SEPTIN9

Inheritance Pattern: AD

Disease ID:MONDO:0008076

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0008076

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0017362

Submitter: ClinGen

SEPTIN9 was first reported in relation to hereditary neuralgic amyotrophy (HNA) in 2005 (PMID: 16186812). Over time the phenotypic spectrum of SEPTIN9 has expanded to include mild to severe episodic and chronic symptoms, with or without dysmorphic features. SEPTIN9 encodes the septin-9 protein, which is a member of the septin family. Septins are GTPases that interact with the cytoskeleton, including microtubules and actin, and function in cellular processes such as cytokinesis, motility, and cell polarity. SEPTING9 consists of 17 exons (including multiple alternative first exons), 18 unique transcripts, and 15+ isoforms. In this curation, we scored genetic evidence for 10 different variants: two missense variants, one intronic variant, and seven intragenic duplications (PMIDs: 16186812, 18492087, 20019224, 31619932, 19139049, 19939853). These variants were reported in >100 individuals across 28 families. All variants included are located in the N terminus or 5’UTR which are only present in a subset of transcripts and isoforms. Some individuals with positive genetic testing are reported to be asymptomatic, possibly due to reduced penetrance or variable expressivity (dysmorphic features with no HNA attacks). Genetic evidence score totaled 4.3. Of note, intragenic duplications are unable to be entered as evidence at this time, so 2 of these points were manually added. Experimental evidence (expression data, mouse model, and functional alteration of non-patient cells, PMIDs: 17468182, 17546647) further supports the gene-disease relationship with a score of 3, for a total of 7.3. A single publication (PMID: 32122354) discusses a possible new phenotype, autosomal dominant CMT with cognitive involvement/decline, in a single family with a novel missense variant (p.Val469Ala). This variant is located in the central domain of the protein and possibly impacts protein-protein interaction, which is different from the variants described above. Other members of the septin family have been associated with neurodegenerative disorders such as Alzheimer's disease and Parkinson’s disease, presumably due to altered septin-septin interactions. This publication was not included in this curation and more evidence will be needed to determine lumping or splitting. In summary, SEPTIN9 is moderately associated with autosomal dominant hereditary neuralgic amyotrophy with or without dysmorphic features. **Recuration Update**: No new literature evidence was found in 2026 so the classification remains unmodified.