Mutated RAP1GDS1 causes a new syndrome of dysmorphic feature, intellectual disability & speech delay

Abstract

BackgroundRAP1GDS1 (RAP1, GTP‐GDP dissociation stimulator 1), also known as SmgGDS, is a guanine nucleotide exchange factor (GEF) that regulates small GTPases, including, RHOA, RAC1, and KRAS. RAP1GDS1 was shown to be highly expressed in different tissue types including the brain. However, mutations in the RAP1GDS1 gene associated with human diseases have not previously been reported.MethodsWe report on four affected individuals, presenting intellectual disability, global developmental delay (GDD), and hypotonia. The probands’ DNA was subjected to whole‐genome sequencing, revealing a homozygous splice acceptor site mutation in the RAP1GDS1 gene (1444‐1G > A). Sanger sequencing was performed to confirm the segregation of the variant in two Saudi families. The possible aberrant splicing in the patients’ RNA was investigated using RT‐PCR and changes in mRNA expression of the patients were confirmed using qRT‐PCR.ResultsThe identified splice variant was found to segregate within the two families. RT‐PCR showed that the mutation affected RAP1GDS1 gene splicing, resulting in the production of aberrant transcripts in the affected individuals. Quantitative gene expression analysis demonstrated that the RAP1GDS1 mRNA expression in all the probands was significantly decreased compared to that of the control, and Sanger sequencing of the probands’ cDNA revealed skipping of exon 13, further strengthening the pathogenicity of this variant.ConclusionWe are the first to report the mutation of the RAP1GDS1 gene as a potential cause of GDD and hypotonia. However, further investigations into the molecular mechanisms involved are required to confirm the role of RAP1GDS1 gene in causing GDD and hypotonia.

Identification of the TTC26 Splice Variant in a Novel Complex Ciliopathy Syndrome with Biliary, Renal, Neurological, and Skeletal Manifestations

“…All reactions were performed in triplicate and repeated independently. Expression-Suite software version 1.1 (Applied Biosystems) was used for analysis [Asiri et al, 2020;Umair et al, 2020].…”

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“…The founder variant we identified in RAP1GDS1 (NM_001100426.1:c.1444-1G>A) is another example. This variant was reported in an apparently new syndrome of dysmorphic facies and intellectual disability (Asiri et al, 2020). We identified the same variant in the two siblings with the same phenotype ( Figure 1B) (Bertoli-Avella et al, submitted).…”

EMC10 homozygous variant identified in a family with global developmental delay, mild intellectual disability, and speech delay

“…Washing was performed using isopropanol, followed by precipitation with 75% ethanol. Quantification and purity tests were performed using standard methods 10 …”

“…Data were analyzed using expression Suite software version 1.1 (Applied Biosystems). PCR cycle conditions were the same as described previously, 10 and GAPDH was used as the endogenous control.…”

“…Quantification and purity tests were performed using standard methods. 10 2.7 | Quantitative real-time PCR . PCR cycle conditions were the same as described previously, 10 and GAPDH was used as the endogenous control.…”