title: FLNA genomic rearrangements cause periventricular nodular heterotopia.
abstract: 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.
authors.affiliation: Harvard-MIT Division of Health Sciences and Technology, Boston, MA, USA.
authors.forename: K R
authors.initials: KR
authors.lastname: Clapham
authors.forename: T W
authors.initials: TW
authors.lastname: Yu
authors.forename: V S
authors.initials: VS
authors.lastname: Ganesh
authors.forename: B
authors.initials: B
authors.lastname: Barry
authors.forename: Y
authors.initials: Y
authors.lastname: Chan
authors.forename: D
authors.initials: D
authors.lastname: Mei
authors.forename: E
authors.initials: E
authors.lastname: Parrini
authors.forename: B
authors.initials: B
authors.lastname: Funalot
authors.forename: L
authors.initials: L
authors.lastname: Dupuis
authors.forename: M M
authors.initials: MM
authors.lastname: Nezarati
authors.forename: C
authors.initials: C
authors.lastname: du Souich
authors.forename: C
authors.initials: C
authors.lastname: van Karnebeek
authors.forename: R
authors.initials: R
authors.lastname: Guerrini
authors.forename: C A
authors.initials: CA
authors.lastname: Walsh
mesh_terms: D000328:Adult; D000927:Anticonvulsants / Q000627:therapeutic use; D056905:Chromosome Breakpoints; D003285:Contractile Proteins / Q000235:genetics*; D004247:DNA / Q000235:genetics; D056915:DNA Copy Number Variations; D004351:Drug Resistance; D005091:Exons / Q000235:genetics; D005260:Female; D064448:Filamins; D015321:Gene Rearrangement / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D046228:Microarray Analysis; D008840:Microfilament Proteins / Q000235:genetics*; D008875:Middle Aged; D009693:Nucleic Acid Hybridization; D010375:Pedigree; D054091:Periventricular Nodular Heterotopia / Q000235:genetics*; D017354:Point Mutation / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011247:Pregnancy; D060888:Real-Time Polymerase Chain Reaction; D012640:Seizures / Q000209:etiology / Q000235:genetics
chemical_list: D000927:Anticonvulsants; D003285:Contractile Proteins; D064448:Filamins; D008840:Microfilament Proteins; D004247:DNA