Novel molecular mechanism in Malan syndrome uncovered through genome sequencing reanalysis, exon‐level Array, and RNA sequencing

Abstract The NFIX gene encodes a DNA‐binding protein belonging to the nuclear factor one (NFI) family of transcription factors. Pathogenic variants of NFIX are associated with two autosomal dominant Mendelian disorders, Malan syndrome (MIM 614753) and Marshall–Smith syndrome (MIM 602535), which are clinically distinct due to different disease‐causing mechanisms. NFIX variants associated with Malan syndrome are missense variants mostly located in exon 2 encoding the N‐terminal DNA binding and dimerization domain or are protein‐truncating variants that trigger nonsense‐mediated mRNA decay (NMD) resulting in NFIX haploinsufficiency. NFIX variants associated with Marshall–Smith syndrome are protein‐truncating and are clustered between exons 6 and 10, including a recurrent Alu‐mediated deletion of exons 6 and 7, which can escape NMD. The more severe phenotype of Marshall–Smith syndrome is likely due to a dominant‐negative effect of these protein‐truncating variants that escape NMD. Here, we report a child with clinical features of Malan syndrome who has a de novo NFIX intragenic duplication. Using genome sequencing, exon‐level microarray analysis, and RNA sequencing, we show that this duplication encompasses exons 6 and 7 and leads to NFIX haploinsufficiency. To our knowledge, this is the first reported case of Malan Syndrome caused by an intragenic NFIX duplication.