Submission Details


Marshall-Smith 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 Marshall-Smith 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 six probands in two publications (20673863: Malan et al. 2010; 24924640: Schanze et al. 2014). All were heterozygous de novo predicted null variants, which clustered in exons 6-10. Evidence that a protein product is synthesized and escapes nonsense-mediated decay was available for two variants. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease association is supported by expression studies, a mouse model, and in vitro functional assays (20673863: Malan et al. 2010; 17353270: Driller et al. 2007). The mechanism of disease has been proposed to involve a dominant-negative mechanism. In summary, NFIX is definitively associated with autosomal dominant Marshall-Smith syndrome. Of note, this gene has also been implicated in Malan syndrome and this association has been assessed separately. Lumping and Splitting: According to the criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in phenotypic variability and disease mechanism. Based on review of a large number of patients, Priolo et al. (2018) (PMID 29897170) conclude that Malan syndrome and Marshall-Smith syndrome should be considered separate disease entities, with important differences for clinical care. However, they note that future data may still provide further evidence for a disease spectrum. The syndromes differ in that Malan results in tall stature while Marshall-Smith results in short stature, with some additional more minor defining features. Some other features do overlap. Rarely, both syndromes may be considered as potentially diagnostic in a single patient. Malan syndrome has been proposed to result from NFIX haploinsufficiency, whereas Marshall-Smith syndrome has been proposed to result through a dominant-negative mechanism. Genotype-phenotype correlations have been proposed. Marshall-Smith variants tend to be scattered throughout exons 6–10 of the NFIX gene, while most point mutations causing Malan syndrome are clustered in exon 2. However, careful functional studies of reported variants are needed to confirm these associations. For these reasons, we have split curations for the disease entities Marshall-Smith syndrome and Malan syndrome.
PubMed IDs:
20673863 24924640 17353270
Assertion Criteria:
Submitter Submitted Date:

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