Further characterization of NFIB‐associated phenotypes: Report of two new individuals

Abstract

Nuclear Factor I B (NFIB) haploinsufficiency has recently been identified as a cause of intellectual disability (ID) and macrocephaly. Here we report on two new individuals carrying a microdeletion in the chromosomal region 9p23-p22.3 containing NFIB. The first is a 7-year 9-month old boy with developmental delays, ID, definite facial anoma-

Marked intrafamilial variability of clinical and neuroimaging manifestations in NFIB‐related developmental disorder

“…In humans, among the 23 postnatally diagnosed patients with pathogenic NFIB variants (from 19 families), the degree of clinical severity appears to be quite variable; no clear genotype–phenotype correlations have been observed so far, although Schanze et al proposed that individuals with larger deletions including additional genes tended to have more marked facial dysmorphisms and less pronounced macrocephaly (Schanze et al, 2018). Variants were found to have arisen apparently de novo in 12 individuals, while they were inherited from a reportedly symptomatic parent in three unrelated children: a boy with mild intellectual disability and a girl with similar cognitive impairment and macrocephaly whose carrier mothers showed overlapping phenotypes, and a third boy with facial dysmorphisms, borderline cognitive level, brain and spinal cord anomalies and minor heart defects who inherited the gene deletion from his similarly dysmorphic mother also presenting mild intellectual disability and some brain abnormalities (Marinella et al, 2022; Schanze et al, 2018).…”

“… a Barrus et al (2020), Marinella et al (2022), Rao & Goel (2020), Schanze et al (2018), and Zenker et al (2019). …”

“…Corpus callosum anomalies were the commonest defect, being detected in two‐thirds (4 patients out 12 with agenesis and the rest with hypoplasia or dysmorphisms); other rarer unspecific abnormalities included ventricular enlargement, white matter abnormalities and arachnoid cysts. Up to now, only two children have been reported with few periventricular heterotopic nodules, associated with perisylvian cortical dysplasia in one (Marinella et al, 2022; Schanze et al, 2018). Our proband also presented some periventricular nodular heterotopias and bilateral dysplasia of the insular cortex.…”

“…A range of structural brain anomalies can be present, mainly involving the corpus callosum. Moreover, small heterotopic nodules lining the wall of the frontal horns of the lateral ventricles have been reported in two unrelated patients, associated with thickening of the posterior perisylvian cortex in one (Marinella et al, 2022; Schanze et al, 2018). Yet, no cerebellar defects have been detected to date.…”

“…Heterozygous NFIB molecular defects have recently been associated with human developmental disorders; overall, 23 individuals from 19 unrelated families have been reported, including 13 patients harboring microdeletions of chromosomal region 9p23‐p22.2 and 10 with truncating or missense single nucleotide variants causing inactivation of the NFIB protein (Barrus et al, 2020; Marinella et al, 2022; Rao & Goel, 2020; Schanze et al, 2018). The NFIB‐related phenotype includes developmental delay and mild‐to‐moderate ID, macrocephaly and nonspecific facial dysmorphisms [MIM 618286].…”