Intragenic deletions of ALDH7A1 in pyridoxine-dependent epilepsy caused by Alu-Alu recombination

Heather C. Mefford; Matthew Zemel; Eileen Geraghty; Joseph Cook; Peter T. Clayton; Karl Paul; Barbara Plecko; Philippa B. Mills; Douglas R. Nordli; Sidney M. Gospe

doi:10.1212/WNL.0000000000001883

Intragenic deletions of ALDH7A1 in pyridoxine-dependent epilepsy caused by Alu-Alu recombination

Heather C. Mefford^*, Matthew Zemel, Eileen Geraghty, Joseph Cook, Peter T. Clayton, Karl Paul, Barbara Plecko, Philippa B. Mills, Douglas R. Nordli, Sidney M. Gospe

^*Corresponding author for this work

Pediatrics

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16 Scopus citations

Abstract

Objective: To investigate the role of intragenic deletions of ALDH7A1 in patients with clinical and biochemical evidence of pyridoxine-dependent epilepsy but only a single identifiable mutation in ALDH7A1. Methods: We designed a custom oligonucleotide array with high-density probe coverage across the ALDH7A1 gene. We performed array comparative genomic hybridization in 6 patients with clinical and biochemical evidence of pyridoxine-dependent epilepsy but only a single detectable mutation in ALDH7A1 by sequence analysis. Results: We found partial deletions of ALDH7A1 in 5 of 6 patients. Breakpoint analysis reveals that the deletions are likely a result of Alu-Alu recombination in all cases. The density of Alu elements within introns of ALDH7A1 suggests susceptibility to recurrent rearrangement. Conclusion: Patients with clinical pyridoxine-dependent epilepsy and a single identifiable mutation in ALDH7A1 warrant further investigation for copy number changes involving the ALHD7A1 gene.

Original language	English (US)
Pages (from-to)	756-762
Number of pages	7
Journal	Neurology
Volume	85
Issue number	9
DOIs	https://doi.org/10.1212/WNL.0000000000001883
State	Published - Sep 1 2015

ASJC Scopus subject areas

Clinical Neurology

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@article{abd64e1880b64ba89576556c6e528ec1,

title = "Intragenic deletions of ALDH7A1 in pyridoxine-dependent epilepsy caused by Alu-Alu recombination",

abstract = "Objective: To investigate the role of intragenic deletions of ALDH7A1 in patients with clinical and biochemical evidence of pyridoxine-dependent epilepsy but only a single identifiable mutation in ALDH7A1. Methods: We designed a custom oligonucleotide array with high-density probe coverage across the ALDH7A1 gene. We performed array comparative genomic hybridization in 6 patients with clinical and biochemical evidence of pyridoxine-dependent epilepsy but only a single detectable mutation in ALDH7A1 by sequence analysis. Results: We found partial deletions of ALDH7A1 in 5 of 6 patients. Breakpoint analysis reveals that the deletions are likely a result of Alu-Alu recombination in all cases. The density of Alu elements within introns of ALDH7A1 suggests susceptibility to recurrent rearrangement. Conclusion: Patients with clinical pyridoxine-dependent epilepsy and a single identifiable mutation in ALDH7A1 warrant further investigation for copy number changes involving the ALHD7A1 gene.",

author = "Mefford, {Heather C.} and Matthew Zemel and Eileen Geraghty and Joseph Cook and Clayton, {Peter T.} and Karl Paul and Barbara Plecko and Mills, {Philippa B.} and Nordli, {Douglas R.} and Gospe, {Sidney M.}",

note = "Funding Information: Supported by the research endowments of the Division of Pediatric Neurology, University of Washington and Seattle Children{\textquoteright}s Hospital. H.C.M. is supported by a Career Award for Medical Scientists from the Burroughs Wellcome Fund and the NIH (National Institute of Neurological Disorders and Stroke R01 NS069605). P.T.C. and P.B.M. were supported by funding from the Wellcome Trust and from Great Ormond Street Children{\textquoteright}s Charity. This work was also supported by the UW Intellectual and Developmental Disabilities Research Center Genetics Core (NIH U54HD083091). The authors report no disclosures relevant to the manuscript document. Go to Neurology.org for full disclosures.",

year = "2015",

month = sep,

day = "1",

doi = "10.1212/WNL.0000000000001883",

language = "English (US)",

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Intragenic deletions of ALDH7A1 in pyridoxine-dependent epilepsy caused by Alu-Alu recombination. / Mefford, Heather C.; Zemel, Matthew; Geraghty, Eileen; Cook, Joseph; Clayton, Peter T.; Paul, Karl; Plecko, Barbara; Mills, Philippa B.; Nordli, Douglas R.; Gospe, Sidney M.

In: Neurology, Vol. 85, No. 9, 01.09.2015, p. 756-762.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Intragenic deletions of ALDH7A1 in pyridoxine-dependent epilepsy caused by Alu-Alu recombination

AU - Mefford, Heather C.

AU - Zemel, Matthew

AU - Geraghty, Eileen

AU - Cook, Joseph

AU - Clayton, Peter T.

AU - Paul, Karl

AU - Plecko, Barbara

AU - Mills, Philippa B.

AU - Nordli, Douglas R.

AU - Gospe, Sidney M.

N1 - Funding Information: Supported by the research endowments of the Division of Pediatric Neurology, University of Washington and Seattle Children’s Hospital. H.C.M. is supported by a Career Award for Medical Scientists from the Burroughs Wellcome Fund and the NIH (National Institute of Neurological Disorders and Stroke R01 NS069605). P.T.C. and P.B.M. were supported by funding from the Wellcome Trust and from Great Ormond Street Children’s Charity. This work was also supported by the UW Intellectual and Developmental Disabilities Research Center Genetics Core (NIH U54HD083091). The authors report no disclosures relevant to the manuscript document. Go to Neurology.org for full disclosures.

PY - 2015/9/1

Y1 - 2015/9/1

N2 - Objective: To investigate the role of intragenic deletions of ALDH7A1 in patients with clinical and biochemical evidence of pyridoxine-dependent epilepsy but only a single identifiable mutation in ALDH7A1. Methods: We designed a custom oligonucleotide array with high-density probe coverage across the ALDH7A1 gene. We performed array comparative genomic hybridization in 6 patients with clinical and biochemical evidence of pyridoxine-dependent epilepsy but only a single detectable mutation in ALDH7A1 by sequence analysis. Results: We found partial deletions of ALDH7A1 in 5 of 6 patients. Breakpoint analysis reveals that the deletions are likely a result of Alu-Alu recombination in all cases. The density of Alu elements within introns of ALDH7A1 suggests susceptibility to recurrent rearrangement. Conclusion: Patients with clinical pyridoxine-dependent epilepsy and a single identifiable mutation in ALDH7A1 warrant further investigation for copy number changes involving the ALHD7A1 gene.

AB - Objective: To investigate the role of intragenic deletions of ALDH7A1 in patients with clinical and biochemical evidence of pyridoxine-dependent epilepsy but only a single identifiable mutation in ALDH7A1. Methods: We designed a custom oligonucleotide array with high-density probe coverage across the ALDH7A1 gene. We performed array comparative genomic hybridization in 6 patients with clinical and biochemical evidence of pyridoxine-dependent epilepsy but only a single detectable mutation in ALDH7A1 by sequence analysis. Results: We found partial deletions of ALDH7A1 in 5 of 6 patients. Breakpoint analysis reveals that the deletions are likely a result of Alu-Alu recombination in all cases. The density of Alu elements within introns of ALDH7A1 suggests susceptibility to recurrent rearrangement. Conclusion: Patients with clinical pyridoxine-dependent epilepsy and a single identifiable mutation in ALDH7A1 warrant further investigation for copy number changes involving the ALHD7A1 gene.

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JO - Neurology

JF - Neurology

SN - 0028-3878

IS - 9

ER -

Intragenic deletions of ALDH7A1 in pyridoxine-dependent epilepsy caused by Alu-Alu recombination

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