NFIB Haploinsufficiency Is Associated with Intellectual Disability and Macrocephaly

Area of Science:

• Genetics
• Neuroscience
• Developmental Biology

Background:

• The nuclear factor I (NFI) family, including NFIA and NFIX, are known to influence brain development and are associated with intellectual disability (ID).
• NFIB, another NFI family member, had not previously been linked to human disease.
• Understanding the role of NFIB in neurodevelopment is crucial for identifying new genetic causes of ID.

Purpose of the Study:

• To investigate the role of NFIB in human neurodevelopmental disorders.
• To identify the genetic basis and phenotypic spectrum associated with NFIB haploinsufficiency.
• To explore the functional consequences of NFIB disruption on brain structure using a mouse model.

Main Methods:

• Clinical evaluation of 18 individuals with mild ID and behavioral issues.
• Genetic analysis including microdeletions and sequence variations (point mutations, single-nucleotide variations) in NFIB.
• In vitro reporter assay to determine protein activity of NFIB variants.
• Phenotypic characterization including neuroimaging and histology in a cortex-specific Nfib conditional knockout mouse model.

Main Results:

• Identified 18 individuals with NFIB haploinsufficiency, presenting with mild ID, behavioral issues, and variable neurodevelopmental phenotypes.
• Common phenotypes included muscular hypotonia, motor and speech delay, attention deficit disorder, autism spectrum disorder, and macrocephaly.
• Nfib conditional knockout mice exhibited cerebral cortex enlargement without significant disruption to overall brain structure or connectivity.

Conclusions:

• NFIB haploinsufficiency is a newly identified cause of mild intellectual disability and associated neurodevelopmental phenotypes in humans.
• Macrocephaly is a frequent clinical feature associated with NFIB disruption.
• NFIB plays a critical role in regulating brain size, particularly cerebral cortex development.