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

Abstract

a Background and Aim. Sotos syndrome 2 (MIM #614753), known also as Malan syndrome, is caused by heterozygous mutations/deletions of the NFIX gene located on chromosome 19p13.2. It manifests in developmental delay, intellectual impairment, macrocephaly, central nervous system anomalies, postnatal overgrowth, and craniofacial dysmorphism. Unusual behavior with/without autistic traits, ophthalmologic, gastrointestinal, musculo-skeletal, and hand/foot abnormalities are also frequent. Due to the limited number of such cases, no definitive conclusions about genotypephenotype correlations have been possible. In the following paper, we discuss physical features consistent with Sotos syndrome 2 based on literature review and two new cases [a patient with de novo 19p13.2 deletion encompassing a part of the NFIX gene and a patient with de novo (not described so far) heterozygous missense mutation c.367C>T (p.Arg123Trp) in the NFIX gene]. Results. Apart from overgrowth and psychomotor developmental delay, the most consistent physical features of our two patients are dysmorphism including high forehead, downslanting palpebral fissures, pointed chin, and abnormalities of the pinna. Both show abnormal behavior and present with long, tapered fingers and toenail defect. No severe congenital malformations were noted. Conclusions. We hope these data will serve as a material for further studies and provide an opportunity to make more reliable genotype-phenotype correlations.

Further delineation of Malan syndrome

“…Most variants were in exon 2. Only three variants (missense variants p.Arg38Cys and p.Arg115Trp; in frame deletion p.Glu53_Glu59del) had been previously reported (Jazela‐Staneck et al., 2016, Martinez et al., 2015, Priolo et al., 2012). The remaining variants are novel.…”

“…Of the 14 individuals in whom the deleted region included CACNA1A , 10 developed seizures. In contrast, only one patient has been reported with seizures in whom the deletion did not include CACNA1A (Jezela‐Stanek et al., 2016). Klaassens and coworkers (2015) reported a single patient with cyclical vomiting responsive to pizotifen and a literature patient who had episodic ataxia at age nine years.…”

“…Twenty‐three different missense variants have been identified, most of these (22 out of 23) are located in the DNA binding and dimerization domain. There is a predominant involvement of basic residues (in 12 of the 23 missense variants), and some have been altered more than once (at positions Arg38; Arg115; Arg116; Lys125) (Gurrieri et al., 2015; Jezela‐Stanek et al., 2016; Lu et al., 2017; Martinez et al., 2015; Priolo et al., 2012). We found a clustering of NFIX missense variants involving positively charged amino acids (at positions Lys 113, Arg115, Arg116, Arg121, Lys125, and Arg128) in a small region of 15 residues.…”

“…It is caused by heterozygous variants or deletions of the gene nuclear factor I X ( NFIX ; MIM# 164005 ) , located at chromosome 19p13.2 (Malan et al., 2010). Since the first description the entity has been described in 35 individuals, to date (Auvin, Holder‐Espinasse, Lamblin, & Andrieux, 2009; Bonaglia et al., 2010; Dolan et al., 2010; Dong et al., 2016; Gurrieri et al., 2015; Jezela‐Stanek et al., 2016; Jorge et al., 2015; Klaassens et al., 2015; Kuroda et al., ; Lu et al., 2017; Lysy et al., 2009; Martinez et al., 2015; Natiq et al., 2014; Nimmakayalu et al., 2013; Oshima et al., 2017; Priolo et al., 2012; Shimojima et al., 2015; Yoneda et al., 2012). Haploinsufficiency of NFIX has been proposed as leading causative mechanism in Malan syndrome (Gurrieri et al., 2015; Klaassens et al., 2015; Malan et al., 2010).…”

Proteome dynamics during postnatal mouse corpus callosum development

“…Our initial analysis has identified several ACC-associated genes in each cluster (Table 1), which is important given that deficiencies in their stage-specific functions may cause specific defects in the CC, thereby contributing to unique disorders with CC abnormalities6667. Known diseases caused by mutations in the identified genes include: L1 syndrome by mutation in L1cam 6869, Warburg micro syndrome by mutations in Rab18 70, and Miller-Dieker syndrome by deletion of Ywhae 7172 (cluster A); Malan syndrome (Sotos syndrome 2) and Marshall-Smith syndrome by Nfix haploinsufficiency73747576, and FG syndrome by mutation in Flna 7778 (cluster B); Fumarase deficiency by mutations in FH 798081 (cluster D); Pyrvate dehydrogenase deficiency by mutations in pdha1 or pdhb 82 (cluster E). In addition, other identified genes associated with disorders affecting the CC have been identified, such as PlxnA1 and its link with schizophrenia525354.…”