NFIB Haploinsufficiency Is Associated with Intellectual Disability and Macrocephaly

Abstract

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, NFIA and 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 haploinsufficient for 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 dysgenesis of corpus callosum, were variable, individuals most frequently presented with macrocephaly. To determine whether macrocephaly could be a functional consequence of NFIB disruption, we analyzed a cortex-specific Nfib conditional knockout mouse model, which is postnatally viable. Utilizing magnetic resonance imaging and histology, we demonstrate that Nfib conditional knockout mice have enlargement of the cerebral cortex but preservation of overall brain structure and interhemispheric connectivity. Based on our findings, we propose that haploinsufficiency of NFIB causes ID with macrocephaly.

The expanding spectrum of NFIB‐associated phenotypes in a diverse patient population—A report of two new patients

“…In 2018, Schanze and colleagues published a cohort of 18 individuals with pathogenic NFIB variants, including patients with microdeletions and single nucleotide variants (Schanze et al, 2018). They confirmed a causative role for this gene in a phenotype comprising macrocephaly (13/16; 81%), mild DD/ID or learning disability (18/18; 100%), agenesis or other abnormalities of the corpus callosum (5/11; 45%), and diverse dysmorphic features.…”

Postzygotic and germinalde novomutations in ASD: exploring their biological role

“…Three genes were associated in the PZM analysis done by TADA (q-value < 0.1; FRG1, KMT2C and NFIA). FRG1 has not been previously associated with NDDs while both, KMT2C and NFIA, have been previously reported as possible implicated in ASD/ID 44,45 .…”

DRAXIN regulates interhemispheric fissure remodelling to influence the extent of corpus callosum formation

“…All skulls (n = 112) initially underwent twodimensional scans measuring diffusion in the mediolateral direction to identify the commissural phenotype. From this analysis, a subset of brains of each of complete CCD (n = 10), partial CCD (n = 11) and full CC (n = 10) phenotypes were dissected from skulls, incubated for four days in 0.2% gadopentetate dimeglumine (Magnevist, Berlex Imaging, Wayne, NJ, USA), and scanned with a 16.4 Tesla Bruker Avance MRI scanner using a FLASH sequence that was described previously (Schanze et al, 2018): FLASH sequence (voxel size = 0.03 × 0.03 × 0.03 mm, MTX 654 × 380 × 280,FOV 19.6 × 11.4 × 8.4…”