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).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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