Primary immunodeficiency or monogenic inflammatory bowel disease

Gene: SEPT6

I don't know

Comment on list classification: To date, there are 2 unrelated male individuals reported in literature with hemizygous variants in SEPT6 and severe congenital neutropenia. Hence, this gene should remain Amber with the current evidence. A 'watchlist' tag was added in anticipation of more case reports.

Created: 29 Jul 2026, 11:24 a.m. | Last Modified: 29 Jul 2026, 11:24 a.m.

Panel Version: 9.28

PMID: 42088107 Gunderman et al., 2026
2 male sibs with severe nonsyndromic congenital neutropenia, absent circulating B cells, marrow mature myeloid, and rare plasma cell accumulation, as well as tetraploidy, with disease reversal following myeloablative HSCT. Older sibling had T-cell receptor excision circles (TRECs) of 9 copies (normal >20), while younger brother had 0 copies. No infectious symptoms were present. WGS detected a hemizygous SEPTIN6 (NM_145799.4) c.1282T>A; p.*428Kext*9 variant in both brothers (het in the unaffected mother) - diagnosed with X-linked SEPTIN6-related immunodeficiency.

PMID: 34677878 Renella et al., 2023
Report of a Caucasian male proband, presented with severe neutropenia associated with dysmyelopoiesis and tetraploidy as a newborn. The absolute neutrophil count (ANC) was 0.5 G/L at birth, subsequently 0-0.2 G/L. At age 1 year he underwent an allogeneic HLA-DQ-mismatched unrelated HSCT. WGS detected a hemizygous c.1282T>C, p.*428Glnext*9 variant in SEPT6. Second somatic SEPT6 variant was detected in cis: c.43C>T, p.Arg15* (14% of reads).

This gene is not yet associated with a disease entity in OMIM, ClinGen, or G2P (accessed 29th July 2026).

Created: 29 Jul 2026, 11:23 a.m. | Last Modified: 29 Jul 2026, 11:23 a.m.

Panel Version: 9.27

Added new-gene-name tag, new approved HGNC gene symbol for SEPT6 is SEPTIN6.

Created: 29 Jul 2026, 11:08 a.m. | Last Modified: 29 Jul 2026, 11:08 a.m.

Panel Version: 9.27

Mode of inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females

Phenotypes
severe congenital neutropenia, MONDO:0018542; Immunodeficiency, HP:0002721

Publications

• 42088107
• 34677878

Green List (high evidence)

Gunderman et al. described stop loss variant in the X-linked SEPTIN6 gene, they identified 2 hemizygous male siblings. The researchers presented evidence characterized by severe congenital neutropenia, a profound lack of circulating B cells, and variable T cell lymphopenia, noting that maternal carriers show strong negative selection against the mutated allele in their hematopoietic cells. Clinical data and bone marrow analysis revealed progressive dysmyelopoiesis with myeloid tetraploidy and a predisposition to aneuploidy, while xenograft mouse models and spatial transcriptomics further demonstrated that the SEPTIN6 mutation leads to a significant reduction in early lymphoid progenitors rather than an absolute developmental block.

Renella et al. described a single patient with a de novo germline stop-loss mutation in the X-linked gene SEPT6 with a similar phenotype
Sources: Literature

Created: 6 May 2026, 8:20 p.m.

Mode of inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females

Phenotypes
Congenital neutropenia; B cell deficiency; T cell lymphopenia; Abnormal newborn screening for SCID; Hypersegmented neutrophils; Myelodysplasia; Decreased circulating B cells; Leukopenia

Publications

• 42088107, 34677878