[NFIX gene mutation causes Marshall-Smith syndrome in a pair of identical twins and literature review]. / NFIXåŸºå› å˜å¼‚å¯¼è‡´ä¸€å¯¹åŒåµåŒèƒžèƒŽMarshall-Smithç»¼åˆå¾å¹¶æ–‡çŒ®å¤ä¹ .

This article reports on the clinical and genetic characteristics of monozygotic twins with Marshall-Smith syndrome (MRSHSS) due to a mutation in the NFIX gene, along with a review of related literature. Both patients presented with global developmental delays, a prominent forehead, shallow eye sockets, and pectus excavatum. Genetic testing revealed a heterozygous splicing site mutation c.697+1G>A in both children, with parents showing wild-type at this locus. According to the guidelines of the American College of Medical Genetics and Genomics, this mutation is considered likely pathogenic and has not been previously reported in the literature. A review of the literature identified 32 MRSHSS patients with splicing/frameshift mutations. Accelerated bone maturation and moderate to severe global developmental delay/intellectual disability are the primary clinical manifestations of patients with MRSHSS. Genetic testing results are crucial for the diagnosis of this condition.

Pathogenic variant in NFIX gene affecting three sisters due to paternal mosaicism.

We present a family with three girls presenting similar dysmorphic features, including overgrowth, intellectual disability, macrocephaly, prominent forehead, midface retrusion, strabismus, and scoliosis. Both parents were unaffected, suggesting the presence of an autosomal recessive syndrome. Following exome sequencing, a heterozygous nonsense variant was identified in the NFIX gene in all three siblings. The father appeared to have a low-grade (7%) mosaicism for this variant in his blood. Previously, de novo pathogenic variants in NFIX have been identified in Marshall-Smith syndrome and Malan syndrome, which share distinctive phenotypic features shared with the patients of the present family. This case emphasizes the importance of further molecular analysis especially in familial cases, to exclude the possibility of parental mosaicism.

Malan syndrome: Extension of genotype and phenotype spectrum.

Malan syndrome and Marshall-Smith syndrome (MSS) are allelic disorders caused by mutation in NFIX gene. We report a 3-year- 6 months- old female with clinical features suggestive of Malan syndrome with mutation in exon 2 of NFIX gene. NFIX gene, where most of the mutations in Malan syndrome are located. She did not have advanced bone age. The radiographs of long bones showed metaphyseal changes which were not reported previously. This study reports the first mutation proven case from India and highlights the overlap between MSS and Malan syndrome.

A rare cause of intellectual disability: Novel mutations of NFIX gene in two patients with clinical features of Marshall-Smith syndrome and Malan syndrome.

Marshall-Smith syndrome (MSS) and Malan syndrome (MS) are both allelic disorders caused by mutations in the NFIX gene. MS is characterized by overgrowth, intellectual disability, distinctive facial features, and accelerated skeletal maturation. On the other hand, clinical features of MSS consist of advanced bone age, dysmorphic features, intellectual disability, and failure to thrive at birth. In this study, we presented the clinical and molecular findings of two different patients with MS and MSS as a rare cause of intellectual disability and reported two novel variants in the NFIX gene. NFIX gene sequencing revealed a novel heterozygous c.1287delC (p.G430Vfs*34) mutation in patient 1 whose clinical diagnosis was compatible with Marshall-Smith syndrome, and in the second patient, physical features consistent with Malan syndrome, was detected a heterozygous one nucleotide duplication, c.303dupC (pCys102LeufsTer17).

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

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 genotype-phenotype 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.

Novel alternative splice variants of NFIX and their diverse mRNA expression patterns in dairy goat.

The nuclear factor I/X (NFIX) is a member of NFI family and contributes to muscle and brain development. Numerous genes coding for alternative splicing isoforms play potential but different roles in the biological process. To date, transcript variants of NFIX gene and their expression profiles have never been elucidated in dairy goat. Herein, we identified and verified the expression of two novel transcripts (NFIXa and NFIXb) of NFIX gene in dairy goat. Compared with the normal transcript (NFIX), the NFIXa variant lacked the first and ninth exons, while the NFIXb variant lacked the first, seventh and ninth exons; the NFIXa variant was 69 nt longer than the normal transcript in the 5' end site of the seventh exon, while the NFIXb variant was 66 nt longer in the 5' end site of the seventh exon. Quantitative real-time PCR results showed that the expression levels of the three variants were significantly different. The normal NFIX variant was abundantly expressed in the lungs, the NFIXa variant was highly expressed in the pancreas, and the NFIXb variant was abundantly expressed in both the lung and the pancreas. Additionally, the NFIXa variant showed a significantly higher expression level than those of the normal NFIX and the alternative NFIXb variants in the liver, spleen, adipose, intestine and the testis (P<0.01 or P<0.05), respectively. Expression of the NFIXa variant in the brain was significantly higher than that of the NFIXb variant (P<0.01). These findings suggest that the NFIXa isoform is the most abundant isoform in certain tissues of the dairy goat. This study represents the first report on alternative splicing variants of the goat NFIX gene and their expression profiles. It should help elucidate the function of NFIX gene in dairy goat.