title: Elaborating the phenotypic spectrum associated with mutations in ARFGEF2: case study and literature review.
abstract: BACKGROUND
  The BIG2 protein, coded by ARFGEF2 indirectly assists neuronal proliferation and migration during cortical development. Mutations in ARFGEF2 have been reported as a rare cause of periventricular heterotopia.
  
  
  METHODS
  The presence of periventricular heterotopia, acquired microcephaly and suspected recessive inheritance led to mutation analysis of ARFGEF2 in two affected siblings and their healthy consanguineous parents, after mutations in FLNA had been ruled out.
  
  
  RESULTS
  A homozygous c.242_249delins7 (p.Pro81fs) mutation in exon 3 of ARFGEF2 was identified in the siblings. The alteration is a combination of 2 missense mutations (c.242C > A and c.247G > T) and a frameshift mutation (c.249delA) resulting in a premature stop codon. The clinical phenotype was characterized by dystonic quadriplegia, marked developmental delay, obstructive cardiomyopathy, recurrent infections and feeding difficulties. Degenerative features included early regression, acquired microcephaly and cerebral atrophy. Brain MRI revealed bilateral periventricular heterotopia, small corpus callosum, cerebral and hippocampal atrophy and hyperintensity in the putamen.
  
  
  CONCLUSIONS
  Mutations in ARFGEF2 can be anticipated based on characteristic clinical and imaging features.
authors.affiliation: Centre for Medical Genetics, UZ Brussel, Brussels, Belgium.
authors.forename: Ibrahim
authors.initials: I
authors.lastname: Tanyalçin
authors.forename: Helene
authors.initials: H
authors.lastname: Verhelst
authors.forename: Dicky J J
authors.initials: DJ
authors.lastname: Halley
authors.forename: Tim
authors.initials: T
authors.lastname: Vanderhasselt
authors.forename: Laurent
authors.initials: L
authors.lastname: Villard
authors.forename: Cyril
authors.initials: C
authors.lastname: Goizet
authors.forename: Willy
authors.initials: W
authors.lastname: Lissens
authors.forename: Grazia M
authors.initials: GM
authors.lastname: Mancini
authors.forename: Anna C
authors.initials: AC
authors.lastname: Jansen
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology; D004252:DNA Mutational Analysis; D005192:Family Health; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics*; D006801:Humans; D007223:Infant; D008279:Magnetic Resonance Imaging; D008297:Male; D020125:Mutation, Missense / Q000235:genetics*; D054091:Periventricular Nodular Heterotopia / Q000235:genetics*; D010641:Phenotype
chemical_list: C119088:ARFGEF2 protein, human; D020662:Guanine Nucleotide Exchange Factors
keywords: ARFGEF2; BIG2 protein; Dystonia; Microcephaly; Periventricular nodular heterotopia