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Intellectual disability

Gene: SOX3

Amber List (moderate evidence)
SOX3 (SRY-box 3)
EnsemblGeneIds (GRCh38): ENSG00000134595
EnsemblGeneIds (GRCh37): ENSG00000134595
OMIM: 313430, Gene2Phenotype
SOX3 is in 11 panels

8 reviews

Ida Ertmanska (Genomics England Curator)

I don't know

Comment on list classification: While variants in SOX3 have been reported to cause a cognitive impairment, its severity does not meet the panel eligibility criteria of moderate/severe/profound global developmental delay/intellectual disability. Based on available evidence, this gene should be rated Amber for Intellectual disability, until more evidence emerges.
Created: 19 Dec 2025, 12:17 p.m. | Last Modified: 19 Dec 2025, 12:17 p.m.
Panel Version: 9.203
PMID: 35295983 Li et al., 2022
Chinese boy found to have growth hormone deficiency, hypogonadotropic hypogonadism, and borderline intellectual disability (full-scale IQ = 72). WES revealed a hemizygous variant in SOX3 (c.287 delG, p.G96Afs*44), as well as a SEMA3A c.2198G>R (p.R733H) variant.

PMID: 35114986 Du et al., 2022
8yo Chinese boy with a 6 Mb duplication on Xq26.3q27.1 encompassing SOX (and 9 other genes). Presented with congenital hypopituitarism, short stature. Normal intelligence, total IQ = 92.

PMID: 29175558 Jelsig et al., 2018
Family with 3 affected male siblings, harbouring a hemizygous SOX3 variant NM_005634.2:c.449C > A; p.(Ser150Tyr). Phenotype included mild intellectual disability, microphthalmia, coloboma, hypopituitarism, facial dysmorphology, microcephaly and dental anomalies.

SOX3 is associated with Intellectual developmental disorder, X-linked, with isolated growth hormone deficiency, MIM:300123 and Panhypopituitarism, X-linked, MIM:312000 in OMIM (accessed 19th Dec 2025).
Created: 19 Dec 2025, 12:13 p.m. | Last Modified: 19 Dec 2025, 12:19 p.m.
Panel Version: 9.206

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

Phenotypes
Intellectual developmental disorder, X-linked, with isolated growth hormone deficiency, OMIM:300123; X-linked intellectual disability with isolated growth hormone deficiency, MONDO:0019032

Publications

Created: 19 Dec 2025, 12:13 p.m.
Last Modified: 19 Dec 2025, 12:19 p.m.
Panel version: 9.203

Sahana Chatakondu (Cambridge University Hospitals NHS Foundation Trust)

I don't know

CNV: duplication of SOX3 at Xq26.3–27.3 reported in affected male with growth hormone deficiency, ocular dyspraxia, and intellectual disability.
Created: 2 Dec 2025, 6:18 a.m. | Last Modified: 2 Dec 2025, 6:18 a.m.
Panel Version: 9.190

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

Phenotypes
Dyspraxia; Growth Hormone Deficiency; Intellectual Disability; Short stature,

Publications

Mode of pathogenicity
Other

Created: 2 Dec 2025, 6:18 a.m.
Last Modified: 2 Dec 2025, 6:18 a.m.
Panel version: 9.190

Sarah Leigh (Genomics England Curator)

The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Created: 9 Mar 2022, 3:40 p.m. | Last Modified: 9 Mar 2022, 3:40 p.m.
Panel Version: 3.1510
Created: 9 Mar 2022, 3:40 p.m.
Last Modified: 9 Mar 2022, 3:40 p.m.
Panel version: 3.1510

Arina Puzriakova (Genomics England Curator)

Tagged 'for-review' to assess inclusion of SOX3 on this panel in view of the expert review by Zornitza Stark (Australian Genomics) highlighting that disease mainly seems to be caused by gene duplications/deletions rather than SNVs
Created: 7 Dec 2020, 2:25 p.m. | Last Modified: 7 Dec 2020, 2:25 p.m.
Panel Version: 3.635
Created: 7 Dec 2020, 2:25 p.m.
Last Modified: 7 Dec 2020, 2:25 p.m.
Panel version: 3.635

Zornitza Stark (Australian Genomics)

I don't know

Most of the evidence for gene-disease association comes from reports of duplications and deletions of Xq26-27 including SOX3 (Xq27.1). Reports of pathogenic SNVs are rare (I can only find two), and note ID is described as 'mild'. Also note some evidence of polyA expansion being linked to the ID phenotype; conflicting evidence regarding the polyA deletion. I am unclear on how you handle small CNVs: would be Green if those are included in the gene-disease validity assessment.
Created: 14 Feb 2020, 9:25 p.m. | Last Modified: 14 Feb 2020, 9:25 p.m.
Panel Version: 3.3

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

Phenotypes
Mental retardation, X-linked, with isolated growth hormone deficiency, MIM#300123; Panhypopituitarism, X-linked, MIM#312000

Publications

Created: 14 Feb 2020, 9:25 p.m.
Last Modified: 14 Feb 2020, 9:25 p.m.
Panel version: 3.3

Caroline Wright (Sanger)

Green List (high evidence)

Mode of inheritance
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)

Phenotypes
SEX REVERSAL TYPE 3 (SRXX3)

Publications

Created: 5 Nov 2017, 2:42 a.m.

Panel version: 0

BRIDGE consortium (NIHRBR-RD)

Green List (high evidence)

This is a pertinent gene from the NIHR BioResource - Rare Diseases Study (NIHRBR-RD) BRIDGE Study : SPEED (Specialist Pathology: Evaluating Exomes in Diagnostics) which covers epilepsies, movement and microcephaly disorders, this gene is on the SPEED_NEURO_20170705 gene list. Evidences used for SPEED NEURO gene list: in_ddg2p_20141118_conf;in_ddg2p_20141118_conf;in_ddg2p_201507;in_ddg2p_201507_conf;in_ddg2p_2_4_2017;in_ddg2p_2_4_2017_conf;in_gilissen_2014_known . Main mutation mechanism : Loss of function; Cis-regulatory or promotor mutation
Created: 27 Jul 2017, 8:32 p.m.
Evidences key, gene present in following gene lists and main mutation mechanism : ddg2p_20141118; ddg2p_20141118_conf; ddg2p_201507; ddg2p_201507_conf; find_uk10k; gilissen_2014_known; Nijmegen_ID_diagnostic; Nijmegen_ID_candidates; GEL_ID_green_20160217; neuro_20160418_strict; Loss of function; Cis-regulatory or promotor mutation. This is a pertinent gene from the BRIDGE Study : SPEED (Specialist Pathology: Evaluating Exomes in Diagnostics) which covers epilepsies, movement and microcephaly disorders, this gene comes from the SPEED_NEURO_v3.0_20170404 gene list. The following experts from the BRIDGE consortium NIHRBR-RD contributed to this panel: - Professor F. Lucy Raymond, Cambridge Institute for Medical Research, University of Cambridge - Manju Kurian, Paediatric neurologist, Great Ormond Street Hosptial - Keren Carss, NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust - Alba Sanchis-Juan, NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust - Marie Erwood NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust - Louise Daugherty, NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust
Created: 19 Jul 2017, 1:26 p.m.

Mode of inheritance
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)

Publications

Created: 2 Aug 2017, 10:51 p.m.

Panel version: 1.354

Lu Raymond (university of cambridge )

Green List (high evidence)

Created: 23 Feb 2016, 11:01 a.m.

Panel version: 0.306

Details

Mode of Inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females
Sources
  • Expert Review Amber
  • Victorian Clinical Genetics Services
  • Radboud University Medical Center, Nijmegen
  • Emory Genetics Laboratory
Phenotypes
  • Intellectual developmental disorder, X-linked, with isolated growth hormone deficiency, OMIM:300123
  • X-linked intellectual disability with isolated growth hormone deficiency, MONDO:0019032
OMIM
313430
Clinvar variants
Variants in SOX3
Penetrance
Complete
Publications
Panels with this gene

History Filter Activity

19 Dec 2025, Gel status: 2

Set Phenotypes

Ida Ertmanska (Genomics England Curator)

Phenotypes for gene: SOX3 were changed from Mental retardation, X-linked, with isolated growth hormone deficiency, OMIM:300123; Intellectual disability, X-linked, with panhypopituitarism, MONDO:0010252 to Intellectual developmental disorder, X-linked, with isolated growth hormone deficiency, OMIM:300123; X-linked intellectual disability with isolated growth hormone deficiency, MONDO:0019032

19 Dec 2025, Gel status: 2

Set publications

Ida Ertmanska (Genomics England Curator)

Publications for gene: SOX3 were set to

19 Dec 2025, Gel status: 2

Set mode of inheritance

Ida Ertmanska (Genomics England Curator)

Mode of inheritance for gene: SOX3 was changed from X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to X-LINKED: hemizygous mutation in males, biallelic mutations in females

10 Mar 2022, Gel status: 2

Removed Tag

Arina Puzriakova (Genomics England Curator)

Tag for-review was removed from gene: SOX3.

9 Mar 2022, Gel status: 2

Added New Source, Status Update

Arina Puzriakova (Genomics England Curator)

Source Expert Review Amber was added to SOX3. Rating Changed from Green List (high evidence) to Amber List (moderate evidence)

7 Dec 2020, Gel status: 3

Set Phenotypes

Arina Puzriakova (Genomics England Curator)

Phenotypes for gene: SOX3 were changed from Mental retardation, X-linked, with isolated growth hormone deficiency, 300123Panhypopituitarism, X-linked, 312000; SEX REVERSAL TYPE 3 (SRXX3) to Mental retardation, X-linked, with isolated growth hormone deficiency, OMIM:300123; Intellectual disability, X-linked, with panhypopituitarism, MONDO:0010252

7 Dec 2020, Gel status: 3

Added Tag

Arina Puzriakova (Genomics England Curator)

Tag for-review tag was added to gene: SOX3.

29 Sep 2018, Gel status: 4

Added New Source

Louise Daugherty (Genomics England Curator)

Source Victorian Clinical Genetics Services was added to SOX3.

12 Mar 2018, Gel status: 3

Panel promoted to version 2.0

Ellen McDonagh (Genomics England Curator)

12.03.2018: Due to major updates completed (Phase 1, 2 and 3), this panel was promoted to Version 2 in order to reflect the major updates since November 2017 which have resulted in reviews for 836 genes added by Genomics England Curators and the Clinical Team, 130 new Green genes added to the interpretation pipeline (from 751 to 881 Green genes), and the gene total has increased from 1879 to 1927.

13 Nov 2015, Gel status: 4

gel status update

GEL ()

The Gel status was updated for this whole panel

13 Nov 2015, Gel status: 4

gel status update

GEL ()

The Gel status was updated for this whole panel

13 Nov 2015, Gel status: 2

Added New Source

Ellen McDonagh (Genomics England Curator)

SOX3 was added to Intellectual disabilitypanel. Source: Expert Review Green

24 Jun 2015, Gel status: 2

Set Mode of Inheritance

Ellen McDonagh (Genomics England Curator)

Model of inheritance for gene SOX3 was changed to X-LINKED: hemizygous mutation in males, may be caused by monoallelic mutations in females

24 Jun 2015, Gel status: 2

Added New Source

Ellen McDonagh (Genomics England Curator)

SOX3 was added to Intellectual disabilitypanel. Sources: Emory Genetics Laboratory,Radboud University Medical Center, Nijmegen

24 Jun 2015, Gel status: 1

Added New Source

Ellen McDonagh (Genomics England Curator)

SOX3 was added to Intellectual disabilitypanel. Sources: Emory Genetics Laboratory,Radboud University Medical Center, Nijmegen