SOX9

protein-coding

SRY-box transcription factor 9, the group of SRY-box transcription factors

Gene summary

The protein encoded by this gene recognizes the sequence CCTTGAG along with other members of the HMG-box class DNA-binding proteins. It acts during chondrocyte differentiation and, with steroidogenic factor 1, regulates transcription of the anti-Muellerian hormone (AMH) gene. Deficiencies lead to the skeletal malformation syndrome campomelic dysplasia, frequently with sex reversal. [provided by RefSeq, Jul 2008]

Previous symbols:

CMD1
CMPD1

MANE transcript

NM_000346.4

Inheritance

ClinVar variants

P:153U:192B:152

Top phenotype

46, XY sex reversal 10; Campomelic dysplasia

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr17:72,121,020-72,126,416

External References & Databases

Ensembl (ENSG00000125398)

Transcript & Mutation Effects

hg38 • Region Span ~5.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

campomelic dysplasiaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007251

Submitter: Orphanet

isolated Pierre-Robin syndromeLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0009869

Submitter: ClinGen

Pierre Robin Sequence (PRS), a collection of clinical features consisting of mandibular hypoplasia, cleft secondary palate, and glossoptosis leading to obstructive apnea and feeding difficulties, was first described in 1923 by P. Robin. (PMIDs: 8171154, 23799581). PRS can present in isolation as well as in association with various conditions such as Stickler syndrome. Evidence supporting the SOX9-Pierre Robin Sequence gene disease relationship includes segregation data and experimental evidence including a mouse model. Deletions in the non-coding region of SOX9 have been identified in patients with PRS (PMIDs: 19234473, 23532965, 24934569). These variants have been found to cause reduced expression of SOX9 and KCNJ2 (PMIDs: 19234473, 17551083). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the Skeletal Disorders Gene Curation Expert Panel on 8/3/2020.

campomelic dysplasiaSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007251

Submitter: PanelApp Australia

Cooks syndromeLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0007134

Submitter: ClinGen

Cooks syndrome was first described in 1985 by Cooks et al. (PMID: 3978841). It was later associated with SOX9 (PMIDs: 19639023, 27706140, 31358994, 32470376). Evidence supporting this gene disease relationship includes segregation data and expression data. Large duplications at the 17q24.3 locus involving the coding regions of KCNJ2 and KCNJ16 as well as the regulatory region of SOX9 have been reported in patients with Cooks syndrome (PMIDs: 32583964, 32470376, 19639023). The mechanism of disease is thought to be misexpression of Kcnj2 due to a position effect which places the gene under the regulation of a SOX9 enhancer (PMID: 27706140, 32470376). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the Skeletal Disorders Gene Curation Expert Panel on 8/3/2020.

campomelic dysplasiaDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007251

Submitter: G2P

isolated Pierre-Robin syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0009869

Submitter: G2P

campomelic dysplasiaSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007251

Submitter: Labcorp Genetics (formerly Invitae)

46,XX ovotesticular disorder of sex developmentSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0016281

Submitter: Orphanet

46,XY complete gonadal dysgenesisSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0010765

Submitter: Orphanet

46,XX sex reversal 1SUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0010766

Submitter: Orphanet

isolated Pierre-Robin syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0009869

Submitter: Orphanet

campomelic dysplasiaDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007251

Submitter: ClinGen

SOX9 was reported in relations to autosomal dominant Campomelic dysplasia as early as 1994 (Foster et al. PMID: 7990924). This curation includes probands with Campomelic dysplasia, Acampomelic dysplasia, and Campomelic dysplasia with sex reversal. At least 6 unique variants (missense, nonsense, frameshift etc) have been reported in humans. Case-level and experimental data, including a mouse model, support this gene-disease relationship. More evidence is available in the literature, but the maximum score for genetic evidence has been reached. In summary, SOX9 is definitively associated with autosomal dominant Campomelic dysplasia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

46,XY partial gonadal dysgenesisSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0016674

Submitter: Orphanet

Clinical Genomic Database (CGD)

46, XY sex reversal 10; Campomelic dysplasiaAD

Manifestation: Audiologic/Otolaryngologic; Cardiovascular; Craniofacial; Musculoskeletal; Neurologic; Oncologic; Renal; Genitourinary

Intervention: Cardiovascular; Oncologic

Rationale: Individuals with a 46,XY karyotype and genital undermasculinization may have an increased risk of gonadoblastoma, and gonadal removal has been recommended; The conditions can involve congenital cardiac anomalies, and awareness may allow early management

Refs: 10588843; 20301724; 21208124; 25604083

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SOX9 variants in ClinVar

15 Conditions Cataloged

Camptomelic dysplasiaTotal: 358

not providedTotal: 135

Inborn genetic diseasesTotal: 65

not specifiedTotal: 52

SOX9-related disorderTotal: 47

Connective tissue disorderTotal: 11

CAMPOMELIC DYSPLASIA WITH AUTOSOMAL SEX REVERSALTotal: 9

Acampomelic Campomelic DysplasiaTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000346.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			3 clinvar	106 clinvar	4 clinvar	113
missense	19 clinvar	35 clinvar	180 clinvar	30 clinvar	12 clinvar	276
nonsense	23 clinvar	10 clinvar	3 clinvar			36
start loss						0
frameshift	33 clinvar	26 clinvar	5 clinvar			64
splice donor/acceptor (+/-2bp)	7 clinvar		1 clinvar			8
Total	82	71	192	136	16	497

Highest pathogenic variant AF is 0.0000015041937

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 4 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000346.4	RefSeq	NP_000337.1	3	MANE Select
ENST00000245479.3	Ensembl	ENSP00000245479.2	3	MANE Select
ENST00000877559.1	Ensembl	ENSP00000547618.1	3	Standard
ENST00000877559.2	Ensembl	ENSP00000547618.1	3	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
sox9b	Danio rerio	Structure: iridophore Quality: decreased amount abnormal

Gene / Model

Organism

Observed Phenotype

sox9b

Danio rerio

Structure: iridophore

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

cAMP signaling pathway - Homo sapiens (human)
Neural Crest Differentiation
Spinal Cord Injury
Endochondral Ossification
Prostaglandin Synthesis and Regulation

Biological Process

skeletal system development
cartilage condensation
ossification
branching involved in ureteric bud morphogenesis
cell fate specification

Molecular Function

RNA polymerase II proximal promoter sequence-specific DNA binding
DNA-binding transcription factor activity, RNA polymerase II-specific
enhancer sequence-specific DNA binding
DNA-binding transcription activator activity, RNA polymerase II-specific
chromatin binding

Cellular Component

nucleus
nucleoplasm
protein-containing complex
nuclear transcription factor complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000245479
Coding exons: 3
Length: 5401
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.63	230	311	0.740	0.0000171	3299
Missense (PolyPhen)		52	101.25	0.51356		1035
Synonymous	-2.26	182	147	1.24	0.00000974	1012
Loss of Function	3.91	0	17.8	0.00	8.62e-7	181

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Transcriptional regulator that plays a role in chondrocytes differentiation and skeletal development (PubMed:24038782). Binds to the COL2A1 promoter and activates COL2A1 expression, as part of a complex with ZNF219 (By similarity). {ECO:0000250|UniProtKB:Q04887, ECO:0000269|PubMed:24038782}.;
Disease: DISEASE: Campomelic dysplasia (CMD1) [MIM:114290]: A rare, often lethal, osteochondrodysplasia characterized by congenital bowing and angulation of long bones. Other skeletal defects include unusually small scapula, deformed pelvis and spine, and a missing pair of ribs. Craniofacial and ear defects are common. Most patients die soon after birth due to respiratory distress which has been attributed to hypoplasia of the tracheobronchial cartilage and small thoracic cage. Up to two-thirds of affected XY individuals have genital defects or may develop as phenotypic females. {ECO:0000269|PubMed:10446171, ECO:0000269|PubMed:10951468, ECO:0000269|PubMed:11323423, ECO:0000269|PubMed:11754051, ECO:0000269|PubMed:12783851, ECO:0000269|PubMed:19033726, ECO:0000269|PubMed:19921652, ECO:0000269|PubMed:20513132, ECO:0000269|PubMed:24038782, ECO:0000269|PubMed:7485151, ECO:0000269|PubMed:9002675, ECO:0000269|PubMed:9452059}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: 46,XX sex reversal 2 (SRXX2) [MIM:278850]: A condition in which male gonads develop in a genetic female (female to male sex reversal). {ECO:0000269|PubMed:21208124}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: 46,XY sex reversal 10 (SRXY10) [MIM:616425]: A disorder of sex development. Affected individuals have a 46,XY karyotype, show gonadal dysgenesis with streak gonads, look like normal females at birth, do not develop secondary sexual characteristics at puberty and do not menstruate. {ECO:0000269|PubMed:25604083}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.836

Intolerance Scores

RVIS EVS: -0.71
RVIS percentile EVS: 14.4

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.982

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium