Pitfalls in genetic testing: the story of missed SCN1A mutations

Peer reviewe

Late-Onset Myoclonic Epilepsy in Down Syndrome: Investigation of EPM1 Gene Mutations in two Cases

Late-onset myoclonic epilepsy is being increasingly recognized as a late complication in elderly patients with Down syndrome (DS) in association with cognitive decline. This specific syndrome bears some broad clinical and EEG similarities to the progressive myoclonic epilepsies, particularly Unverricht-Lundborg disease (ULD). Our aim was to investigate a possible shared patho-genetic mechanism for clinico-physiological similarities in these different genetic syndromes. Two patients diagnosed with DS and late-onset myoclonic epilepsy were included in the study. Dodecamer repeats and other possible CSTB gene mutations were investigated after isolation of DNA from their blood samples. No dodecamer repeats and point mutations could be found. Our study did not show any mutations of EPM1 gene on chromosome 21 but these findings could not exclude a shared genetic mechanism in these syndromes

Late-Onset Myoclonic Epilepsy in Down Syndrome: Investigation of EPM1 Gene Mutations in two Cases

AbstractLate-onset myoclonic epilepsy is being increasingly recognized as a late complication inelderly patients with Down syndrome (DS) in association with cognitive decline. This specificsyndrome bears some broad clinical and EEG similarities to the progressive myoclonicepilepsies, particularly Unverricht-Lundborg disease (ULD). Our aim was to investigate apossible shared patho-genetic mechanism for clinico-physiological similarities in thesedifferent genetic syndromes. Two patients diagnosed with DS and late-onset myoclonicepilepsy were included in the study. Dodecamer repeats and other possible CSTB genemutations were investigated after isolation of DNA from their blood samples. No dodecamerrepeats and point mutations could be found. Our study did not show any mutations of EPM1gene on chromosome 21 but these findings could not exclude a shared genetic mechanism inthese syndromes

Association of a synonymous SCN1B variant affecting splicing efficiency with Benign Familial Infantile Epilepsy (BFIE)

Benign Familial Infantile Epilepsy (BFIE) is clinically characterized by clusters of brief partial seizures progressing to secondarily generalized seizures with onset at the age of 3-7 months and with favorable outcome. PRRT2 mutations are the most common cause of BFIE, and found in about 80% of BFIE families. In this study, we analyzed a large multiplex BFIE family by linkage and whole exome sequencing (WES) analyses. Genome-wide linkage analysis revealed significant evidence for linkage in the chromosomal region 19p12-q13 (LOD score 3.48). Mutation screening of positional candidate genes identified a synonymous SCN1B variant (c.492T>C, p.Tyr164Tyr) affecting splicing by the removal of a splicing silencer sequence, shown by in silico analysis, as the most likely causative mutation. In addition, the PRRT2 frameshift mutation (c.649dupC/p.Arg217Profs*8) was observed, showing incomplete, but high segregation with the phenotype. In vitro splicing assay of SCN1B expression confirmed the in silico findings showing a splicing imbalance between wild type and mutant exons. Herein, the involvement of the SCN1B gene in the etiology of BFIE, contributing to the disease phenotype as a modifier or part of an oligogenic predisposition, is shown for the first time. (C) 2017 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved

SCN1A gene sequencing in 46 Turkish epilepsy patients disclosed 12 novel mutations

Yalçın Çapan, Özlem (Arel Author)Purpose: The SCN1A gene is one of the most commonly mutated human epilepsy genes associated with a spectrum of phenotypes with variable degrees of severity. Despite over 1200 distinct mutations reported, it is still hard to draw clear genotypephenotype relationships, since genetic and environmental modifiers contribute to the development of a particular disease caused by an SCN1A mutation. We aimed to initiate mutational screening of the SCN1A gene in Turkey and advance further our understanding of the relationship between the SCN1A sequence alterations and disease phenotypes such as GEFS+, DS and related epileptic encephalopathies. Methods: Mutational analysis of the SCN1A gene was carried out in 46 patients with DS, late-onset DS, GEFS+ and unspecified EE using either direct Sanger sequencing of the coding regions and exon/intron boundaries or massively parallel sequencing. Results: Nineteen point mutations, 12 of which were novel were identified, confirming the clinical diagnosis of the patients. Patients with a mutation (either truncating or missense) on linker regions had significantly later disease onset than patients with mutations in homology regions. The presence of SCN1A mutations in two clinically unclassified patients supported the association of SCN1A mutations with a wide range of phenotypes. Conclusion: The conventional Sanger sequencing method was successfully initiated for the detection of SCN1A point mutations in Turkey in epilepsy patients. Furthermore, a modified strategy of massively parallel pyro-sequencing was also established as a rapid and effective mutation detection method for large genes as SCN1A

SCN1A gene sequencing in 46 Turkish epilepsy patients disclosed 12 novel mutations

Purpose: The SCN1A gene is one of the most commonly mutated human epilepsy genes associated with a spectrum of phenotypes with variable degrees of severity. Despite over 1200 distinct mutations reported, it is still hard to draw clear genotype phenotype relationships, since genetic and environmental modifiers contribute to the development of a particular disease caused by an SCN1A mutation. We aimed to initiate mutational screening of the SCN1A gene in Turkey and advance further our understanding of the relationship between the SCN1A sequence alterations and disease phenotypes such as GEFS+, DS and related epileptic encephalopathies