SOX9

Gene Facts

• HGNC Symbol: SOX9 (HGNC:11204)
• HGNC Name: SRY-box transcription factor 9
• Gene type: protein-coding gene
• Locus type: gene with protein product
• Previous symbols: CMD1, CMPD1
• Alias symbols: SRA1
• %HI: 0.56
• pLI: 1
• LOEUF: 0.15
• Cytoband: 17q24.3
• Genomic Coordinates:

  GRCh37/hg19:	chr17:70117161-70122557
  GRCh38/hg38:	chr17:72121020-72126416

• MANE Select Transcript: NM_000346.4 ENST00000245479.3
• Function: Transcription factor that plays a key role in chondrocytes differentiation and skeletal development (PubMed:24038782). Specifically binds the 5'-ACAAAG-3' DNA motif present in enhancers and super-enhancers and promotes expression of genes important for chondrogenesis, including cartilage matrix protein-coding genes COL2A1, COL4A2, COL9A1, COL11A2 and ACAN, SOX5 and SOX6 (PubMed:8640233). Also binds to some promoter regions (By similarity). Plays a central role in successive steps of chondrocyte ... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

• Dosage ID: ISCA-17245
• ClinGen Curation ID: CCID:007926
• Curation Status: Complete
• Issue Type: Dosage Curation - Gene
• Haploinsufficiency: Sufficient Evidence for Haploinsufficiency (3)
• Triplosensitivity: No Evidence for Triplosensitivity (0)
• Last Evaluated: 05/10/2023

Haploinsufficiency (HI) Score Details

• HI Score: 3
• HI Evidence Strength: Sufficient Evidence for Haploinsufficiency

HI Disease

• campomelic dysplasia

HI Evidence

• PUBMED: 7990924
  Foster et al. (1994) found a de novo nonsense change (195X) in SOX9 in a 46,XX female with campomelic dysplasia (CD) and a de novo 4-bp insertion resulting in a frameshift in a 46,XY female aborted fetus with short limbs, cystic hygroma, micrognathia and normal female genitalia.
• PUBMED: 9002675
  Meyer et al. (1997) reported 12 CD patients, 10 of them carrying SOX9 variants. At least 2 nonsense variants are reported de novo and located within exon 1: W86X in a 46,XX female and Q117X in a 46,XY with reported sex reversal.
• PUBMED: 8001137
  Wagner et al. (1994) found a de novo nonsense variant in SOX9 (Y44OX) in an XY female with CD. This variant is not expected to undergo nonsense mediated decay.
• PUBMED: 29542186
  Higeta et al. (2018) identified two siblings with familial campomelic dysplasia and a frameshift variant in SOX9 (NM_000346.3: c.441delC, within exon 2). The siblings' mother was germline mosaic for the variant and the mother had mild skeletal changes.
• PUBMED: 25983619
  Mattos et al. (2015) reported 9 CD patients. At least 4 of them carry heterozygous nonsense and frameshift variants in SOX9 that are expected to undergo NMD, one of them was identified as de novo. Parental testing was only available for this case, parents were reported unaffected for all cases. Other variants identified in these patients are a canonical splice variant within intron 1 and nonsense and frameshift variants located in the last exon. XY sex reversal was reported in one of the three male patients in the study.

• HI Evidence Comments: Haploinsufficiency of SOX9 causes campomelic dysplasia (CD), characterized by skeletal defects and XY sex reversal (in the majority of cases) (PMID: 20301724). Disruptions of the regulatory region of SOX9 (via translocations, etc) have also been associated with CD (PMID 17204049). Multiple additional reports support haploinsufficiency of SOX9 as a mechanism of disease for CD. In HGMD, numerous nonsense and frameshift variants reported within the first 2 exons, expected to undergo nonsense mediated decay (>15 variants). No focal deletions of only the coding region of SOX9 have been reported to our knowledge, all deletions involving SOX9 also involve the upstream region, known to contain regulatory regions. At least 5 de novo nonsense/frameshift variants within first 2 exons have been reported in the literature. Previous publications in curation, not counted as evidence for HI (variants in last exons, other potential mechanisms of disease): PMID 19231556: In 2009, Cost et al. used PCR on a proband with campomelic dysplasia and 46,XY sex reversal. A heterozygous SOX9 deletion, 972delC, was discovered causing a frameshift. This deletion was not tested for in the proband's parents and PCR only tested the coding region of SOX9. This variant is not expected to undergo nonsense mediated decay. PMID 8894698: Cameron et al. (1996) identified a family with 3 affected individuals with CD and sex reversal. They found a 1-bp insertion in SOX9, resulting in a frameshift and stop codon. The 3 individuals carried the same variant, but varied with respect to the gonadal phenotype. The father was shown to be a germ-line mosaic for the variant. This variant is not expected to undergo nonsense mediated decay.

Triplosensitivity (TS) Score Details

• TS Score: 0
• TS Evidence Strength: No Evidence for Triplosensitivity
• TS Evidence Comments: No focal duplications involving only the coding region of SOX9 have been reported in association with a clinical disorder to our knowledge. Larger duplications involving upstream regulatory regions have been associated to 46,XX Developmental Testicular Disorder (PMID: 30552336, Croft et al 2018; and other reports)