Elaborating the phenotypic spectrum associated with mutations in ARFGEF2: Case study and literature review

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.

Jaar van publicatie:2013

Trefwoorden:Microcephaly, Dystonia, periventricular nodular heterotopia, ARFGEF2, BIG2 protein