Critical regions for human brain development include SON and ITSN1 defined by a panel with chromosome 21 interstitial deletions.

Aneuploidies of chromosome 21 (CHR21), including Down syndrome and partial monosomy 21, are major causes of mental retardation and provide unique opportunities to identify candidate genes regulating human brain development. We identified 10 individuals with partial CHR21 deletions and defined molecular breakpoints with high resolution genomic arrays, FISH (fluorescence in situ hybridization) and quantitative Southern blots. Patient records and neuroimaging generated by the authors or by referring physicians were reviewed. We defined regions from proximal to distal on CHR21, a region consistent with a normal range of cognition, a region associated with microcephaly, and a third region associated with polymicrogyria and partial agenesis of the corpus callosum. Three individuals with severe cortical dysgenesis including polymicrogyria (PMG) with callosal hypoplasia or agenesis shared a ~649 kb minimal region at 21q22.11-22.2 whose distal border lies within ITSN1 and contains SON. Seven individuals with large proximal deletions outside this interval, had mild cognitive deficits and did not share this phenotype. Comparison of the human phenotypes with those seen with loss-of function mutations in SON or ITSN1 indicate that the 649kb deleted region disturbs vertebrate brain development with components likely attributable to ITSN1 and SON.