with CMA, we recommend the implementation of CMA in the evaluation of unexplained epilepsy. Ann Neurol 2014;75:943-958

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