The expanding spectrum of NFIB‐associated phenotypes in a diverse patient population—A report of two new patients

Abstract

NFIB (Nuclear Factor I B) haploinsufficiency has recently been identified as a cause of intellectual disability and macrocephaly. Here we describe two patients with pathogenic variants in NFIB. The first is a 6-year-old Latino male with developmental delays, mild hypotonia, facial anomalies, and brain magnetic resonance imaging findings comprising mild thinning of the corpus callosum, with more marked thinning of the splenium and blunting of the rostrum and cavum septum pellucidum. Exome sequencing identified a previously described de novo variant in NFIB, c.265C>T, predicting p.Arg89Ter. The second is a 5-year-old Latino male with developmental delays, hypotonia, dysmorphic features, a preauricular tag and pit, a small ventricular septal defect, and brain magnetic resonance imaging findings including a dysmorphic corpus callosum and a small posterior fossa. A single nucleotide polymorphism microarray identified a 92 kb interstitial deletion at 9p23 including several exons of NFIB and no other known genes. Our two patients add to the knowledge of this rare condition through our addition of new brain MRI findings and dysmorphic features. Additionally, these are the first known Latino patients to be described with NFIB haploinsufficiency, expanding our understanding of the associated facial features in diverse populations. Further data are needed to determine genotype-phenotype relationships for NFIB.

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

“…Contrary to what previously observed, our proband did not have macrocephaly and showed poor growth (Schanze et al, 2018 ). Both had a dysmorphic corpus callosum and small arachnoid cysts, consistent with previously reported MRI findings (Barrus et al, 2020 ; Schanze et al, 2018 ). The periventricular nodular heterotopias (PNH) along the frontal horns of the lateral ventricles observed in Proband 1 appear to be very similar to those found in Patient 7 described by Schanze et al ( 2018 ).…”

“…Her weight was 61 kg (50-75th centile), height Contrary to what previously observed, our proband did not have macrocephaly and showed poor growth (Schanze et al, 2018). Both had a dysmorphic corpus callosum and small arachnoid cysts, consistent with previously reported MRI findings (Barrus et al, 2020;Schanze et al, 2018). The periventricular nodular heterotopias (PNH)…”

“…Recently, haploinsufficiency of NFIB (caused by either deletions of 9p23-p22.2 or NFIB sequence variations), has been shown to cause ID with macrocephaly, along with motor delay, hypotonia, behavioral abnormalities, and variable structural brain anomalies mainly involving the corpus callosum (Barrus et al, 2020;Schanze et al, 2018).…”

“…NFIX duplication has also been observed in a few individuals presenting ID, short stature, small head circumference, and minor dysmorphic features (Dolan et al, 2010 ; Trimouille et al, 2018 ). Recently, haploinsufficiency of NFIB (caused by either deletions of 9p23‐p22.2 or NFIB sequence variations), has been shown to cause ID with macrocephaly, along with motor delay, hypotonia, behavioral abnormalities, and variable structural brain anomalies mainly involving the corpus callosum (Barrus et al, 2020 ; Schanze et al, 2018 ).…”

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

“…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].…”