Submission Details

Autosomal dominant

09/25/2020

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.

26021864 15632069 30388402 30315573