title: A novel splicing mutation in KCNQ2 in a multigenerational family with BFNC followed for 25 years.
abstract: OBJECTIVE
  A large multigenerational family with benign familial neonatal convulsions (BFNC) was revisited to identify the disease-causing mutation and to assess long-term outcome.
  
  
  METHODS
  We supplemented the original data with recent clinical and neurophysiologic data on patients and first-degree relatives, including information on seizure recurrence. We conducted linkage analysis at the EBN1 and EBN2 loci, followed by mutation analysis of KCNQ2. We evaluated the qualitative effect of the KCNQ2 mutation at the messenger RNA (mRNA) level by using reverse-transcribed total RNA isolated from leukocytes.
  
  
  RESULTS
  Thirteen relatives had a history of neonatal convulsions, 11 of whom showed remission within 2 months. One patient showed an atypical course of neonatal convulsions, developing photosensitive myoclonic epilepsy at age 13 years. We found suggestive linkage of the BFNC phenotype to the 20q13-EBN1 locus (lod score, 2.03) and an intronic mutation IVS14-6 C>A in KCNQ2 segregating with the trait in all affected members, but absent in 100 unrelated control subjects. This mutation creates a new, preferentially used, splice site. Alternative splicing adds 4 nt containing a premature stop codon to the transcript, resulting in a truncated protein after position R588.
  
  
  CONCLUSIONS
  We detected and characterized a novel splicing mutation in the brain-specific KCNQ2 gene by using easily accessible blood leukocytes. Aberrant splicing cosegregates with BFNC but not with photosensitivity.
authors: Epilepsy Institute of The Netherlands, Heemstede, Netherlands.
authors: Gerrit-Jan
authors: GJ
authors: de Haan
authors: Dalila
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authors: Pinto
authors: Dietbrandt
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authors: Carton
authors: Adri
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authors: Bader
authors: Jorien
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authors: Witte
authors: Edith
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authors: Peters
authors: Gerard
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authors: van Erp
authors: Willem
authors: W
authors: Vandereyken
authors: Eduard
authors: E
authors: Boezeman
authors: Martin C
authors: MC
authors: Wapenaar
authors: Paul
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authors: Boon
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authors: Halley
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authors: Koeleman
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authors: Lindhout