Missense mutations in the DNA-binding/dimerization domain of NFIX cause Sotos-like features

Abstract

Sotos syndrome is characterized by prenatal and postnatal overgrowth, characteristic craniofacial features and mental retardation. Haploinsufficiency of NSD1 causes Sotos syndrome. Recently, two microdeletions encompassing Nuclear Factor I-X (NFIX) and a nonsense mutation in NFIX have been found in three individuals with Sotos-like overgrowth features, suggesting possible involvements of NFIX abnormalities in Sotos-like features. Interestingly, seven frameshift and two splice site mutations in NFIX have also been found in nine individuals with Marshall-Smith syndrome. In this study, 48 individuals who were suspected as Sotos syndrome but showing no NSD1 abnormalities were examined for NFIX mutations by high-resolution melt analysis. We identified two heterozygous missense mutations in the DNA-binding/dimerization domain of the NFIX protein. Both mutations occurred at evolutionally conserved amino acids. The c.179T4C (p.Leu60Pro) mutation occurred de novo and the c.362G4C (p.Arg121Pro) mutation was inherited from possibly affected mother. Both mutations were absent in 250 healthy Japanese controls. Our study revealed that missense mutations in NFIX were able to cause Sotos-like features. Mutations in DNA-binding/dimerization domain of NFIX protein also suggest that the transcriptional regulation is abnormally fluctuated because of NFIX abnormalities. In individuals with Sotos-like features unrelated to NSD1 changes, genetic testing of NFIX should be considered.

Malan syndrome (Sotos syndrome 2) in two patients with 19p13.2 deletion encompassing NFIX gene and novel NFIX sequence variant

“…Links between NFIX gene disturbances and phenotype resembling Sotos syndrome were also verified shortly after by Yoneda et al who identified different heterozygous missense mutations in 2 patients negative for NSD1 mutation 11 . In 2012, Priolo et al found in frame deletion of NFIX gene in a patient with overgrowth and suspected a mild form of Marshall-Smith syndrome (i.a.…”

“…Descriptions of patients presented so far in the literature comprise several cases of chromosomal aberrations in 19p13.2/19p13.13 band reported by Lysy et al 1 , Dolan et al 2 , Malan et al 3 , Bassuk et al 4 , Wangensteen et al 5 , Natiq et al 6 , Schwemmle et al 7 , Klaassens et al 8 , Shimojima et al 9 and point mutations in NFIX gene (localized within 19p13.2) reported by Malan et al 3 , Klaassens et al 8 , Priolo et al 10 , Yoneda et al 11 in patients with Sotos-like and Marshall-Smith (MRSHSS) syndromes. Unfortunately, due to the limited number of these cases, no definitive conclusions about the genotype-phenotype correlations can be made.…”

Novel mutations of NFIX gene causing Marshall-Smith syndrome or Sotos-like syndrome: one gene, two phenotypes

“…Including the present study, a total of 20 NFIX point mutations have been reported so far (see Figure 2). All these mutations are unique, except for the first base of intron 6, mutated in three unrelated patients (2)(3)(4)(5).…”

“…In addition, some mutations in NFIX gene can cause a Sotoslike phenotype, in NSD1 mutation-negative patients, an overgrowth disorder with a less severe phenotype than MSS. So far only six different point mutations that cause Sotos-like syndrome and nine mutations resulting in MSS have been reported (2)(3)(4)(5). Consequently, the range of genetic variants in the NFIX gene that gives rise to these clinical entities is scarce.…”

Malan syndrome: Sotos-like overgrowth with de novo NFIX sequence variants and deletions in six new patients and a review of the literature

“…A variety of variant types have been seen in association with the Sotos-like phenotype, including whole gene deletions (10 patients), one nonsense variant and missense variants and in-frame deletions affecting the DNA-binding domain (3 patients). [4][5][6][7][8][9][10] Five of the reported NFIX deletions also encompass the nearby CACNA1A gene, haploinsufficiency of which causes episodic ataxia type 2 or familial hemiplegic migraine.…”