NFIB Haploinsufficiency Is Associated with Intellectual Disability and Macrocephaly

Ina Schanze, Jens Bunt, Jonathan W.C. Lim, Denny Schanze, Ryan J. Dean, Marielle Alders, Patricia Blanchet, Tania Attié-Bitach, Siren Berland, Steven Boogert, Sangamitra Boppudi, Caitlin J. Bridges, Megan T. Cho, William B. Dobyns, Dian Donnai, Jessica Douglas, Dawn L. Earl, Timothy J. Edwards, Laurence Faivre, Brieana FregeauDavid Genevieve, Marion Gérard, Vincent Gatinois, Muriel Holder-Espinasse, Samuel F. Huth, Kosuke Izumi, Bronwyn Kerr, Elodie Lacaze, Phillis Lakeman, Sonal Mahida, Ghayda M. Mirzaa, Sian M. Morgan, Catherine Nowak, Hilde Peeters, Florence Petit, Daniela T. Pilz, Jacques Puechberty, Eyal Reinstein, Jean Baptiste Rivière, Avni B. Santani, Anouck Schneider, Elliott H. Sherr, Constance Smith-Hicks, Ilse Wieland, Elaine Zackai, Xiaonan Zhao, Richard M. Gronostajski, Martin Zenker, Linda J. Richards

Research output: Contribution to journalArticlepeer-review

9 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)752-768
Number of pages17
JournalAmerican journal of human genetics
Issue number5
StatePublished - Nov 1 2018


  • NFIB
  • agenesis of the corpus callosum
  • chromosome 9p22.3
  • chromosome 9p23
  • developmental delay
  • haploinsufficiency
  • intellectual disability
  • macrocephaly
  • megalencephaly
  • nuclear factor I

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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