Journal Article

Re-analysis of whole-exome sequencing data reveals a novel splicing variant in the SLC2A1 in a patient with GLUT1 Deficiency Syndrome 1 accompanied by hemangioma: a case report

Bozkurt, Tugce, Alanay, Yasemin, Isik, Ugur, Sezerman, Ugur

2021

Overview

Background GLUT1 Deficiency Syndrome 1 (GLUT1DS1) is a neurological disorder caused by either heterozygous or homozygous mutations in the Solute Carrier Family 2, Member 1 ( SLC2A1 ) gene. SLC2A1 encodes Glucose transporter type 1 (GLUT1) protein, which is the primary glucose transporter at the blood–brain barrier. A ketogenic diet (KD) provides an alternative fuel for brain metabolism to treat impaired glucose transport. By reanalyzing exome data, we identified a de novo heterozygous SLC2A1 variant in a girl with epilepsy. After reversed phenotyping with neurometabolic tests, she was diagnosed with GLUT1DS1 and started on a KD. The patient's symptoms responded to the diet. Here, we report a patient with GLUT1DS1 with a novel SLC2A1 mutation. She also has a hemangioma which has not been reported in association with this syndrome before. Case presentation A 5-year 8-month girl with global developmental delay, spasticity, intellectual disability, dysarthric speech, abnormal eye movements, and hemangioma. The electroencephalography (EEG) result revealed that she had epilepsy. Magnetic resonance imaging (MRI) showed that non-specific white matter abnormalities. Whole Exome Sequencing (WES) was previously performed, but the case remained unsolved. The re-analysis of WES data revealed a heterozygous splicing variant in the SLC2A1 gene. Segregation analysis with parental DNA samples indicated that the variant occurred de novo. Lumbar puncture (LP) confirmed the diagnosis, and the patient started on a KD. Her seizures responded to the KD. She has been seizure-free since shortly after the initiation of the diet. She also had decreased involuntary movements, her speech became more understandable, and her vocabulary increased after the diet. Conclusions We identified a novel de novo variant in the SLC2A1 gene in a patient who previously had a negative WES result. The patient has been diagnosed with GLUT1DS1. The syndrome is a treatable condition, but the differential diagnosis is not an easy process due to showing a wide range of phenotypic spectrum and the overlapping symptoms with other neurological diseases. The diagnosis necessitates a genomic testing approach. Our findings also highlight the importance of re-analysis to undiagnosed cases after initial WES to reveal disease-causing variants.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Biomedical and Life Sciences / Biomedicine / Blood-brain barrier / Carbohydrate Metabolism, Inborn Errors - genetics / Case Report / Case studies / Child, Preschool / Convulsions & seizures / Data analysis / Diagnosis / Diagnostic tests / Diet / Diet, Ketogenic / Differential diagnosis / Dystonia / EEG / Epilepsy / Exome Sequencing / Female / Gene Expression / Genetic aspects / Genetic disorders / Genetic variation / Genomes / Genomics / Genotype & phenotype / Glucose / Glucose metabolism / Glucose transport / Glucose transporter / Glucose Transporter Type 1 - deficiency / Glucose Transporter Type 1 - genetics / GLUT1 Deficiency Syndrome 1 / Hemangioma / Hemangioma - genetics / High fat diet / Human Genetics / Humans / Intellectual disabilities / Ketogenesis / Ketogenic diet / Low carbohydrate diet / Magnetic resonance imaging / Microarrays / Microcephaly / Monosaccharide Transport Proteins - deficiency / Monosaccharide Transport Proteins - genetics / Movement disorders / Mutation / Neuroimaging / Neurological diseases / Patients / Pediatric research / Phenotyping / Prognostics and diagnostics/biomarkers / RNA splicing / RNA Splicing - genetics / Seizures / SLC2A1 / Spasticity / Speech / Substantia alba / Whole exome sequencing