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. 2024 Sep;35(3):334-345.
doi: 10.1007/s00335-024-10046-3. Epub 2024 Jun 11.

Fine mapping and candidate gene analysis of Dravet syndrome modifier loci on mouse chromosomes 7 and 8

Nicole A Hawkins  1 , Nathan Speakes  1 , Jennifer A Kearney  2
Affiliations

Fine mapping and candidate gene analysis of Dravet syndrome modifier loci on mouse chromosomes 7 and 8

Nicole A Hawkins et al. Mamm Genome. 2024 Sep.

Abstract

Dravet syndrome is a developmental and epileptic encephalopathy (DEE) characterized by intractable seizures, comorbidities related to developmental, cognitive, and motor delays, and a high mortality burden due to sudden unexpected death in epilepsy (SUDEP). Most Dravet syndrome cases are attributed to SCN1A haploinsufficiency, with genetic modifiers and environmental factors influencing disease severity. Mouse models with heterozygous deletion of Scn1a recapitulate key features of Dravet syndrome, including seizures and premature mortality; however, severity varies depending on genetic background. Here, we refined two Dravet survival modifier (Dsm) loci, Dsm2 on chromosome 7 and Dsm3 on chromosome 8, using interval-specific congenic (ISC) mapping. Dsm2 was complex and encompassed at least two separate loci, while Dsm3 was refined to a single locus. Candidate modifier genes within these refined loci were prioritized based on brain expression, strain-dependent differences, and biological relevance to seizures or epilepsy. High priority candidate genes for Dsm2 include Nav2, Ptpn5, Ldha, Dbx1, Prmt3 and Slc6a5, while Dsm3 has a single high priority candidate, Psd3. This study underscores the complex genetic architecture underlying Dravet syndrome and provides insights into potential modifier genes that could influence disease severity and serve as novel therapeutic targets.

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Conflict of interest statement

JAK serves on the Scientific Advisory Boards of the Dravet Syndrome Foundation and FamilieSCN2A Foundation. JAK receives research funding from Praxis Precision Medicines and Neurocrine Biosciences. NAH provides paid consulting services to Takeda Pharmaceuticals. All other authors have declared that no competing interests exist.

Figures

Fig. 1
Fig. 1
Fine mapping of Dsm2 with ISC strains. A Dsm2 lines have varying 129-derived intervals (red) on a congenic B6 background (grey). B6.129-Dsm2 ISC7 lines were crossed with 129.Scn1a+/− mice and survival of Scn1a+/− offspring was monitored to 8 weeks of age. B Hazard ratios for all Dsm2 ISC lines compared to F1 controls plotted against −log10(P-values) determined by Mantel-Cox LogRank test (n = 18–24 per line). C Kaplan Meier survival plots are shown for each ISC7 line (red) compared to F1.Scn1a+/− controls (black). Shaded area represents 95% confidence interval for F1. Scn1a+/− controls
Fig. 2
Fig. 2
Analysis of Dsm2 positional candidate genes. A–E Differential expression of candidate modifier genes based on analysis of our previously published RNA-seq datasets (Hawkins et al. 2019, 2016). A–C Comparing F1.Scn1a+/− mice with or without seizures in the 24 h preceding tissue collection, three genes were differentially expressed in hippocampus, Ldha (A), Ptpn5 (B), and Sergef (C). D Ano5 had lower hippocampal expression in F1.Scn1a+/− compared to 129.Scn1a+/− mice at postnatal day 14 (P14). E Nav2 had lower hippocampal expression in wild-type (WT) 129 versus F1 mice at postnatal day 24 (P24). F Summary of strain-dependent differences in candidate genes and their association with seizures and/or epilepsy. Six genes had strain-dependent differences and an existing biological link with seizures or epilepsy. ***FDR-adjusted p < 0.0001, **FDR-adjusted p < 0.003, *FDR-adjusted p < 0.07 (from DeSeq2 reported in (Hawkins et al. 2019))
Fig. 3
Fig. 3
Fine mapping of Dsm3 with ISC strains. A Dsm3 lines have varying 129-derived chromosome 8 intervals (blue) on a congenic B6 background (grey). B6.129-Dsm3 ISC8 lines were crossed with 129.Scn1a+/− mice and survival of Scn1a+/− offspring was monitored to 8 weeks of age. B Hazard ratios for all Dsm3 ISC lines compared to F1 controls plotted against -log10(P-values) determined by Mantel-Cox LogRank test (n = 19–24 per line). C Kaplan Meier survival plots are shown for each ISC8 line (blue) compared to F1.Scn1a+/− controls (black). Shaded area represents 95% confidence interval for F1.Scn1a+/− controls
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