NFIX

Inheritance Pattern: AD

Disease ID:MONDO:0011244

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0013885

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0013885

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0013885

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0013885

Submitter: Illumina

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.

Inheritance Pattern: AD

Disease ID:MONDO:0011244

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0011244

Submitter: ClinGen

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).

Inheritance Pattern: AD

Disease ID:MONDO:0013885

Submitter: ClinGen

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).

Inheritance Pattern: AD

Disease ID:MONDO:0011244

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0011244

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0013885

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0011244

Submitter: Illumina

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.

Inheritance Pattern: AD

Disease ID:MONDO:0011244

Submitter: Orphanet