Abstracts

Rationale: Infantile spasms (IS) is a severe epileptic encephalopathy of infancy characterized by epileptic spasms and often associated with hypsarrhythmia and developmental regression. More than 50 genes have been associated with IS and yet many patients remain without a clear etiology suggesting additional undiscovered genes. Methods: WES was performed on 21 patients with IS and their unaffected parents in a trio-based study. Patients treated with ACTH were enrolled as part of a pharmacogenomics project. Using a well-established analysis pipeline, rare, potentially deleterious exonic variants were identified and segregated by inheritance patterns. Variants were further prioritized based on in silico evidence for relevance to disease phenotype and/or known associations with infantile spasms, epilepsy or neurologic disease to generate a refined group of potentially pathogenic candidates. Results: 21 patients with IS were enrolled as part of the pharmacogenomics study. Two patients had brain imaging that supports an acquired etiology rather than genetic and two patients had Down Syndrome. There were six patients with developmental brain anomalies including one with septo-optic dysplasia, one with Aicardi Syndrome, two patients with heterotopias and dysplastic brain formation, and two with possible cortical dysplasia. The remaining eleven patients had normal or non-specific MRI findings without any clear genetic etiologies on clinical evaluations. A patient with optic nerve hypoplasia and otherwise normal brain MRI was found to have a de novo missense mutation in NR2F1 (c.329T>G (p.Phe110Cys)) which represents the third reported patient with infantile spasms with mutations in NR2F1. The two patients with heterotopia and focal polymicrogyria were noted to have mutations in known disease-associated genes, expanding the previously reported phenotypes. The first of these patients had compound heterozygous mutations in STRADA (c.1134G>A (p.Arg395His) and c.226G>A (p.Gly765Ser)) and the second had compound heterozygous mutations in TBCD (c.2852+3A>G and c.2566A>G (p.Met856Val)). In addition, the patient with septo-optic dysplasia was found to have compound heterozygous mutations (c.1918A>G (p.Lys640Glu) and c.2324G>T (p.Arg775Leu)) in RALGAPB, a gene that is believed to play an important role in neural signaling.  Additionally, candidate variants were identified in CELSR1, DMXL2, ASXL1, CDS1, FAT3, and SH3KBP1 which are suggestive, but will require confirmation either by discovery of additional cases with mutations in these genes or   by functional studies to support their relevance in disease etiology. Conclusions: This study supports the utility of WES in uncovering the genetic etiology in undiagnosed patients with infantile spasms. WES is not only a tool for the discovery of novel, potentially deleterious gene variants, but is also provides additional support for previously described but very rare disease associated genes, often expanding the mutational spectrum observed in previously described patients. Funding: This research was supported by an unrestricted research grant from Mallinckrodt Pharmaceuticals (Benke) as well as the Ponzio Family Endowed Chair in Neurology Research (Benke).