A de novo heterozygous missense BSCL2 variant in 2 siblings with intractable developmental and epileptic encephalopathy
Por:
Fernández-Marmiesse A, Sánchez-Iglesias S, Darling A, O'Callaghan-Gordo M, Tonda R, Jou-Munoz C and Araújo-Vilar D
Publicada:
1 oct 2019
Ahead of Print:
25 jul 2019
Resumen:
Purpose: 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.
Filiaciones:
Fernández-Marmiesse A:
Genomes and Disease, Centre for Research in Molecular Medicine and Chronic Diseases (CIMUS), Universidade de Santiago de Compostela - IDIS, Santiago de Compostela, 15706, Spain
Sánchez-Iglesias S:
Thyroid and Metabolic Diseases Unit (U.E.T.eM.), Department of Psychiatry, Radiology, Public Health, Nursing and Medicine (Medicine Area), Centre for Research in Molecular Medicine and Chronic Diseases (CIMUS)-IDIS, University of Santiago de Compostela, 15782, Santiago de Compostela, Spain
Darling A:
Departamento de Neurología - Anatomía Patológica. Institut de Recerca Pediàtrica-Hospital Sant Joan de Déu (IRP-HSJD), Barcelona, Spain
O'Callaghan-Gordo M:
Centro de Investigación Biomédica de Enfermedades Raras, Instituto de Salud Carlos III, Madrid, Spain
Departamento de Neurología - Anatomía Patológica. Institut de Recerca Pediàtrica-Hospital Sant Joan de Déu (IRP-HSJD), Barcelona, Spain
Tonda R:
CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Baldiri i Reixac 4, 08028, Barcelona, Spain
Universitat Pompeu Fabra (UPF), Barcelona, Spain
Jou-Munoz C:
Centro de Investigación Biomédica de Enfermedades Raras, Instituto de Salud Carlos III, Madrid, Spain
Departamento de Neurología - Anatomía Patológica. Institut de Recerca Pediàtrica-Hospital Sant Joan de Déu (IRP-HSJD), Barcelona, Spain
Araújo-Vilar D:
Thyroid and Metabolic Diseases Unit (U.E.T.eM.), Department of Psychiatry, Radiology, Public Health, Nursing and Medicine (Medicine Area), Centre for Research in Molecular Medicine and Chronic Diseases (CIMUS)-IDIS, University of Santiago de Compostela, 15782, Santiago de Compostela, Spain
Green Submitted, Bronze
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