Submission Details

GDI1 was first reported in relation to non-syndromic X-linked intellectual disability in 1996 (Hamel et al., PMID: 8826463). Frequently reported phenotypic features in males include intellectual disability varying from mild to severe. Female carriers range from mild intellectual disability to intellect in the normal range. Five variants (missense, protein truncating, and frameshift) that have been reported in five probands in six publications (PMIDs: 8826463, 9106537, 9620768, 9668174, 22002931, and 28863211) are included in this curation. For four of the reported probands, segregation scoring was included based on published LOD scores within the appropriate articles. The mechanism of pathogenicity is most likely loss of function.

The gene-disease relationship is also supported by animal models and functional alteration data (PMIDs: 9620768, 20159109, 22291894, and 10473636). GDI1 knockout mouse models showed behavioral features consistent with neurodevelopmental disorders such as impaired short term memory, altered social behavior, cognitive impairment in mazes, and impaired attention (PMID: 9620768). Rat-derived neurons treated with GDI1 knockdown antisense oligonucleotides had reduced growth and function, suggesting GDI1 plays an important role in neurodevelopment (PMIDs: 9620768 and 10473636).

This gene-disease pair was originally evaluated by the Intellectual Disability and Autism Gene Curation Expert Panel on May 24, 2018 (SOP Version 5). It was reevaluated on April 27, 2023 (SOP Version 10). As a result of this reevaluation, the classification did not change. This gene-disease pair remains classified as moderate due to limited reported variants. Additionally, the reported phenotypes have been nonspecific and testing has been targeted to X-linked genes rather than comprehensive exome or genome sequencing.

GDI1 was first reported in relation to non-syndromic X-linked intellectual disability in 1996 (Hamel et al., PMID: 8826463). Frequently reported phenotypic features in males include intellectual disability varying from mild to severe. Female carriers range from mild intellectual disability to intellect in the normal range. Five variants (missense, protein truncating, and frameshift) that have been reported in five probands in six publications (PMIDs: 8826463, 9620768, 9106537, 9668174, 22002931, and 28863211) are included in this curation. For four of the reported probands, segregation scoring was included based on published LOD scores within the appropriate articles.

The mechanism of pathogenicity is most likely loss of function. The gene-disease relationship is also supported by animal models and functional alteration data (PMIDs: 9620768, 20159109, 22291894, and 10473636). GDI1 knockout mouse models showed behavioral features consistent with neurodevelopmental disorders such as impaired short term memory, altered social behavior, cognitive impairment in mazes, and impaired attention (PMID: 9620768). Rat-derived neurons treated with GDI1 knockdown antisense oligonucleotides had reduced growth and function, suggesting GDI1 plays an important role in neurodevelopment (PMIDs: 9620768 and 10473636).

This gene-disease pair was originally evaluated by the Intellectual Disability and Autism GCEP on May 24, 2018 (SOP Version 5) . It was reevaluated on April 27, 2023 (SOP Version 10). As a result of this reevaluation, the classification did not change. This gene-disease pair remains classified as moderate due to limited reported variants. Additionally, the reported phenotypes have been nonspecific and testing has been targeted to X-linked genes rather than comprehensive exome or genome sequencing.