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 Jr; Sidney M Gospe Jr

doi:10.1212/WNL.0000000000001883

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

Neurology. 2015 Sep 1;85(9):756-62. doi: 10.1212/WNL.0000000000001883. Epub 2015 Jul 29.

Affiliations

¹ From the Department of Pediatrics, Division of Genetic Medicine (H.C.M., M.Z., E.G., J.C.), and the Departments of Neurology and Pediatrics, Division of Pediatric Neurology (S.M.G.), University of Washington, Seattle; the Division of Genetic Medicine (H.C.M.), Seattle Children's Hospital, WA; the Centre for Translational Omics, Genetics, and Genomic Medicine (P.T.C., P.B.M.), UCL Institute of Child Health, London, UK; the Department of Pediatrics (K.P., B.P.), Division of Child Neurology, University Hospital Graz, Austria; the Division of Child Neurology (B.P.), University Children's Hospital Zurich, University of Zurich, Switzerland; the Departments of Pediatrics and Neurology (D.R.N.), Northwestern University Feinberg School of Medicine, Evanston, IL; the Departments of Pediatrics and Neurology (D.R.N.), Ann & Robert H. Lurie Children's Hospital of Chicago, IL; and the Departments of Neurology and Pediatrics, Division of Pediatric Neurology (S.M.G.), Seattle Children's Hospital, WA. [email protected] [email protected].
² From the Department of Pediatrics, Division of Genetic Medicine (H.C.M., M.Z., E.G., J.C.), and the Departments of Neurology and Pediatrics, Division of Pediatric Neurology (S.M.G.), University of Washington, Seattle; the Division of Genetic Medicine (H.C.M.), Seattle Children's Hospital, WA; the Centre for Translational Omics, Genetics, and Genomic Medicine (P.T.C., P.B.M.), UCL Institute of Child Health, London, UK; the Department of Pediatrics (K.P., B.P.), Division of Child Neurology, University Hospital Graz, Austria; the Division of Child Neurology (B.P.), University Children's Hospital Zurich, University of Zurich, Switzerland; the Departments of Pediatrics and Neurology (D.R.N.), Northwestern University Feinberg School of Medicine, Evanston, IL; the Departments of Pediatrics and Neurology (D.R.N.), Ann & Robert H. Lurie Children's Hospital of Chicago, IL; and the Departments of Neurology and Pediatrics, Division of Pediatric Neurology (S.M.G.), Seattle Children's Hospital, WA.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Aldehyde Dehydrogenase / genetics*
Comparative Genomic Hybridization
Epilepsy / genetics*
Humans
Oligonucleotide Array Sequence Analysis / methods
Sequence Deletion*

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

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