Authors :
Presenting Author: Olivia Kim-McManus, MD – Rady Children's Institute for Genomic Medicine
Liana Protopsaltis, MS, CGC – Rady Children's Institute for Genomic Medicine
Shahad Olsson, MS, CGC – Rady Children's Institute for Genomic Medicine
Joseph Gleeson, MD – UC San Diego Rady Children's Institute for Genomic Medicine
Qing Zhang, PhD – Illumina
Nafeesa Kahn, PhD – Illumina
Ali Crawford, PhD – Illumina
Stephen Kingsmore, MD – Rady Children's Institute for Genomic Medicine
Rationale:
Monoallelic SCN2A variants cause developmental epileptic encephalopathy 11 (DEE11), a rare disease characterized by early-onset seizures, involuntary movements, and neurodevelopmental delay. A n=1 clinical trial utilizing individualized allele-specific antisense oligonucleotide (ASO) therapy demonstrated substantial seizure reduction. The ASO downregulates the pathogenic allele by selectively binding to the reference sequence for a common single nucleotide polymorphism (SNP). This ASO can potentially treat other SCN2A patients carrying the same target SNP. Identifying patients with the correct diplotype amenable to ASO treatment necessitates accurate haplotype phasing of the target SNP and disease-causing variant via whole genome sequencing (WGS). We analyzed a cohort of SCN2A patients identified by WGS to assess the potential reach of this treatment.
Methods:
Standard paired-end short-read sequences were visualized to determine phasing of the de novo disease-causing variant and the target SNP. Illumina’s constellation WGS utilizing cluster proximity information was performed on the clinical samples to confirm the phasing.
Results:
Nineteen SCN2A-associated DEE11 probands were investigated. Patients’ ages at diagnosis ranged from 2-weeks-old to 12-years-old and some presented with extra-neurological symptoms not typically seen in DEE11 including dysmorphic features (9/19, 47%), cardiac (5/19, 26%) and renal (4/19, 21%) phenotypes. The target SNP was harbored by 8/19 (42%) patients and 3/19 (16%) were identified to have the correct SNP configuration amenable to ASO treatment.
Conclusions:
WGS is a comprehensive single test capable of both diagnosing conditions and guiding therapy selection. With the aid of WGS for diagnosis and therapy selection, this study showcases an innovative approach that broadens the use of individualized ASOs. This application can transform individualized ASO "N of 1" clinical trials into widely accessible "N of Many" studies, thereby expanding access to targeted genetic therapies for patients.
Funding: California Institute for Regenerative Medicine (Kim-McManus, CIRM CLIN2-15085)