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Deletions and duplications/amplifications of the α1-sodium channel subunit (SCN1A) gene occur in about 12% of patients with Dravet syndrome (DS) who are otherwise mutation-negative. Such genomic abnormalities cause loss of function, with severe phenotypes, reproductive disadvantage and, therefore, sporadic occurrence. Inherited mutations, occurring in ∼5% of patients with DS, are usually missense; transmission occurs from a mildly affected parent exhibiting febrile seizures (FS) or the generalized epilepsy with febrile seizures plus (GEFS+) spectrum. We identified an intragenic SCN1A deletion in a three-generation, clinically heterogeneous family. Sequence analysis of SCN9A, a putative modifier, ruled out pathogenic mutations, variants, or putative disease–associated haplotype segregating with phenotype severity. Intrafamilial variability in phenotype severity indicates that SCN1A loss of function causes a phenotypic spectrum in which seizures precipitated by fever are prominent and schematic syndrome subdivisions would be inappropriate. SCN1A deletions should be ruled out even in individuals with mild phenotypes.
The α1-sodium channel subunit (SCN1A) gene is the main genetic player in the etiology of severe myoclonic epilepsy of infancy [SMEI or Dravet syndrome (DS); Online Mendelian Inheritance in Man (OMIM) 607208]. SCN1A heterozygous de novo mutations account for most individuals with DS (Mulley et al., 2005). Chromosomal rearrangements such as deletions and duplications/amplifications of SCN1A have been detected in about 12% of patients with DS who are otherwise mutation-negative (Marini et al., 2009), with an overall frequency of 2–3%. Inherited SCN1A mutations, usually missense, are found in ∼5% of patients with DS. The family history of DS probands with inherited mutations is characterized by the occurrence of milder phenotypes, consistent with febrile seizures (FS), febrile seizure plus (FS+), or generalized epilepsy with febrile seizures plus (GEFS+; OMIM 604233) in the previous generation (Singh et al., 2001; Nabbout et al., 2003).
Possible reasons for intrafamilial and clinical heterogeneity have been widely discussed in the literature. The genetic and environmental background likely influences the variable familial expression of SCN1A mutations, whereas parental mosaicism accounts for only a few cases (Depienne et al., 2010). However, no definitive conclusion on the factors involved has been reached.
Herein we report a three-generation, clinically heterogeneous family in which we identified a genomic rearrangement leading to a partial SCN1A deletion.
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This family exhibits remarkable clinical heterogeneity, comprising various phenotypes, all of which had been associated previously with SCN1A abnormalities. Heterogeneity involved both seizure severity and cognitive impairment. Clinical variability highlights the difficulties in correlating SCN1A mutations with phenotype severity, even when dealing with a loss-of-function mutation.
Inherited loss-of-function mutations of SCN1A (including missense mutations in the pore-forming regions, frameshifts, nonsense, splice-site mutations, and genomic rearrangements) are rare, as they are usually associated with the most severe phenotypes and reproductive disadvantage (Nabbout et al., 2003; Marini et al., 2007; Gökben et al., 2009; Depienne et al., 2010). Two nonsense mutations, the p.Glu289X (Nabbout et al., 2003) and the p.Arg1645X (Gökben et al., 2009), as well as a deletion of one base pair resulting in the p.Asp1293ValfsX7 mutation (Marini et al., 2007), were inherited by patients with DS whose carrier parents had experienced isolated seizures (Marini et al., 2007; Gökben et al., 2009) or mild epilepsy (Nabbout et al., 2003).
Deletions involving the SCN1A gene vary in size from the megabase range, involving contiguous genes, down to one exon (Marini et al., 2009). Because SCN1A deletions result in loss of function, the associated phenotypes would be expected to be severe. Indeed, with very few exceptions, deletion carriers present as severe, sporadic cases (Marini et al., 2009; Suls et al., 2010). Conversely, in the family we are reporting, phenotypic heterogeneity, also including milder phenotypes, has permitted transmission through three generations. Patient I:1 had had FS+. Patient II:2, exhibiting FS+ and focal seizures with normal cognition, has a much milder phenotype with respect to her brother (II:3), whose clinical features are compatible with a severe form of DS. The proband (III:1) exhibits a clinical syndrome, the severity of which is intermediate between that observed in her mother (II:2) and uncle (II:3), with mild to moderate cognitive impairment, FS, and febrile status, as well as afebrile generalized and focal seizures. The proband’s brother (III:2) appears to be less severely affected, although he is still too young to be assigned a severity rate with confidence. Our observation confirms that by Suls et al. (2010), who described a clinically heterogeneous four-generation Bulgarian family with a deletion encompassing the SCN1A and TTC21B genes.
The phenotypic expression of SCN1A can be altered by genetic modifiers or somatic mosaicism. In particular, it has been indicated that SCN9A might be a putative modifier of SCN1A in DS (Singh et al., 2009). In addition, a mild phenotype in parents of severely affected individuals has been related to somatic mosaicism in rare cases (Gennaro et al., 2006; Morimoto et al., 2006; Depienne et al., 2009, 2010; Marini et al., 2009; Singh et al., 2009). Sequence analysis of the SCN9A gene revealed no pathogenic mutations, variants, or putative disease–associated haplotype segregating with the phenotype severity within the family we are reporting. Furthermore, somatic mosaicism was not identified in individual I:1.
Remarkable variability in phenotype severity within a family favors the concept that SCN1A loss of function causes a spectrum of epilepsy phenotypes in which seizures precipitated by fever are the prominent feature and schematic subdivisions would be inappropriate. For example, individuals II:2 and III:1 (mother and daughter) might have been classified as having either borderline DS or a combination of focal seizure and GEFS+, with or without febrile status. However, cognitive level was normal in individual II:2, but clearly impaired in her daughter.
Our findings demonstrate that the search for SCN1A abnormalities should rule out a deletion even in individuals with particularly mild phenotypes. Remarkable intrafamilial variability is in line with hypotheses favoring a crucial role of, as yet unknown, modifiers genes in modulating the phenotypic counterpart of SCN1A mutations.