NFIB haploinsufficiency is associated with intellectual disability and macrocephaly

2018
The nuclear factor I(NFI) family of transcription factors play an important role in normal development of multiple organs. Three NFI family members are highly expressed in the brain, and deletions or sequence variants in two of these, NFIAand NFIX, have been associated with intellectual disability (ID) and brain malformations. NFIB, however, has not previously been implicated in human disease. Here, we present a cohort of 18 individuals with mild ID and behavioral issues who are haploinsufficientfor NFIB. Ten individuals harbored overlapping microdeletions of the chromosomal 9p23-p22.2 region, ranging in size from 225 kb to 4.3 Mb. Five additional subjects had point sequence variations creating a premature termination codon, and three subjects harbored single-nucleotide variations resulting in an inactive protein as determined using an in vitro reporter assay. All individuals presented with additional variable neurodevelopmental phenotypes, including muscular hypotonia, motor and speech delay, attention deficit disorder, autism spectrum disorder, and behavioral abnormalities. While structural brain anomalies, including dysgenesisof corpus callosum, were variable, individuals most frequently presented with macrocephaly. To determine whether macrocephalycould be a functional consequence of NFIBdisruption, we analyzed a cortex-specific Nfibconditional knockout mousemodel, which is postnatally viable. Utilizing magnetic resonance imaging and histology, we demonstrate that Nfibconditional knockout mice have enlargement of the cerebral cortex but preservation of overall brain structure and interhemispheric connectivity. Based on our findings, we propose that haploinsufficiencyof NFIBcauses ID with macrocephaly.
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