Molecular genetics of GLUT1DS Italian pediatric cohort: 10 novel related-disease variants and structural analysis

Abstract

GLUT1 deficiency syndrome (GLUT1DS1; OMIM #606777) is a rare genetic metabolic disease, characterized by infantile-onset epileptic encephalopathy, global developmental delay, progressive microcephaly and movement disorders (e.g. spasticity and dystonia). It is caused by heterozygous mutations in the SLC2A1 gene, which encodes the GLUT1 protein, a glucose transporter across the blood-brain barrier (BBB). Most commonly these variants arise de novo resulting in sporadic cases, although several familial cases with AD inheritance pattern have been described. Twenty-seven Italian pediatric patients clinically suspect of GLUT1DS from both sporadic and familial cases have been enrolled. We detected by trios sequencing analysis 25 different variants causing GLUT1DS. Of these, 40% of the identified variants (10 out of 25) had never been reported before, including missense, frameshift and splice site variants. Their X-ray structure analyses strongly suggested the potential pathogenic effects of these novel disease-related mutations, broadening the genotypic spectrum heterogeneity found in the SLC2A1 gene. Moreover, 24% is located in a vulnerable region of the GLUT1 protein that involves transmembrane 4 and 5 helices encoded by exon 4, confirming a mutational hotspot in the SLC2A1 gene. Lastly, we investigated possible correlations between mutation type and clinical and biochemical data observed in our GLUT1DS cohort, revealing that splice site and frameshift variants are related to a more severe phenotype and low CSF parameters. Author summaryWe investigated the molecular data of 27 pediatric patients clinically suspect of GLUT1 deficiency syndrome. By performing trios sequencing analysis, we highlighted ten novel disease-related variants, and their X-ray structure analyses, suggesting the pathogenic effects of these identified mutations. Moreover, the wide clinical and genetic heterogeneity observed in our cohort allowed possible correlations between mutation type and clinical and biochemical data. This analysis enabled to delineate that splice site and frameshift variants are related to a more severe phenotype and low CSF/glucose values. Further clinical and genetic/epigenetics studies could clearly the high phenotypic variability observed in these patients.