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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.

SUBMITTER: Schanze I

PROVIDER: S-EPMC6218805 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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NFIB Haploinsufficiency Is Associated with Intellectual Disability and Macrocephaly.

Schanze Ina I Bunt Jens J Lim Jonathan W C JWC Schanze Denny D Dean Ryan J RJ Alders Marielle M Blanchet Patricia P Attié-Bitach Tania T Berland Siren S Boogert Steven S Boppudi Sangamitra S Bridges Caitlin J CJ Cho Megan T MT Dobyns William B WB Donnai Dian D Douglas Jessica J Earl Dawn L DL Edwards Timothy J TJ Faivre Laurence L Fregeau Brieana B Genevieve David D Gérard Marion M Gatinois Vincent V Holder-Espinasse Muriel M Huth Samuel F SF Izumi Kosuke K Kerr Bronwyn B Lacaze Elodie E Lakeman Phillis P Mahida Sonal S Mirzaa Ghayda M GM Morgan Sian M SM Nowak Catherine C Peeters Hilde H Petit Florence F Pilz Daniela T DT Puechberty Jacques J Reinstein Eyal E Rivière Jean-Baptiste JB Santani Avni B AB Schneider Anouck A Sherr Elliott H EH Smith-Hicks Constance C Wieland Ilse I Zackai Elaine E Zhao Xiaonan X Gronostajski Richard M RM Zenker Martin M Richards Linda J LJ

American journal of human genetics 20181101 5

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 haploinsuffici ...[more]

PMID: 30388402

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Project description:BACKGROUND: Nineteen patients with deletions in chromosome 6p22-p24 have been published so far. The syndromic phenotype is varied, and includes intellectual disability, behavioural abnormalities, dysmorphic features and structural organ defects. Heterogeneous deletion breakpoints and sizes (1-17 Mb) and overlapping phenotypes have made the identification of the disease causing genes challenging. We suggest JARID2 and ATXN1, both harbored in 6p22.3, as disease causing genes. METHODS AND RESULTS: We describe five unrelated patients with de novo deletions (0.1-4.8 Mb in size) in chromosome 6p22.3-p24.1 detected by aCGH in a cohort of approximately 3600 patients ascertained for neurodevelopmental disorders. Two patients (Patients 4 and 5) carried non-overlapping deletions that were encompassed by the deletions of the remaining three patients (Patients 1-3), indicating the existence of two distinct dosage sensitive genes responsible for impaired cognitive function in 6p22.3 deletion-patients. The smallest region of overlap (SRO I) in Patients 1-4 (189 kb) included the genes JARID2 and DTNBP1, while SRO II in Patients 1-3 and 5 (116 kb) contained GMPR and ATXN1. Patients with deletion of SRO I manifested variable degrees of cognitive impairment, gait disturbance and distinct, similar facial dysmorphic features (prominent supraorbital ridges, deep set eyes, dark infraorbital circles and midface hypoplasia) that might be ascribed to the haploinsufficiency of JARID2. Patients with deletion of SRO II showed intellectual disability and behavioural abnormalities, likely to be caused by the deletion of ATXN1. Patients 1-3 presented with lower cognitive function than Patients 4 and 5, possibly due to the concomitant haploinsufficiency of both ATXN1 and JARID2. The chromatin modifier genes ATXN1 and JARID2 are likely candidates contributing to the clinical phenotype in 6p22-p24 deletion-patients. Both genes exert their effect on the Notch signalling pathway, which plays an important role in several developmental processes. CONCLUSIONS: Patients carrying JARID2 deletion manifested with cognitive impairment, gait disturbance and a characteristic facial appearance, whereas patients with deletion of ATXN1 seemed to be characterized by intellectual disability and behavioural abnormalities. Due to the characteristic facial appearance, JARID2 haploinsufficiency might represent a clinically recognizable neurodevelopmental syndrome.

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NFIB Haploinsufficiency Is Associated with Intellectual Disability and Macrocephaly.

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NFIB Haploinsufficiency Is Associated with Intellectual Disability and Macrocephaly.

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