Submission Details


Malan overgrowth syndrome
Mode Of Inheritance:
Autosomal dominant
Evaluated Date:
The NFIX gene is located on chromosome 19 at 19p13.13 and encodes the nuclear factor IX protein, a transcription factor that binds a palindromic sequence in cellular and viral promoters, promotes adenovirus replication, and has been implicated in brain and skeletal development. The NFIX gene was first reported in relation to autosomal dominant Malan syndrome in 2010 (20673863: Malan et al. 2010). Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least eight probands in three publications (20673863: Malan et al. 2010; 22301465: Yoneda et al. 2012; 29897170: Priolo et al. 2018). Variants included five missense, two frameshift, and one stop-gained. Seven occurred de novo; one missense variant was inherited from a parent who may have had a very mild phenotype. The majority of missense variants occur in the DNA binding and dimerization domain. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease relationship is supported by expression studies, a mouse model, and in vitro functional assays (20673863: Malan et al. 2010; 17353270: Driller et al. 2007). Haploinsufficiency has been proposed as the mechanism of disease. In summary, NFIX is definitively associated with autosomal dominant Malan syndrome. Of note, this gene has also been implicated in Marshall-Smith syndrome. This relationship has been assessed separately.
PubMed IDs:
20673863 22301465 29897170 17353270
Assertion Criteria:
Submitter Submitted Date:

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