The NFIX gene is located on chromosome 19 at 19p13.13 and encodes nuclear factor IX, a transcription factor implicated in brain and skeletal development. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in molecular mechanisms and phenotypic variability. Therefore, the following disease entities have been split into multiple disease entities, Malan overgrowth syndrome (OMIM:614753) and Marshall-Smith syndrome (OMIM:602535). The split curation for autosomal dominant Malan overgrowth syndrome has been curated separately. Marshall-Smith syndrome is characterized by feeding difficulties, failure to thrive, craniofacial dysmorphism, recurrent respiratory issues, developmental delay, abnormal bone morphology and hypertrichosis. The NFIX gene was first reported in relation to autosomal dominant Marshall-Smith syndrome in 2010 (Malan et al., PMID 20673863). Two canonical splice site, two exon deletion, one nonsense and 12 frameshift alleles have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in 24 unrelated individuals in four publications (PMID: 20673863; Schanze et al., 2014, PMID: 24924640; Martinez et al., 2015, PMID: 26600704; Aggarwal et al., 2017, PMID: 28442439) are included in this curation. There was no segregation data reported for these cases. This gene-disease relationship is also supported by mouse model experimental data (Driller et al., 2007, PMID: 17353270). A dominant negative mechanism of action has been proposed for alleles associated with Marshall-Smith syndrome, but this has yet to be experimentally demonstrated. In summary, NFIX is definitively associated with autosomal dominant Marshall-Smith syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Syndromic Disorders Gene Curation Expert Panel on the meeting date 08.03.2022 (SOP Version 9).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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