Exome sequencing identifies a novel mutation of the GDI1 gene in a Chinese non-syndromic X-linked intellectual disability family

Abstract

X-linked intellectual disability (XLID) has been associated with various genes. Diagnosis of XLID, especially for non-syndromic ones (NS-XLID), is often hampered by the heterogeneity of this disease. Here we report the case of a Chinese family in which three males suffer from intellectual disability (ID). The three patients shared the same phenotype: no typical clinical manifestation other than IQ score ≤ 70. For a genetic diagnosis for this family we carried out whole exome sequencing on the proband, and validated 16 variants of interest in the genomic DNA of all the family members. A missense mutation (c.710G > T), which mapped to exon 6 of the Rab GDP-Dissociation Inhibitor 1 (GDI1) gene, was found segregating with the ID phenotype, and this mutation changes the 237th position in the guanosine diphosphate dissociation inhibitor (GDI) protein from glycine to valine (p. Gly237Val). Through molecular dynamics simulations we found that this substitution results in a conformational change of GDI, possibly affecting the Rab-binding capacity of this protein. In conclusion, our study identified a novel GDI1 mutation that is possibly NS-XLID causative, and showed that whole exome sequencing provides advantages for detecting novel ID-associated variants and can greatly facilitate the genetic diagnosis of the disease.

A systematic genotype-phenotype map for missense variants in the human intellectual disability-associated geneGDI1

“…For this variant, we obtained a fitness score of 0.74 +/- 0.03. Individuals in a family carrying the Gly237Val variant had moderate ID 33 , and we observed a corresponding lower fitness score of 0.55 +/- 0.07 for Gly237Val. Thus, the order of the fitness scores for these two variants agreed with the reported order of ID severity.…”

“…The set of presumed damaging variants consists of the two missense variants with “pathogenic” clinical significance on ClinVar, Leu92Pro 11 and Arg423Pro 15 , as well as a third variant described more recently, Gly237Val 33 . Additionally, four variants were included which were shown to inhibit GDI1 function in functional assays, Tyr39Val, Glu233Ser, Met250Tyr, and Thr248Pro 27 .…”

“…Our set of presumed damaging human variants contained Leu92Pro (11), Arg423Pro (15), and Gly237Val (33). Arg423pro is currently annotated as "pathogenic" on ClinVar.…”

“…Gly237Val was added to ClinVar more recently and is also annotated as having "uncertain significance", however this variant seemed likely to be deleterious based on familial segregation analysis by Duan et. al (33). We included four additional variants, Tyr39Val, Glu233Ser, Met250Tyr, and Thr248Pro (27), which have not been observed in humans, but which were shown to inhibit GDI1 function in functional assays.…”

Overexpression of GDP dissociation inhibitor 1 gene associates with the invasiveness and poor outcomes of colorectal cancer

“…Rab GDI reduces the expression of Rab3A, an active protein related to synaptic vesicles, in the brain tissues of schizophrenic patients [ 32 ]. Previous studies have shown that GDI1 is associated with intellectual disability [ 33 ], hyperexcitability [ 34 , 35 ] and memory formation in the forebrain region of mice [ 36 ]. However, the role of GDI1 in tumors has not been reported.…”