Genomic analysis identifies a new EIF2B3 gene variant detected in an uncertain case of CADASIL disease

Introduction: Vanishing white matter disease (VWM) is an autosomal recessive leukodystrophy caused by mutations genes encoding the translational initiation factor 2B: EIF2B1-EIFB5. It is a heterogeneous neurological disorder with prominent cerebellar ataxia and spasticity in childhood-onset form and behavioural changes, dementia and seizures in adult-onset form (#15% of cases). The course of the disease is chronic progressive with episodes of stress-provoked rapid neurological deterioration. Purpose of the study: We present the case of a 60 years old patient, MTHFR homozygous, presenting white matter lesions and a subcortical vascular encephalopathy being diagnosed. To investigate a possible genetic cause, suspecting CADASIL, genetic and genomic analysis were performed. Materials and Methods: For genetic and genomic investigations, Sanger sequencing of NOTCH3 gene, linked to CADASIL disease, and Next Generation Sequencing (NGS) analysis were performed on the patient. NOTCH3 sequencing was performed using primer pairs for all 22 exons, while for NGS analysis, we used a genes panel including 753 genes involved in neurological diseases. Libraries were prepared using Ion Ampliseq Library preparation kit 2.0 (Thermo Fisher Scientific) and they were run on Ion Torrent PGM (Thermo Fisher Scientific). We performed the alignment using Torrent Suite v. 5.10 and we used ANNOVAR for annotation step. Results: Sanger sequencing did not reveal any mutation in NOTCH3 gene, excluding CADASIL disease as the genetic cause responsible for the clinical history of our patient. NGS detected a novel heterozygous non- synonimous variant in exon 5 of EIF2B3 gene (c. C554G; p. S185C), whose mutations have been strongly related to leukoencephalopathy and VWM disease. Furthermore, all in silico analysis conducted on this variant predicts its deleterious impact that could affect protein function. Conclusion: S185C variant in EIF2B3 gene was discovered in an atypical condition of adult onset Leukodistrophy, a disease that usually occurs in childhood. It is uncertain if S185C could be responsible for the clinical history of our patient or if the peculiarity of his symptoms could be related to the potential contribution of this new detected variant on the phenotypical spectrum observed in the disease.