SCN1A variants associated with sudden infant death syndrome

Abstract

We identified SCN1A variants in 2 infants who died of sudden infant death syndrome (SIDS) with hippocampal abnormalities from an exome sequencing study of 10 cases of SIDS but no history of seizures. One harbored SCN1A G682V, and the other had 2 SCN1A variants in cis: L1296M and E1308D, a variant previously associated with epilepsy. Functional evaluation in a heterologous expression system demonstrated partial loss of function for both G682V and the compound variant L1296M/E1308D. Our cases represent a novel association between SCN1A and SIDS, extending the SCN1A spectrum from epilepsy to SIDS. Our findings provide insights into SIDS and support genetic evaluation focused on epilepsy genes in SIDS.

Keywords: dentate gyrus; epilepsy; hippocampus; sodium channel; sudden unexpected death.

Figure 1.

Hippocampal developmental lesions in two infants with SIDS and variants in SCN1A. A. Case 1: SIDS infant with SCN1A c.2045G>T, p.Gly682Val variant. Low power photograph of the hippocampus shows the abnormal dentate gyrus with a region of focal bilamination highlighted in the black rectangle. (Haematoxylin + Eosin stain, x4). B. Case 1: Focal dentate bilamination with two layers of granule cells and intervening neuropil (arrow). Other abnormalities include mild hyperconvolution of the dentate gyrus, immature neuronal-like precursors in the subgranular zone, ectopic granule cells in the molecular layer and hilus, and mild hilar gliosis. (Haematoxylin + Eosin stain, x20). C. Control dentate gyrus in an age-matched infant showing the normal single layer of dentate gyrus granule cells in row. (Haematoxylin + Eosin stain, x20). D. Case 2: SIDS infant with c.3886T>A, Leu1296Met and c. 3924A>T, Glu1308Asp variants in cis: Low power photograph of the hippocampus shows dentate gyrus bilamination in two foci (black rectangle, arrow). The dentate gyrus is slightly hyperconvoluted. Other abnormalities include immature neuronal-like precursors in the subgranular zone, ectopic granule cells in the molecular layer and hilus, and mild hilar gliosis. (Haematoxylin + Eosin stain, x2). E. Case 2: Focal dentate bilamination (and trilamination) (arrow) in the rectangle from Fig. 1.D. (Haematoxylin + Eosin stain, x20). F. Hilar gliosis in Case 2, demonstrated with standard immunocytochemistry for glial fibrillary acidic protein (GFAP) to label reactive astrocytes (short arrow). GFAP, x40. Abbreviations: CP, choroid plexus; DG, dentate gyrus, ML, LGN, lateral geniculare nucleus; molecular layer.

Figure 2.

Model of SCN1A protein and predicted pathogenic variants seen in two cases of SIDS. Case 1: c.2045G>T, p.Gly682Val. Case 2: c.3886T>A, Leu1296Met and c. 3924A>T, Glu1308Asp (present in cis configuration). Pathologic variants in close proximity to G682V, affecting the same transmembrane domain, have been associated with Dravet syndrome (D674G) and borderline severe myoclonic epilepsy of infancy, (T685LfsX5) and are depicted by dots on the model to show relative position. Previously reported pathologic variants in close proximity to Leu1296 are W1284X and F1289del; the patients were diagnosed with severe myoclonic epilepsy of infancy.

Figure 3.

Functional evaluation of SCN1A variants. A. Representative whole-cell sodium currents recorded from tsA201 cells expressing either WT Na_V1.1 or SIDS associated variants. B. Current-voltage relationships of WT Na_V1.1 and SIDS associated variants. All data are expressed as mean ± SEM for 14–15 measurements. Statistical differences were determined by ANOVA (*, p<0.05 for both variants compared to WT; ‡, p<0.05 between WT and L1296M / E1308D).