Confirming the recessive inheritance of SCN1B mutations in developmental epileptic encephalopathy

Abstract

Dominant SCN1B mutations are known to cause several epilepsy syndromes in humans. Only 2 epilepsy patients to date have been reported to have recessive mutations in SCN1B as the likely cause of their phenotype. Here, we confirm the recessive inheritance of 2 novel SCN1B mutations in 5 children from 3 families with developmental epileptic encephalopathy. The recessive inheritance and early death in these patients is consistent with the Dravet-like phenotype observed in Scn1b mice. The 'negative' clinical exome in one of these families highlights the need to consider recessive mutations in the interpretation of variants in typically dominant genes.

Developmental and epileptic encephalopathy in two siblings with a novel, homozygous missense variant in SCN1B

“…Polyphen‐2 analysis also predicted this variant to be probably damaging (http://genetics.bwh.harvard.edu/pph2/). Furthermore, this variant occurred in the vicinity of other codons affected by homozygous missense variants in SCN1B that were reported in cases of developmental and epileptic encephalopathy, including p.Ile106Phe, p.Arg125Cys, and p.Tyr119Asp (Ogiwara et al, ; Patino et al, ; Ramadan et al, ) (Figure ). The p.Arg89Cys variant was also located near heterozygous missense variants reported in association with GEFS+ (p.Arg85Cys, p.Arg85His, and p.Glu87His) (Scheffer et al, ).…”

“…Patients present with infantile‐onset FS and afebrile seizures of mild to moderate severity, which may be responsive to antiepileptic drugs (Audenaert et al, ; Scheffer et al, ; Wallace et al, ). Although heterozygous variants have been described in families with GEFS+ or in patients with a “Dravet‐like” phenotype, only three cases of homozygous, missense variants in SCN1B have been reported in association with an autosomal recessive form of developmental and epileptic encephalopathy with phenotypic features distinct from Dravet syndrome (DS) (Ogiwara et al, ; Patino et al, ; Ramadan et al, ). These previously described variants include p.Ile106Phe, p.Arg125Cys, and p.Tyr119Asp in SCN1B .…”

Scn1b deletion in adult mice results in seizures and SUDEP

“…Results from mouse models suggest that epilepsy in DS initiates from disinhibition through reduced sodium current density in cortical and hippocampal parvalbumin‐positive GABAergic interneurons . While the majority of DS patients have de novo , heterozygous variants in SCN1A , inherited, homozygous loss‐of‐function variants in SCN1B, encoding the VGSC β 1/ β 1B subunits, also result in DS, or a DS‐like DEE . Scn1b null mice are a DS model, with severe seizures, ataxia, and 100% lethality prior to weaning .…”

Mapt deletion fails to rescue premature lethality in two models of sodium channel epilepsy

“…Homozygous Scn1b −/− mice are underweight, have cardiac defects, develop severe seizures at approximately postnatal day (P) 10, and 100% die by approximately P21. SCN1B is the only known genetic link to DS that is due to recessive inheritance . The limited number of reported SCN1B ‐linked DS cases show seizure onset in the first months of life, dramatic cognitive and motor delays, microcephaly, generalized wasting, severe kyphoscoliosis, central hypotonia, and spastic quadriplegia .…”

“…SCN1B is the only known genetic link to DS that is due to recessive inheritance . The limited number of reported SCN1B ‐linked DS cases show seizure onset in the first months of life, dramatic cognitive and motor delays, microcephaly, generalized wasting, severe kyphoscoliosis, central hypotonia, and spastic quadriplegia . SCN8A encodes Na v 1.6, a pore‐forming α subunit of the voltage‐gated sodium channel.…”