Phenotype and genotype spectrum of variants in guanine nucleotide exchange factor genes in a broad cohort of Iranian patients

Abstract

Background Guanine nucleotide exchange factors (GEFs) play pivotal roles in neuronal cell functions by exchanging GDP to GTP nucleotide and activation of GTPases. We aimed to determine the genotype and phenotype spectrum of GEF mutations by collecting data from a large Iranian cohort with intellectual disability (ID) and/or developmental delay (DD). Methods We collected data from nine families with 20 patients extracted from Iranian cohort of 640 families with ID and/or DD. Next‐generation sequencing (NGS) was used to identify the causing variants in recruited families. We also compared our clinical and molecular findings with previously reported patients carrying mutations in these GEF genes in the literature published until mid‐2021. Results We identified disease‐causing variants in eight GEF genes including ALS2, IQSEC2, MADD, RAB3GAP1, RAB3GAP2, TRIO, ITSN1, and DENND2A. The major clinical manifestations in 203 previously reported cases along with our 20 patients with disease causing variants in eight GEF genes were as follow; speech disorder (85.2%), ID (81.6%), DD (81.1%), inability to walk (71.3%), facial dysmorphisms features (52.4%), abnormalities in skull morphology (55.6%), hypotonia and muscle weakness (47%), and brain MRI abnormalities (43.4%). Conclusion Our study provides new insights into the genotype and phenotype spectrum of mutations in GEF genes.

Further evidence of involvement of ITSN1 in autosomal dominant neurodevelopmental disorder

“…The ITSN1 variant p.(Trp949*) identified in this study lies in the SH3 domain of and in close proximity of previously known variants [p.(Met948Val*41) and p.(Tyr965*)] for ASD 1,4 . Furthermore, biallelic variants in the ITSN1 gene have also been known to cause autosomal recessive intellectual disability (ARID) 5 …”

Identifying shared genetic factors underlying epilepsy and congenital heart disease in Europeans

“…In the HGMD Professional version, the phenotypes listed as being associated with DENND2A were 'congenital heart disease' and 'intellectual disability'. It has been reported that mutations in DENND2A are associated with multiple phenotypes, including ischemic stroke, Parkinson's disease and non-syndromic intellectual disability (Lang et al 2019;Mosallaei et al 2022). However, we did not nd any overlapping genes between the UK Biobank and BioMe BioBank results for genes associated with both EP and CHD (likely due to phenotyping and genotyping differences between the biobanks, as well as sample sizes; see Methods).…”

Identifying Shared Genetic Factors Underlying Epilepsy and Congenital Heart Disease in Europeans

“…In HGMD Professional, the phenotypes listed as being associated with DENND2A were 'congenital heart disease' and 'intellectual disability'. It has been reported that mutations in DENND2A are associated with multiple phenotypes, including ischemic stroke, Parkinson's disease, and non-syndromic intellectual disability (Lang et al 2019;Mosallaei et al 2022). However, we did not find any overlapping genes between the UK Biobank and BioMe BioBank results for genes associated with both EP and CHD (likely due to phenotyping and genotyping differences between the biobanks, as well as sample sizes; see Methods).…”