Submission Details

ARHGEF6 was first reported in relation to nonsyndromic X-linked intellectual disability (ID) in 2000 by Kutsche et al. (PMID: 11017088). They described a male with ID and an apparently balanced X;21 translocation disrupting ARHGEF6, inherited from his unaffected mother. The translocation was molecularly unbalanced, with a 10-bp deletion on the X chromosome and a 9-bp deletion in the β-satellite DNA on chromosome 21. No additional studies were done to determine the effects on ARHGEF6 expression. The mother did not show preferential inactivation of her normal X. This translocation was not counted as evidence because the impact of the breakpoints on neighboring genes cannot be ruled out. These authors went on to screen 119 additional patients with nonspecific ID for variants in ARHGEF6 and identified a variant within the first intron in all (tested) affected males in a large Dutch family. This variant has been found at a higher than expected frequency in the general population and is therefore not considered evidence in this evaluation. Two additional missense variants were described by Tarpey et al. (2009, PMID: 19377476); both have been observed at frequencies in the general population too high to be considered as evidence in this evaluation. According to gnomAD (v2.1.1), ARHGEF6 is highly constrained for protein truncating variants (pLI 1) but not for missense variants (Z score 1.35). Accordingly, and given the lack of functional studies, we decided not to score several other missense variants that have been reported in individuals with ID or autism spectrum disorder (PMIDs: 22511880, 23849776, 26350204, 28397838). There is also a report of two brothers with ID and a multi-gene duplication involving ARHGEF6 (Madrigal et al. 2010, PMID: 20861843; family also described in Madrigal et al. 2007, PMID: 17304053); this is not counted as evidence due to the multi-gene nature of the CNV.

In terms of experimental evidence, a knockout mouse model shows altered dendritic length and spine density in the hippocampus and deficits in spatial learning (Ramakers et al. 2012, PMID: 21989057). However, because of the lack of convincing human genetic evidence, we did not score this animal model.

In summary, the evidence supporting the relationship between ARHGEF6 and nonsyndromic X-linked ID has been disputed and no valid evidence remains to support the claim. More evidence is needed to either support or entirely refute the role ARHGEF6 plays in this disease. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on October 20, 2020 (SOP Version 8). Note that this gene-disease relationship was originally curated in June 2018 and given a limited classification. Changes in scoring practices resulted in the classification being updated.

The relationship between ARHGEF6 and nonsyndromic X-linked intellectual disability (ID) was first reported in 2000 by Kutsche et al. (PMID: 11017088). They described a male with ID and an apparently balanced X;21 translocation disrupting ARHGEF6, inherited from his unaffected mother. Using genomic walking, the authors showed that the translocation was molecularly unbalanced, with a 10-bp deletion on the X chromosome and a 9-bp deletion in the β-satellite DNA on chromosome 21. No additional studies were done to determine the effects on ARHGEF6 expression. The mother did not show preferential inactivation of her normal X. This translocation was not counted as evidence because the impact of the breakpoints on neighboring genes cannot be ruled out. These authors went on to screen 119 additional patients with nonspecific ID for variants in ARHGEF6 and identified a variant within the first intron in all (tested) affected males in a large Dutch family. This variant has been found at a higher than expected frequency in the general population and is therefore not considered evidence in this evaluation. Two additional missense variants were described by Tarpey et al. (2009, PMID: 19377476); both have been observed at frequencies in the general population too high to be considered as evidence in this evaluation. According to gnomAD (v2.1.1), ARHGEF6 is highly constrained for protein truncating variants (pLI 1) but not for missense variants (Z score 1.35). Accordingly, and given the lack of functional studies, we decided not to score several other missense variants that have been reported in individuals with ID or autism spectrum disorder (PMID: 22511880, 23849776, 26350204, 28397838). There is also a report of two brothers with ID and a multi-gene duplication involving ARHGEF6 (Madrigal et al. 2010, PMID: 20861843; family also described in Madrigal et al. 2007, PMID: 17304053); this is not counted as evidence due to the multi-gene nature of the CNV. In terms of experimental evidence, a knockout mouse model shows altered dendritic length and spine density in the hippocampus and deficits in spatial learning (Ramakers et al. 2012, PMID: 21989057). However, because of the lack of convincing human genetic evidence, we did not score this animal model. In summary, the evidence supporting an association between nonsyndromic X-linked ID and ARHGEF6 is disputed. This classification was approved by the ClinGen ID/Autism Expert Panel 10/20/2020. Note that this gene-disease relationship was originally curated in 06/2018 and given a limited classification. Changes in scoring practices resulted in the classification being updated.