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Intellectual disability

Gene: SOX4

Green List (high evidence)

SOX4 (SRY-box 4)
EnsemblGeneIds (GRCh38): ENSG00000124766
EnsemblGeneIds (GRCh37): ENSG00000124766
OMIM: 184430, Gene2Phenotype
SOX4 is in 4 panels

3 reviews

Louise Daugherty (Genomics England Curator)

Comment on phenotypes: added OMIM MIM id
Created: 19 Aug 2019, 9:57 a.m. | Last Modified: 19 Aug 2019, 9:57 a.m.
Panel Version: 2.1015

Rebecca Foulger (Genomics England curator)

Comment on list classification: Updated rating from Grey to Green: Gene added and reviewed by Konstantinos Varvagiannis based on a recent publication (PMID:30661772, Zawerton et al 2019) which provides 4 unrelated cases of patients with ID and DD, and a heterozygous variant in SOX4. Therefore sufficient cases for diagnostic rating on this panel.
Created: 25 Feb 2019, 5:12 p.m.
PMID:30661772 (Zawerton et al 2019, doi.org/10.1016/j.ajhg.2018.12.014) identified de novo SOX4 heterozygous missense variants in 4 children:a child recruited with syndromic ID, and 3 other children identified through the DDD study. All four subjects were from unrelated families of different heritage (Italian, Scottish-Hungarian, French and Scottish) and their SOX4 variants were distinct. All four children had global development delay and ID but in varying degrees (very mild, mild, severe and very severe). All case subjects also had characteristic facial dysmorphism and fifth-finger clinodactyly.
Created: 25 Feb 2019, 5:09 p.m.

Konstantinos Varvagiannis (Other)

Green List (high evidence)

Zawerton et al. (DDD study among the co-authors - doi.org/10.1016/j.ajhg.2018.12.014 - PMID:NA) report on 4 unrelated individuals with de novo SOX4 pathogenic variants. The common phenotype consisted of DD/ID (4/4 - very mild to severe), overlapping facial features as well as digital anomalies (5th finger clinodactyly in 4/4).

SOX4 is a member of the SOX family of transcription factors, all presenting at least 50% identity with SRY (the first identified member of this family) in the HMG (DNA-binding) domain. Most SOX genes have important roles in cell fate / differentiation. Mutations in other genes of this family (eg. SRY, SOX9, SOX10, SOX5) are associated with severe human syndromes.

SOX4 is highly expressed in human brain during gestation - particularly in areas of active neurogenesis - with progressive decrease thereafter until the 3rd - 4th decade of life.

Knockdown of the SOX4 ortholog in Xenopus laevis embryos resulted in smaller head size, microphthalmia, shorter body length and underdevelopment of fore- and mid-brain. (Growth deficiency was a common feature in affected individuals, and microcephaly in 2/4).

Sox4-null mice die in utero due to heart septation defects, while such abnormalities were not reported in heterozygous mice. One affected subject had a VSD. Sox4 inactivation in mice results in impaired skeletal growth (similarly to the patients).

All 4 different missense variants clustered in the HMG domain (aa 58-133) which appears relatively (more) depleted in missense variants (only 12 missense HMG-domain variants in gnomAD). [Overall the Z-score for missense variants is 3.72. pLI = 0.38. %HI in DECIPHER : 24.67%].

The 4 missense variants presented impaired DNA binding and transcription activation in COS-1 transfected cells which appeared to distinguish them from the 12 gnomAD ones. Synthesis, stability and nuclear translocation appeared to be similar to wt.

Other parameters eg. residue conservation in the SOX family, presence of "equivalent" known disease causing mutations in other SOX genes or in silico analyses suggesting structural consequences were supportive of a deleterious effect for the 4 variants (but also for some of the 12 gnomAD ones).

SOX4 and SOX11 have almost identical DNA-binding domains, while the mechanism of mutations reported and the phenotypes appear to be relatively similar, as commented by the authors.
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SOX4 is not associated with any phenotype in G2P, nor in OMIM.
This gene is not - at least commonly - included in gene panels for ID offered by diagnostic laboratories.
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As a result SOX4 can be considered for inclusion in the ID panel as green (or amber).
Sources: Literature
Created: 19 Jan 2019, 6:47 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Global developmental delay; Intellectual disability; Growth delay; Clinodactyly of the 5th finger; Abnormality of head or neck

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert Review Green
Phenotypes
  • Coffin-Siris syndrome 10, 618506
  • Syndromic intellectual disability
  • Global developmental delay
  • Intellectual disability
  • Growth delay
  • Clinodactyly of the 5th finger
  • facial dysmorphism
OMIM
184430
Clinvar variants
Variants in SOX4
Penetrance
unknown
Publications
Panels with this gene

History Filter Activity

19 Aug 2019, Gel status: 3

Set Phenotypes

Louise Daugherty (Genomics England Curator)

Phenotypes for gene: SOX4 were changed from Syndromic intellectual disability; Global developmental delay; Intellectual disability; Growth delay; Clinodactyly of the 5th finger; facial dysmorphism to Coffin-Siris syndrome 10, 618506; Syndromic intellectual disability; Global developmental delay; Intellectual disability; Growth delay; Clinodactyly of the 5th finger; facial dysmorphism

25 Feb 2019, Gel status: 3

Entity classified by Genomics England curator

Rebecca Foulger (Genomics England curator)

Gene: sox4 has been classified as Green List (High Evidence).

25 Feb 2019, Gel status: 0

Set Phenotypes

Rebecca Foulger (Genomics England curator)

Phenotypes for gene: SOX4 were changed from Global developmental delay; Intellectual disability; Growth delay; Clinodactyly of the 5th finger; Abnormality of head or neck to Syndromic intellectual disability; Global developmental delay; Intellectual disability; Growth delay; Clinodactyly of the 5th finger; facial dysmorphism

25 Feb 2019, Gel status: 0

Set publications

Rebecca Foulger (Genomics England curator)

Publications for gene: SOX4 were set to

19 Jan 2019, Gel status: 0

Created, Added New Source, Set mode of inheritance, Set Phenotypes, Set penetrance

Konstantinos Varvagiannis (Other)

gene: SOX4 was added gene: SOX4 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: SOX4 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Phenotypes for gene: SOX4 were set to Global developmental delay; Intellectual disability; Growth delay; Clinodactyly of the 5th finger; Abnormality of head or neck Penetrance for gene: SOX4 were set to unknown Review for gene: SOX4 was set to GREEN