Journal
NEUROLOGY
Volume 78, Issue 4, Pages 269-278Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1212/WNL.0b013e31824365e4
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Funding
- Nancy Lurie Marks family foundation
- Harvard-MIT Health Sciences and Technology and Beth Israel Deaconess Medical Center
- Pfizer, Inc.
- Merck and Co., Inc.
- NINDS [RO1 NS35129]
- Manton Center for Orphan Disease Research
- ISS [PRE 178/07 COR-F]
- SPARC from the Broad Institute of Harvard and Massachusetts Institute of Technology
- EU [LSH-2005-2.1.3-2]
- Nancy Lurie Marks Foundation
- BC Children's Hospital Foundation, Vancouver, Canada
- Biocodex
- Eisai Inc.
- Japanese Epilepsy Society
- Weill Cornell Medical College in Qatar
- Italian Ministry of Health
- European Community Sixth Framework Thematic Priority Life Sciences, Genomics and Biotechnology for Health
- Italian Ministry of Education, University and Research
- Tuscany Region
- Telethon Foundation
- Mariani Foundation
- Autism Consortium
- Merck Foundation
- McKnight Foundation
- Generation Health
- NIH (NINDS/NIMH)
- NLM Family Foundation
- Simons Foundation
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Objective: To identify copy number variant (CNV) causes of periventricular nodular heterotopia (PNH) in patients for whom FLNA sequencing is negative. Methods: Screening of 35 patients from 33 pedigrees on an Affymetrix 6.0 microarray led to the identification of one individual bearing a CNV that disrupted FLNA. FLNA-disrupting CNVs were also isolated in 2 other individuals by multiplex ligation probe amplification. These 3 cases were further characterized by high-resolution oligo array comparative genomic hybridization (CGH), and the precise junctional breakpoints of the rearrangements were identified by PCR amplification and sequencing. Results: We report 3 cases of PNH caused by nonrecurrent genomic rearrangements that disrupt one copy of FLNA. The first individual carried a 113-kb deletion that removes all but the first exon of FLNA. A second patient harbored a complex rearrangement including a deletion of the 3' end of FLNA accompanied by a partial duplication event. A third patient bore a 39-kb deletion encompassing all of FLNA and the neighboring gene EMD. High-resolution oligo array CGH of the FLNA locus suggests distinct molecular mechanisms for each of these rearrangements, and implicates nearby low copy repeats in their pathogenesis. Conclusions: These results demonstrate that FLNA is prone to pathogenic rearrangements, and highlight the importance of screening for CNVs in individuals with PNH lacking FLNA point mutations. Neurology (R) 2012;78:269-278
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