Four generations of epilepsy caused by an inherited microdeletion of the SCN1A gene

Abstract

We report an inherited SCN1A gene deletion not exclusively associated with Dravet syndrome. Moreover, our results demonstrate that SCN1A haploinsufficiency can cause a significant intrafamilial clinical variability including moderately affected to syndromal patients. The involvement of multiple genetic and environmental factors could be the basis of this difference in phenotype severity.

A novel inherited SCN1A mutation associated with different neuropsychological phenotypes: Is there a common core deficit?

“…On the basis of clinical examination, different phenotypes have been identified for these four subjects: one subject was affected by GEFS + (IIa2), one had showed rare febrile seizures (IIc2), another one was affected by Dravet syndrome (IIc1), and the last one (IIIa) has a diagnosis compatible with PEFS +: he had presented complex partial seizures in the first year of life and showed EEG alterations with a right occipital focus. Our observations confirm those by Guerrini et al and Suls et al, who described two clinically heterogeneous families with a deletion encompassing the SCN1A gene [9,10]. A similar variability can be observed in the present family, in which the nucleotide alteration is thought to alter the mRNA splicing.…”

“…Previous reports have documented remarkable clinical heterogeneity in both epilepsy-related factors and cognitive level [9,10]. However, variability of neuropsychological functioning in familial cases has been incompletely investigated.…”

Genetic background modulates impaired excitability of inhibitory neurons in a mouse model of Dravet syndrome

“…During and after the second year of life, patients develop psychomotor delay, ataxia, cognitive impairment, and social interaction deficits (Genton et al, 2011; Li et al, 2011). Eighty percent of the identified mutations in DS arise de novo; however, ten to twenty percent of DS cases are inherited from mildly affected or unaffected parents (Claes et al, 2003; Claes et al, 2001; Depienne et al, 2010; Suls et al, 2010). Individual patients with apparently complete loss-of-function mutations demonstrate a broad range of disease severity and a wide-ranging combination of symptoms, suggesting that genetic background can strongly influence the severity and clinical presentation of DS (Dravet et al, 2005).…”

Genetic contribution to common epilepsies

“…Proposed explanations for phenotypic variability include the unmasking of recessive mutations or functional polymorphisms by a pathogenic deletion; epigenetic, environmental or compensatory factors; mosaicism; and -not mutually exclusive with the above possibilities -a two-hit model involving CNVs and/or point mutations. There are rare examples of each of these mechanisms: unmasking of a COMT polymorphism associated with schizophrenia risk in 22q11 deletion syndrome [38 ]; Kcna1 vs. Cacna1 changes in a mouse model of epilepsy [39]; mosaicism for SCN1A microdeletion [40 ]; and severe phenotypes in individuals with 16p12.1 microdeletion and a second large CNV [41 ]. Heinzen and colleagues [27 ] searched for rare sequence changes in the nondeleted copy of 16p13.11 in patients with the microdeletion, but found none; based on expression studies, they proposed haploinsufficiency as a mechanism.…”