Please use this identifier to cite or link to this item: https://ahro.austin.org.au/austinjspui/handle/1/34742
Title: Leveraging multiple approaches for detection of pathogenic deep intronic variants in developmental and epileptic encephalopathies: a case report.
Austin Authors: Nyaga, Denis M;Hildebrand, Michael S ;de Valles-Ibáñez, Guillem;Keenan, Ngaire F;Ye, Zimeng;LaFlamme, Christy W;Mefford, Heather C;Bennett, Mark F ;Bahlo, Melanie;Sadleir, Lynette G
Affiliation: Department of Paediatrics and Child Health, University of Otago, Wellington, New Zealand.
Medicine (University of Melbourne)
Department of Paediatrics and Child Health, University of Otago, Wellington, New Zealand.
Center for Pediatric Neurological Disease Research, St. Jude Children's Research Hospital, Memphis, TN, USA.
Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.;Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
Department of Paediatrics and Child Health, University of Otago, Wellington, New Zealand.
Issue Date: 21-Dec-2023
Date: 2023
Publication information: Epilepsia Open 2023-12-21
Abstract: 50% of individuals with developmental and epileptic encephalopathies (DEEs) are unsolved following genetic testing. Deep intronic variants, defined as >100 bp from exon-intron junctions, contribute to disease by affecting the splicing of mRNAs in clinically relevant genes. Identifying deep intronic pathogenic variants is challenging and resource intensive, and interpretation is difficult due to limited functional annotations. We aimed to identify deep intronic variants in individuals suspected to have unsolved single gene DEEs. In a research cohort of unsolved cases of DEEs, we searched for children with a DEE syndrome predominantly caused by variants in specific genes in >80% of described cases. We identified two children with Dravet Syndrome and one individual with classic lissencephaly. Multiple sequencing and bioinformatics strategies were employed to interrogate intronic regions in SCN1A and PAFAH1B1. A novel de novo deep intronic 12kb deletion in PAFAH1B1 was identified in the individual with lissencephaly. We showed experimentally that the deletion disrupts mRNA splicing, which results in partial intron retention after exon 2 and disruption of the highly conserved LisH motif. We demonstrate that targeted interrogation of deep intronic regions using multiple genomics technologies, coupled with functional analysis, can reveal hidden causes of unsolved monogenic DEE syndromes.
URI: https://ahro.austin.org.au/austinjspui/handle/1/34742
DOI: 10.1002/epi4.12887
ORCID: 0000-0001-6240-4017
0000-0002-0808-3475
0000-0001-7188-522X
0000-0001-5132-0774
0000-0002-5355-7115
Journal: Epilepsia Open
PubMed URL: 38129960
ISSN: 2470-9239
Type: Journal Article
Subjects: PAFAH1B1
SCN1A
SNP arrays
genetic testing
structural variants
whole-genome sequencing
Appears in Collections:Journal articles

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