title: A clinical variant in SCN1A inherited from a mosaic father cosegregates with a novel variant to cause Dravet syndrome in a consanguineous family.
abstract: A consanguineous family from Turkey having two children with intellectual disability exhibiting myoclonic, febrile and other generalized seizures was recruited to identify the genetic origin of these phenotypes. A combined approach of SNP genotyping and exome sequencing was employed both to screen genes associated with Dravet syndrome and to detect homozygous variants. Analysis of exome data was extended further to identify compound heterozygosity. Herein, we report identification of two paternally inherited genetic variants in SCN1A (rs121917918; p.R101Q and p.I1576T), one of which was previously implicated in Dravet syndrome. Interestingly, the previously reported clinical variant (rs121917918; p.R101Q) displayed mosaicism in the blood and saliva of the father. The study supported the genetic diagnosis of affected children as Dravet syndrome possibly due to the combined effect of one clinically associated (rs121917918; p.R101Q) and one novel (p.I1576T) variants in SCN1A gene. This finding is important given that heterozygous variants may be overlooked in standard exome scans of consanguineous families. Thus, we are presenting an interesting example, where the inheritance of the condition may be misinterpreted as recessive and identical by descent due to consanguinity and mosaicism in one of the parents.
authors.affiliation: Istanbul University, Institute of Experimental Medicine, Department of Genetics, Istanbul, Turkey.
authors.forename: Feyza N
authors.initials: FN
authors.lastname: Tuncer
authors.affiliation: The Scientific and Technological Research Council of Turkey (TUBITAK-BILGEM), Advanced Genomics and Bioinformatics Research Center, Kocaeli, Turkey.
authors.forename: Zeliha
authors.initials: Z
authors.lastname: Gormez
authors.affiliation: Harran University, Faculty of Medicine, Department of Pediatric Neurology, Sanliurfa, Turkey.
authors.forename: Mustafa
authors.initials: M
authors.lastname: Calik
authors.affiliation: Istanbul University, Istanbul Faculty of Medicine, Department of Neurology, Clinical Neurophysiology Unit, Istanbul, Turkey.
authors.forename: Gunes
authors.initials: G
authors.lastname: Altiokka Uzun
authors.affiliation: The Scientific and Technological Research Council of Turkey (TUBITAK-BILGEM), Advanced Genomics and Bioinformatics Research Center, Kocaeli, Turkey.
authors.forename: Mahmut S
authors.initials: MS
authors.lastname: Sagiroglu
authors.affiliation: The Scientific and Technological Research Council of Turkey (TUBITAK-BILGEM), Advanced Genomics and Bioinformatics Research Center, Kocaeli, Turkey.
authors.forename: Betul
authors.initials: B
authors.lastname: Yuceturk
authors.affiliation: The Scientific and Technological Research Council of Turkey (TUBITAK-MAM), Genetic Engineering and Biotechnology Institute, Kocaeli, Turkey.
authors.forename: Bayram
authors.initials: B
authors.lastname: Yuksel
authors.affiliation: Istanbul University, Istanbul Faculty of Medicine, Department of Neurology, Clinical Neurophysiology Unit, Istanbul, Turkey.
authors.forename: Betul
authors.initials: B
authors.lastname: Baykan
authors.affiliation: Istanbul University, Istanbul Faculty of Medicine, Department of Neurology, Clinical Neurophysiology Unit, Istanbul, Turkey.
authors.forename: Nerses
authors.initials: N
authors.lastname: Bebek
authors.affiliation: Bezmialem Vakif University, Faculty of Medicine, Department of Pediatric Neurology, Istanbul, Turkey.
authors.forename: Akin
authors.initials: A
authors.lastname: Iscan
authors.affiliation: Istanbul University, Institute of Experimental Medicine, Department of Genetics, Istanbul, Turkey. Electronic address: sibel.ugur@istanbul.edu.tr.
authors.forename: Sibel A
authors.initials: SA
authors.lastname: Ugur Iseri
authors.affiliation: Istanbul University, Institute of Experimental Medicine, Department of Genetics, Istanbul, Turkey.
authors.forename: Ugur
authors.initials: U
authors.lastname: Ozbek
mesh_terms: D002648:Child; D003241:Consanguinity; D004252:DNA Mutational Analysis; D004569:Electroencephalography; D004831:Epilepsies, Myoclonic / Q000235:genetics* / Q000503:physiopathology; D005091:Exons; D005192:Family Health; D005260:Female; D006801:Humans; D008297:Male; D008958:Models, Molecular; D009030:Mosaicism; D062550:NAV1.1 Voltage-Gated Sodium Channel / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D014421:Turkey
chemical_list: D062550:NAV1.1 Voltage-Gated Sodium Channel; C568242:SCN1A protein, human
keywords: Compound heterozygosity; Dravet syndrome; Exome sequencing; Mosaicism; SCN1A