Disruption of human neural precursor proliferation can give rise to a small brain (microcephaly), and failure of neurons to migrate properly can lead to an abnormal arrest of cerebral cortical neurons in proliferative zones near the lateral ventricles (periventricular heterotopia). Here we show that an autosomal recessive condition characterized by microcephaly and periventricular heterotopia 1 maps to chromosome 20 and is caused by mutations in the gene ADP-ribosylation factor guanine nucleotide-exchange factor-2 (ARFGEF2). By northernblot analysis, we found that mouse Arfgef2 mRNA levels are highest during embryonic periods of ongoing neuronal proliferation and migration, and by in situ hybridization, we found that the mRNA is widely distributed throughout the embryonic central nervous system (CNS). ARFGEF2 encodes the large (>200 kDa) brefeldin A (BFA)-inhibited GEF2 protein (BIG2), which is required for vesicle and membrane trafficking from the trans-Golgi network (TGN). Inhibition of BIG2 by BFA, or by a dominant negative ARFGEF2 cDNA, decreases cell proliferation in vitro, suggesting a cell-autonomous regulation of neural expansion. Inhibition of BIG2 also disturbed the intracellular localization of such molecules as E-cadherin and β-catenin by preventing their transport from the Golgi apparatus to the cell surface. Our findings show that vesicle trafficking is an important regulator of proliferation and migration during human cerebral cortical development.Autosomal recessive periventricular heterotopia with microcephaly (ARPHM) is a severe malformation of the cerebral cortex, characterized by severe developmental delay and recurrent infections 1 . No anomalies extrinsic to the CNS, such as dysmorphic features or grossly abnormal endocrine or other conditions, have been observed in individuals with ARPHM. Magnetic resonance imaging of the brains of affected individuals shows notable periventricular heterotopia, resulting from the failure of neurons to migrate normally from the lateral ventricular proliferative zone, where they are formed, to the cerebral cortex ( Fig. 1a-d). Abnormal magnetic resonance image signals in subcortical white matter and elsewhere also suggest a delay in the normal myelination by glial cells.An initial genome-wide screen at 10-cM intervals of two Turkish families with ARPHM identified shared homozygosity at a single locus on chromosome 20q11.21-13.2, which we refined by further marker analysis (Fig. 1e,f). Because the two families had indistinguishable clinical and radiographic features, we assumed that they had an allelic disorder and summed their linkage results. The ARPHM region (66.16-77.75 cM on chromosome 20) that was identical by descent in each of the two families yielded a summed multipoint lod score of 4.41 (Fig. 1g). Two-point analyses gave combined maximal lod scores of 3.28 (pedigree 1 = 1.53 and pedigree 2 = 1.75) at marker D20S109 (Fig. 1h).We sequenced several candidate genes in the minimal linked region and found a different deleterious mutation in ARFGEF2 (encod...