The relationship between genotype and phenotype in Chinese children with glucose transporter type 1 deficiency syndrome

Mei-Jiao Zhang¹Shi-Min Zhang²Qingping Zhang¹Yongxin Wen³Wang Jiaping⁴Hui Xiong⁴Yuwu Jiang¹Xinhua Bao^1*

• ¹Department of Pediatrics, First Hospital, Peking University, Beijing, China
• ²Department of Pediatrics, Peking University People’s Hospital, Beijing, China, beijing, China
• ³Department of Pediatric Neurology, Guangdong Women and Children Hospital, Guangdong,, Guangdong, China
• ⁴Department of Neurology, Beijing Children′s Hospital, Capital Medical University, Beijing, China, beijing, China

ABSTRACT RunningTitleBackgroundGlucosetransporter type 1 deficiency syndrome (Glut1DS) is a treatable neurogeneticmetabolicdisordercausedbypathogenic variants in the SLC2A1 gene. The relationship between genotypeandphenotypehasnotbeenextensivelystudiedin large cohorts within China. This study aimed to analyze the clinical and genetic characteristics and the genotype-phenotype correlation in Chinese children with Glut1DS.MethodsClinicaldataofGlut1DSpatients, including age ofonset,clinicalmanifestations, cerebrospinal fluid (CSF) analysis,andSLC2A1 gene variants, were collected and analyzed. ResultsAtotal of 93 patients with Glut1DS were included,amongwhom65 (70%) were classical phenotypes (including55early-onset classical cases and 10 late-onset classical cases),and28 (30%)werenon-classicalphenotypes. Significant differenceswereobservedamongearly-onsetclassical,late-onset classical, and non-classical groups in terms of age of onset (p < 0.001),episodicpsychiatric/behavioral abnormalities (p = 0.012),CSF glucose levels (p < 0.001), the CSFglucosetobloodglucose (p = 0.003).Geneticvariantanalysisidentified 40 previously reported and 32 novel SLC2A1 variants.Thesevariant wereclassifiedintothree types: Type A (missense and in-frame indel variants, n = 52), Type B (frameshift, nonsense, splicing site, and initiation codon variants, n = 32), and Type C (single/multiple exon or whole-gene deletions, n = 9). No statistically significant difference Running Title was found in the distribution of these three genotypes across early-onset classical, late-onset classical, and non-classical phenotype. However, there were differences in age of onset among the three genetic variant groups (p = 0.009), with Type A variants showing a later age of onset compared to Type B variants (p = 0.014). No significant differences were observed among the three variant groups regarding CSF glucose levels, the ratio of CSF glucose to blood glucose, or CSF lactate levels. Furthermore, patients with identical variants exhibited phenotypic variability, for example, among eight patients (9%) harboring the c.997C>T (p.Arg333Trp) variant, six had early-onset classical phenotypes, while two had non-classical phenotypes. Conclusion Glut1DS predominantly manifests as the classical phenotype, with the early-onset classical phenotype presenting at the youngest age and exhibiting the most severe clinical symptoms. Patients with this type also showed lower CSF glucose levels and a lower CSF glucose to blood glucose ratio compared to other types. Missense and in-frame indel variants were associated with a later age of onset compared to other types of genetic variants. No significant correlations were found between genotype and clinical classification or CSF glucose levels.