Intellectual disability - microarray and sequencing
Gene: ARHGEF6PMID: 22511880 (2012) - a variant in the ARHGEF6 gene (p.I444N) was identified in a male patient with autism. However, this individual harboured variants in other genes (UBE3B) that were likely to explain their phenotype so conclusions about the consequence of the ARHGEF6 variant cannot be made in this case.
Comment on publications: PMIDs: 22511880 (2012) and 26177020 (2015) were identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniquesCreated: 26 Feb 2024, 12:19 p.m. | Last Modified: 26 Feb 2024, 12:21 p.m.
Panel Version: 5.461
Following discussion with the clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza StarkCreated: 17 Aug 2020, 9:21 a.m. | Last Modified: 17 Aug 2020, 9:21 a.m.
Panel Version: 3.250
We have rated this gene as Red considering some of the evidence was from cytogenetic abnormalities and other reported variants are now found to be present in the population at high frequency.Created: 29 Jan 2020, 1:36 a.m. | Last Modified: 29 Jan 2020, 1:36 a.m.
Panel Version: 3.0
Phenotypes
MENTAL RETARDATION X-LINKED TYPE 46
Comment on list classification: demoted from Green to AmberCreated: 2 Apr 2019, 10:09 a.m.
Literature review identifies lack of clarity about published data on this gene. As per note in OMIM entry:
ARHGEF6, IVS1AS, T-C, -11 (rs140322310)
RCV000012185
This variant, formerly titled MENTAL RETARDATION, X-LINKED 46, has been reclassified based on a review of the ExAC database by Hamosh (2018).
In affected males in a large Dutch family with nonspecific X-linked mental retardation (MRX46; 300436), Kutsche et al. (2000) identified a mutation in the ARHGEF6 gene. The base change IVS1-11T-C had a marginal effect on the predicted splicing efficiency but was not detected in 170 control chromosomes. In affected males, RT-PCR amplification demonstrated products of 2 different sizes: a larger amplicon corresponding to the wildtype fragment, and a smaller amplicon in which exon 1 was spliced to exon 3. Thus, all mentally retarded males in the MRX46 family exhibited enhanced skipping of exon 2.
Hamosh (2018) found that the IVS1-11T-C variant (rs140322310) was present in 53 hemizygotes in the ExAC database (November 21, 2018), suggesting that the variant is not pathogenicCreated: 26 Mar 2019, 2:33 p.m.
Literature review identifies lack of clarity about published data on this gene. As per note in OMIM entry:
ARHGEF6, IVS1AS, T-C, -11 (rs140322310)
RCV000012185
This variant, formerly titled MENTAL RETARDATION, X-LINKED 46, has been reclassified based on a review of the ExAC database by Hamosh (2018).
In affected males in a large Dutch family with nonspecific X-linked mental retardation (MRX46; 300436), Kutsche et al. (2000) identified a mutation in the ARHGEF6 gene. The base change IVS1-11T-C had a marginal effect on the predicted splicing efficiency but was not detected in 170 control chromosomes. In affected males, RT-PCR amplification demonstrated products of 2 different sizes: a larger amplicon corresponding to the wildtype fragment, and a smaller amplicon in which exon 1 was spliced to exon 3. Thus, all mentally retarded males in the MRX46 family exhibited enhanced skipping of exon 2.
Hamosh (2018) found that the IVS1-11T-C variant (rs140322310) was present in 53 hemizygotes in the ExAC database (November 21, 2018), suggesting that the variant is not pathogenicCreated: 26 Mar 2019, 2:32 p.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
300436
Comment on publications: PMID: 21989057 - mouse model of gene knockout have an imbalance in activity of different Rho GTPases, and exhibited impaired spatial and complex learning and less behavioral control in mildly stressful situations. PMID: 20861843 - report a Xq26.2-Xq26.3 duplication in two brothers with severe mental retardation, hypotonia, growth delay, craniofacial disproportion and dental malocclusion. This encompasses 24 known genes, including ARHGEF6, PHF6, HPRT1 and SLC9A6.Created: 15 May 2018, 12:47 p.m.
Mode of inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females
Phenotypes
MENTAL RETARDATION X-LINKED TYPE 46
Publications
Publications for gene: ARHGEF6 were set to 21989057; 20861843; 17304053; 11017088; 26177020; 22511880
Publications for gene: ARHGEF6 were set to 21989057; 20861843; 17304053; 11017088; 26177020
Publications for gene: ARHGEF6 were set to 21989057; 20861843; 17304053; 11017088
Phenotypes for gene: ARHGEF6 were changed from Mental retardation, X-linked 46, 300436; Mental Retardation, X-linked; MENTAL RETARDATION X-LINKED TYPE 46 to Intellectual developmental disorder, X-linked 46, OMIM:300436
Source Expert Review Red was added to ARHGEF6. Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Gene: arhgef6 has been classified as Amber List (Moderate Evidence).
Source Victorian Clinical Genetics Services was added to ARHGEF6.
Publications for ARHGEF6 were set to 21989057; 20861843; 17304053; 11017088
Publications for ARHGEF6 were set to 21989057; 20861843; 17304053
Publications for ARHGEF6 were set to 21989057; 20861843
Publications for ARHGEF6 were set to 21989057; 20861843
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.
The Gel status was updated for this whole panel
The Gel status was updated for this whole panel
ARHGEF6 was added to Intellectual disabilitypanel. Source: Expert Review Green Model of inheritance for gene ARHGEF6 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Model of inheritance for gene ARHGEF6 was changed to X-LINKED: hemizygous mutation in males, may be caused by monoallelic mutations in females
ARHGEF6 was added to Intellectual disabilitypanel. Sources: Illumina TruGenome Clinical Sequencing Services,Radboud University Medical Center, Nijmegen
ARHGEF6 was added to Intellectual disabilitypanel. Sources: Illumina TruGenome Clinical Sequencing Services,Radboud University Medical Center, Nijmegen