NFIB

Inheritance Pattern: AD

Disease ID:MONDO:0032658

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0032658

Submitter: Illumina

The NFIB gene is located on chromosome 9 at 9p23-p22.3 and encodes nuclear factor 1 B, a transcription factor that regulates adenovirus DNA replication and transcription throughout mammalian development. It has been specifically implicated in brain and lung development. NFIB was first reported in association with autosomal dominant acquired macrocephaly with impaired intellectual development in 2018 (30388402: Schanze et al. 2018). In addition to the primary features of intellectual disability and macrocephaly, additional features include motor and speech delay, behavioral abnormalities, corpus callosum abnormalities, seizures, hypotonia, genital anomalies, and other brain malformations. Variants in this gene have been reported in at least eight indviduals from two publications, including four predicted null and four missense variants (30388402: Schanze et al. 2018; 30315573: Kahrizi et al. 2019). Six of the variants occurred de novo, while one was identified in an affected parent-child pair. The maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease is haploinsufficiency. This gene-disease relationship is also supported by high expression in developing the brain, particularly in the cortical plate; a shared function as a transcriptional regulator that is shared with members of the same protein family that result in similar, overlapping phenotypes (e.g., NFIX, NFIA); and partial recapitulation of the human phenotype, including macrocephaly and callosal and other brain defects, in conventional and telencephalon-specific knockout mice (15632069: Steele-Perkins et al. 2005; 26021864: Bunt et al. 2015; 30388402: Schanze et al. 2018). In addition, in vitro analyses of patient-identified missense variants demonstrated disrupted transcriptional regulation in a luciferase assay (Schanze et al. 2018). In summary, there is strong evidence to support the relationship between NFIB and acquired macrocephaly with impaired intellectual development, autosomal dominant. Additional reports in humans published three years since the first proposal of the association are needed to reach a definitive classification.

Inheritance Pattern: AD

Disease ID:MONDO:0032658

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0032658

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0800439

Submitter: ClinGen

*NFIB* was first reported in connection with autosomal dominant (AD) syndromic complex neurodevelopmental disorder in 2018 (Schanze et al., 2018 PMID: 30388402). Affected individuals share a tetrad of potentially recognizable features: neurodevelopmental disorder(mild-to-moderate ID and/or autism spectrum disorder); craniofacial dysmorphisms (such as facial asymmetry, broad forehead, sparse eyebrows, short and/or down-slanting palpebral fissures, and midface hypoplasia); macrocephaly; and corpus callosum anomalies (PMID:36756855). Additional features may include lung and heart defects. Eleven variants, 7 of which were *de novo* (4 nonsense, 3 microdeletions, 4 missense), reported in 2 publications are included in this curation (PMIDs: 30388402, 36756855). Molecular mechanism of pathogenicity is known to be loss-of-function whereby heterozygous *NFIB* molecular defects cause inactivation of the protein (PMID:36756855). The maximum score for genetic evidence (12 pts.) has been reached, however, more case-level data is available in literature (PMIDs: 32902921, 36321570, 33130023, 35433561). This gene-disease relationship is also supported by two mouse models (PMIDs: 30388402, 15632069). MRI and histology analysis on cortex-specific Nfib conditional knockout mice revealed enlargement of the cerebral cortex but preservation of overall brain structure and interhemispheric connectivity (PMID: 30388402). Furthermore, Nfib-deficient mice possess unique defects in lung maturation and exhibit callosal agenesis and forebrain defects (PMID:15632069). Loss of Nfib also results in defects in basilar pons formation and hippocampus development. Heterozygous Nfib-deficient animals exhibit callosal agenesis and delayed lung maturation, indicating haploinsufficiency at the Nfib locus. In summary, there is definitive evidence to support the relationship between *NFIB* and AD syndromic complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism GCEP on June 18th, 2024 (SOP Version 10).

Inheritance Pattern: AD

Disease ID:MONDO:0032658

Submitter: Ambry Genetics