Chromosomal microarray mapping suggests a role for BSX and Neurogranin in neurocognitive and behavioral defects in the 11q terminal deletion disorder (Jacobsen syndrome)

We performed a prospective analysis on 14 11q- patients to determine the relationship between the degree of cognitive impairment and relative deletion size. Seventeen measures of cognitive function were assessed. All nine patients with a deletion of at least 12.1 Mb had severe global cognitive impairment, with full-scale IQ <50, whereas all five patients with smaller deletions, ≤11.8 Mb, demonstrated mild cognitive impairment, with a full-scale IQ of 63 or higher (p < 0.001). Among these five patients, the two patients with the larger deletions (11.4, 11.8 Mb) had a selective impairment in freedom from distractability compared to the three patients with smaller deletions (≤9.1 Mb). We propose the presence of a proximal critical region that contains a gene for global cognitive function and a distal critical region that contains a gene essential for auditory attention, which may be necessary for optimizing intellectual function. The proximal critical region is 300 kb and contains three annotated genes. One of these genes, BSX, encodes a brain-specific homeobox protein that in gene-targeted mice has been shown previously to have a role in regulating locomotory behavior via BSX-expressing neurons in the hypothalamus. The distal critical region, ∼2.2 Mb, contains 18 annotated genes. One gene in this region, Neurogranin, has been demonstrated previously in mice to be critical for synapse plasticity and long-term potentiation. Taken together, our results implicate the presence of at least two loci in distal 11q that when deleted, cause global and selective deficits in neurocognitive function. These findings have important implications for genetic counseling and potential gene-specific therapies.