Variations in NFIX gene causing Marshall Smith syndrome is clustered around exons 6-8 in canonical isoform, regions outside of those coding for the DNA binding and dimerization domain. Most variants are frameshift and escape nonsense mediated decay leading to dominant negative effect and hence, cause a more severe phenotype than Malan syndrome.
Variants associated with Malan syndrome are mostly restricted to the 5′ part of the gene and most commonly involve exon 2, encoding for DNA-binding and dimerization domain. Nonsense, missense, frameshift and splice site variants causing premature stop codons that undergo non sense mediated decay are common. Multiexon deletions and whole gene deletions as part of contiguous gene disorder have also been reported in significant number of cases. Haploinsufficiency is the common mechanism underlying Malan syndrome.
Targeted molecular testing of gene by sanger or exome sequencing should be performed. If negative, gene targeted deletion analysis can be performed by multiplex ligation probe amplification (MLPA) using specific probe set or cytogenetic microarray (CMA) if contiguous gene syndrome is suspected in Malan syndrome.
NFIX