Submission Details

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 Marshall-Smith syndrome has been curated separately. Malan overgrowth syndrome is characterized by overgrowth, macrocephaly, craniofacial dysmorphism, behavioral issues, developmental delay, and abnormal bone morphology. The NFIX gene was first reported in relation to autosomal dominant Malan overgrowth syndrome in 2010 (Malan et al., PMID 20673863). One nonsense, three missense and five unique frameshift alleles have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants reported in 10 unrelated individuals from four publications are included in this curation (PMID: 20673863; Yoneda at al., 2012, PMID: 22301465; Priolo et al., 2018, PMID: 29897170; Tabata et al., 2020, PMID: 32193017). There were no segregation data reported for these cases. This gene-disease relationship is also supported by mouse model experimental data (Oishi et al., 2019, PMID: 30503862). Haploinsufficiency has been proposed as the mechanism of action for alleles associated with Malan overgrowth syndrome. In summary, NFIX is definitively associated with autosomal dominant Malan overgrowth 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).