Sánchez Iglesias, SofíaJou, CristinaAraujo-Vilar, DavidFernández Marmiesse, AnaDarling, AlejandraO'Callaghan, MarTonda, Raul2024-01-292024-01-292019Ana Fernández-Marmiesse, Sofía Sánchez-Iglesias, Alejandra Darling, María M. O'Callaghan, Raúl Tonda, Cristina Jou, David Araújo-Vilar, A de novo heterozygous missense BSCL2 variant in 2 siblings with intractable developmental and epileptic encephalopathy, Seizure, Volume 71, 2019, Pages 161-165, ISSN 1059-1311, https://doi.org/10.1016/j.seizure.2019.07.019.http://hdl.handle.net/10347/32027Purpose: We present the case of 2 siblings with profound refractory epilepsy and neurological regression that began at the ages of 3 and 6 months. Diagnosis remained elusive despite extensive metabolic and genetic workups, including use of a targeted next-generation sequencing panel for epilepsy genes. Methods: Whole-exome sequencing was performed for the 2 siblings and their unaffected parents, in addition to fibroblast cell culture, RNA extraction and reverse-transcription, and cDNA PCR. Brain tissue from one of the siblings was collected post-mortem for neuropathological examination, including histology and immunohistochemistry. Results: Ade novo nucleotide change (c.566 T > A; p.(Met189Lys)) in exon 4 of the BSCL2 gene was detected in the 2 siblings, and confirmed by Sanger sequencing. This variant was absent in the parents and in a third, unaffected sibling. Conclusion: Given thede novo nature of the variant, its absence from public and in-house databases, our in silico pathogenicity predictions, and co-segregation of the variant with the disease phenotype, we believe that this novel variant is associated with the epileptic encephalopathy phenotype of the 2 siblings. Our findings provide the first evidence of an association between a heterozygous BSCL2 variant and developmental and early infantile epileptic encephalopathy. Further functional studies will be needed to elucidate the pathophysiological mechanisms underlying this new BSCL2-associated phenotype.engCC BYWhole exome sequencingBSCL2SeipinEarly infantile epileptic encephalopathyjournal article10.1016/j.seizure.2019.07.019open access