Intellectual disabilityGene: SOX4 Green List (high evidence)
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
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.
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.
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.
As a result SOX4 can be considered for inclusion in the ID panel as green (or amber).
Created: 19 Jan 2019, 6:47 p.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Global developmental delay; Intellectual disability; Growth delay; Clinodactyly of the 5th finger; Abnormality of head or neck
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
Gene: sox4 has been classified as Green List (High Evidence).
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
Publications for gene: SOX4 were set to
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
If promoting or demoting a gene, please provide comments to justify a decision to move it.
Genes included in a Genomics England gene panel for a rare disease category (green list) should fit the criteria A-E outlined below.
These guidelines were developed as a combination of the ClinGen DEFINITIVE evidence for a causal role of the gene in the disease(a), and the Developmental Disorder Genotype-Phenotype (DDG2P) CONFIRMED DD Gene evidence level(b) (please see the original references provided below for full details). These help provide a guideline for expert reviewers when assessing whether a gene should be on the green or the red list of a panel.
A. There are plausible disease-causing mutations(i) within, affecting or encompassing an interpretable functional region(ii) of this gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
B. There are plausible disease-causing mutations(i) within, affecting or encompassing cis-regulatory elements convincingly affecting the expression of a single gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
C. As definitions A or B but in 2 or 3 unrelated cases/families with the phenotype, with the addition of convincing bioinformatic or functional evidence of causation e.g. known inborn error of metabolism with mutation in orthologous gene which is known to have the relevant deficient enzymatic activity in other species; existence of an animal model which recapitulates the human phenotype.
D. Evidence indicates that disease-causing mutations follow a Mendelian pattern of causation appropriate for reporting in a diagnostic setting(iv).
E. No convincing evidence exists or has emerged that contradicts the role of the gene in the specified phenotype.
(i)Plausible disease-causing mutations: Recurrent de novo mutations convincingly affecting gene function. Rare, fully-penetrant mutations - relevant genotype never, or very rarely, seen in controls. (ii) Interpretable functional region: ORF in protein coding genes miRNA stem or loop. (iii) Phenotype: the rare disease category, as described in the eligibility statement. (iv) Intermediate penetrance genes should not be included.
It’s assumed that loss-of-function variants in this gene can cause the disease/phenotype unless an exception to this rule is known. We would like to collect information regarding exceptions. An example exception is the PCSK9 gene, where loss-of-function variants are not relevant for a hypercholesterolemia phenotype as they are associated with increased LDL-cholesterol uptake via LDLR (PMID: 25911073).
If a curated set of known-pathogenic variants is available for this gene-phenotype, please contact us at [email protected]
We classify loss-of-function variants as those with the following Sequence Ontology (SO) terms:
Term descriptions can be found on the PanelApp homepage and Ensembl.
If you are submitting this evaluation on behalf of a clinical laboratory please indicate whether you report variants in this gene as part of your current diagnostic practice by checking the box
Standardised terms were used to represent the gene-disease mode of inheritance, and were mapped to commonly used terms from the different sources. Below each of the terms is described, along with the equivalent commonly-used terms.
A variant on one allele of this gene can cause the disease, and imprinting has not been implicated.
A variant on the paternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on the maternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on one allele of this gene can cause the disease. This is the default used for autosomal dominant mode of inheritance where no knowledge of the imprinting status of the gene required to cause the disease is known. Mapped to the following commonly used terms from different sources: autosomal dominant, dominant, AD, DOMINANT.
A variant on both alleles of this gene is required to cause the disease. Mapped to the following commonly used terms from different sources: autosomal recessive, recessive, AR, RECESSIVE.
The disease can be caused by a variant on one or both alleles of this gene. Mapped to the following commonly used terms from different sources: autosomal recessive or autosomal dominant, recessive or dominant, AR/AD, AD/AR, DOMINANT/RECESSIVE, RECESSIVE/DOMINANT.
A variant on one allele of this gene can cause the disease, however a variant on both alleles of this gene can result in a more severe form of the disease/phenotype.
A variant in this gene can cause the disease in males as they have one X-chromosome allele, whereas a variant on both X-chromosome alleles is required to cause the disease in females. Mapped to the following commonly used term from different sources: X-linked recessive.
A variant in this gene can cause the disease in males as they have one X-chromosome allele. A variant on one allele of this gene may also cause the disease in females, though the disease/phenotype may be less severe and may have a later-onset than is seen in males. X-linked inactivation and mosaicism in different tissues complicate whether a female presents with the disease, and can change over their lifetime. This term is the default setting used for X-linked genes, where it is not known definitately whether females require a variant on each allele of this gene in order to be affected. Mapped to the following commonly used terms from different sources: X-linked dominant, x-linked, X-LINKED, X-linked.
The gene is in the mitochondrial genome and variants within this can cause this disease, maternally inherited. Mapped to the following commonly used term from different sources: Mitochondrial.
Mapped to the following commonly used terms from different sources: Unknown, NA, information not provided.
For example, if the mode of inheritance is digenic, please indicate this in the comments and which other gene is involved.