SCN1A Variants as the Underlying Cause of Genetic Epilepsy with Febrile Seizures Plus in Two Multi-Generational Colombian Families

Genetic epilepsy with febrile seizures plus (GEFS+) is an autosomal dominant disorder with febrile or afebrile seizures that exhibits phenotypic variability. Only a few variants in SCN1A have been previously characterized for GEFS+, in Latin American populations where studies on the genetic and phenotypic spectrum of GEFS+ are scarce. We evaluated members in two multi-generational Colombian Paisa families whose affected members present with classic GEFS+. Exome and Sanger sequencing were used to detect the causal variants in these families. In each of these families, we identified variants in SCN1A causing GEFS+ with incomplete penetrance. In Family 047, we identified a heterozygous variant (c.3530C > G; p.(Pro1177Arg)) that segregates with GEFS+ in 15 affected individuals. In Family 167, we identified a previously unreported variant (c.725A > G; p.(Gln242Arg)) that segregates with the disease in a family with four affected members. Both variants are located in a cytoplasmic loop region in SCN1A and based on our findings the variants are classified as pathogenic and likely pathogenic, respectively. Our results expand the genotypic and phenotypic spectrum associated with SCN1A variants and will aid in improving molecular diagnostics and counseling in Latin American and other populations.

[1]  Christopher G Chute,et al.  The Human Phenotype Ontology in 2021 , 2020, Nucleic Acids Res..

[2]  R. Nabbout,et al.  Impact of predictive, preventive and precision medicine strategies in epilepsy , 2020, Nature Reviews Neurology.

[3]  L. Chertkoff,et al.  Molecular diagnosis of epileptic encephalopathy of the first year of life applying a customized gene panel in a group of Argentinean patients , 2020, Epilepsy & Behavior.

[4]  L. Kádasi,et al.  A Study among the Genotype, Functional Alternations, and Phenotype of 9 SCN1A Mutations in Epilepsy Patients , 2020, Scientific Reports.

[5]  S. Berkovic,et al.  Genetics of Epilepsy , 2019 .

[6]  S. Berkovic,et al.  Epilepsy genetics: clinical impacts and biological insights , 2020, The Lancet Neurology.

[7]  Ryan L. Collins,et al.  The mutational constraint spectrum quantified from variation in 141,456 humans , 2020, Nature.

[8]  D. Hampson,et al.  Sexually Divergent Mortality and Partial Phenotypic Rescue After Gene Therapy in a Mouse Model of Dravet Syndrome , 2019, Human gene therapy.

[9]  S. Schorge,et al.  SCN1A variants from bench to bedside—improved clinical prediction from functional characterization , 2019, Human mutation.

[10]  Marina C. Gonsales,et al.  Multimodal Analysis of SCN1A Missense Variants Improves Interpretation of Clinically Relevant Variants in Dravet Syndrome , 2019, Front. Neurol..

[11]  Brian E. Cade,et al.  Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program , 2019, Nature.

[12]  Gregory M. Cooper,et al.  CADD: predicting the deleteriousness of variants throughout the human genome , 2018, Nucleic Acids Res..

[13]  Chunlei Liu,et al.  ClinVar: improving access to variant interpretations and supporting evidence , 2017, Nucleic Acids Res..

[14]  I. Scheffer,et al.  Genetic epilepsy with febrile seizures plus , 2017, Neurology.

[15]  M. T. Magaña-Torres,et al.  Determination of SCN1A genetic variants in Mexican patients with refractory epilepsy and Dravet syndrome. , 2017, Genetics and molecular research : GMR.

[16]  J. Sambrook,et al.  Isolation of High-Molecular-Weight DNA Using Organic Solvents. , 2017, Cold Spring Harbor protocols.

[17]  Edouard Hirsch,et al.  ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology , 2017, Epilepsia.

[18]  N. Tommerup,et al.  Gene Panel Testing in Epileptic Encephalopathies and Familial Epilepsies , 2016, Molecular Syndromology.

[19]  Pietro Liò,et al.  The BioMart community portal: an innovative alternative to large, centralized data repositories , 2015, Nucleic Acids Res..

[20]  H. Rehm,et al.  Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology , 2015, Genetics in Medicine.

[21]  P. Striano,et al.  Rescuable folding defective NaV1.1 (SCN1A) mutants in epilepsy: Properties, occurrence, and novel rescuing strategy with peptides targeted to the endoplasmic reticulum , 2015, Neurobiology of Disease.

[22]  J. H. Cross,et al.  ILAE Official Report: A practical clinical definition of epilepsy , 2014, Epilepsia.

[23]  Lars Feuk,et al.  The Database of Genomic Variants: a curated collection of structural variation in the human genome , 2013, Nucleic Acids Res..

[24]  Bradley P. Coe,et al.  Copy number variation detection and genotyping from exome sequence data , 2012, Genome research.

[25]  Helga Thorvaldsdóttir,et al.  Integrative Genomics Viewer , 2011, Nature Biotechnology.

[26]  Serafim Batzoglou,et al.  Identifying a High Fraction of the Human Genome to be under Selective Constraint Using GERP++ , 2010, PLoS Comput. Biol..

[27]  Andrew Escayg,et al.  Sodium channel SCN1A and epilepsy: Mutations and mechanisms , 2010, Epilepsia.

[28]  M. DePristo,et al.  The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. , 2010, Genome research.

[29]  H. Hakonarson,et al.  ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data , 2010, Nucleic acids research.

[30]  W. Hauser,et al.  The descriptive epidemiology of epilepsy—A review , 2009, Epilepsy Research.

[31]  Gonçalo R. Abecasis,et al.  The Sequence Alignment/Map format and SAMtools , 2009, Bioinform..

[32]  Richard Durbin,et al.  Sequence analysis Fast and accurate short read alignment with Burrows – Wheeler transform , 2009 .

[33]  Alan F. Scott,et al.  McKusick's Online Mendelian Inheritance in Man (OMIM®) , 2008, Nucleic Acids Res..

[34]  Aldo Quattrone,et al.  Identification of an Nav1.1 sodium channel (SCN1A) loss-of-function mutation associated with familial simple febrile seizures. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[35]  G. Bedoya,et al.  A novel SCN1A mutation associated with severe GEFS+ in a large South American pedigree , 2005, Seizure.

[36]  A. L. Goldin,et al.  Generalized epilepsy with febrile seizures plus type 2 mutation W1204R alters voltage-dependent gating of Nav1.1 sodium channels , 2003, Neuroscience.

[37]  I. Scheffer,et al.  Generalized epilepsy with febrile seizures plus. A genetic disorder with heterogeneous clinical phenotypes. , 1997, Brain : a journal of neurology.