Abstract
Purpose
Neurodevelopmental disorders (NDDs) often result from rare genetic variation, but
genomic testing yield for NDDs remains below 50%, suggesting that clinically relevant
variants may be missed by standard analyses. Here, we analyze “poison exons” (PEs),
which are evolutionarily conserved alternative exons often absent from standard gene
annotations. Variants that alter PE inclusion can lead to loss of function and may
be highly penetrant contributors to disease.
Methods
We curated published RNA sequencing data from developing mouse cortex to define 1937
conserved PE regions potentially relevant to NDDs, and we analyzed variants found
by genome sequencing in multiple NDD cohorts.
Results
Across 2999 probands, we found 6 novel clinically relevant variants in PE regions.
Five of these variants are in genes that are part of the sodium voltage-gated channel
alpha subunit family (SCN1A, SCN2A, and SCN8A), which is associated with epilepsies. One variant is in SNRPB, associated with cerebrocostomandibular syndrome. These variants have moderate to
high computational impact assessments, are absent from population variant databases,
and in genes with gene-phenotype associations consistent with each probands reported
features.
Conclusion
With a very minimal increase in variant analysis burden (average of 0.77 variants
per proband), annotation of PEs can improve diagnostic yield for NDDs and likely other
congenital conditions.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
ACMG Member Login
Are you an ACMG Member? Sign in for online access.Subscribe:
Subscribe to Genetics in MedicineAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Genetics of intellectual disability.Curr Opin Genet Dev. 2008; 18: 241-250https://doi.org/10.1016/j.gde.2008.07.008
- DECIPHER (Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources) GRCh37. Mapping the clinical genome. Cambridge: Wellcome Trust Sanger Institute.https://decipher.sanger.ac.ukDate accessed: March 9, 2022
- The therapeutic odyssey: positioning genomic sequencing in the search for a child’s best possible life.AJOB Empir Bioeth. 2021; 12: 179-189https://doi.org/10.1080/23294515.2021.1907475
- The genetic basis of Mendelian phenotypes: discoveries, challenges, and opportunities.Am J Hum Genet. 2015; 97: 199-215https://doi.org/10.1016/j.ajhg.2015.06.009
- Meta-analysis and multidisciplinary consensus statement: exome sequencing is a first-tier clinical diagnostic test for individuals with neurodevelopmental disorders.Genet Med. 2019; 21: 2413-2421https://doi.org/10.1038/s41436-019-0554-6
- Diagnostic utility of transcriptome sequencing for rare Mendelian diseases.Genet Med. 2020; 22: 490-499https://doi.org/10.1038/s41436-019-0672-1
- Auto- and cross-regulation of the hnRNP L proteins by alternative splicing.Mol Cell Biol. 2009; 29: 1442-1451https://doi.org/10.1128/MCB.01689-08
- Unproductive splicing of SR genes associated with highly conserved and ultraconserved DNA elements.Nature. 2007; 446: 926-929https://doi.org/10.1038/nature05676
- Rbfox proteins regulate alternative splicing of neuronal sodium channel SCN8A.Mol Cell Neurosci. 2012; 49: 120-126https://doi.org/10.1016/j.mcn.2011.10.005
- Aberrant regulation of a poison exon caused by a non-coding variant in a mouse model of Scn1a-associated epileptic encephalopathy.PLoS Genet. 2021; 17e1009195https://doi.org/10.1371/journal.pgen.1009195
- Novel splice variants of the voltage-sensitive sodium channel alpha subunit.NeuroReport. 1998; 9: 1267-1272https://doi.org/10.1097/00001756-199805110-00002
- Alternative splicing of the sodium channel SCN8A predicts a truncated two-domain protein in fetal brain and non-neuronal cells.J Biol Chem. 1997; 272: 24008-24015https://doi.org/10.1074/jbc.272.38.24008
- Aberrant inclusion of a poison exon causes Dravet syndrome and related SCN1A-associated genetic epilepsies.Am J Hum Genet. 2018; 103: 1022-1029https://doi.org/10.1016/j.ajhg.2018.10.023
- Disrupted auto-regulation of the spliceosomal gene SNRPB causes cerebro-costo-mandibular syndrome.Nat Commun. 2014; 5: 4483https://doi.org/10.1038/ncomms5483
- Cell-type-specific alternative splicing governs cell fate in the developing cerebral cortex.Cell. 2016; 166: 1147-1162.e15https://doi.org/10.1016/j.cell.2016.07.025
- Re-annotation of 191 developmental and epileptic encephalopathy-associated genes unmasks de novo variants in SCN1A.NPJ Genom Med. 2019; 4: 31https://doi.org/10.1038/s41525-019-0106-7
- Implementing genomic medicine in the clinic: the future is here.Genet Med. 2013; 15: 258-267https://doi.org/10.1038/gim.2012.157
- Systematic discovery of regulated and conserved alternative exons in the mammalian brain reveals NMD modulating chromatin regulators.Proc Natl Acad Sci U S A. 2015; 112: 3445-3450https://doi.org/10.1073/pnas.1502849112
- The UCSC Table Browser data retrieval tool.Nucleic Acids Res. 2004; 32: D493-D496https://doi.org/10.1093/nar/gkh103
- Track data hubs enable visualization of user-defined genome-wide annotations on the UCSC Genome Browser.Bioinformatics. 2014; 30: 1003-1005https://doi.org/10.1093/bioinformatics/btt637
- BEDTools: a flexible suite of utilities for comparing genomic features.Bioinformatics. 2010; 26: 841-842https://doi.org/10.1093/bioinformatics/btq033
- The UCSC Genome Browser Database: update 2006.Nucleic Acids Res. 2006; 34: D590-D598https://doi.org/10.1093/nar/gkj144
- OMIM.org: Online Mendelian Inheritance in Man (OMIM®), an online catalog of human genes and genetic disorders.Nucleic Acids Res. 2015; 43: D789-D798https://doi.org/10.1093/nar/gku1205
- The NYCKidSeq project: study protocol for a randomized controlled trial incorporating genomics into the clinical care of diverse New York City children.Trials. 2021; 22: 56https://doi.org/10.1186/s13063-020-04953-4
- The TeleKidSeq Pilot Study: incorporating telehealth into clinical care of children from diverse backgrounds undergoing whole genome sequencing.Pilot Feasibility Stud. 2023; 9: 47https://doi.org/10.1186/s40814-023-01259-5
- Genome sequencing as a first-line diagnostic test for hospitalized infants.Genet Med. 2022; 24: 851-861https://doi.org/10.1016/j.gim.2021.11.020
- Accelerating evidence-based practice of genomic medicine.Am J Hum Genet. 2016; 98 (Published correction appears in Am J Hum Genet. 2016;99(1):246. doi: 10.1016/j.ajhg.2016.06.002): 1051-1066https://doi.org/10.1016/j.ajhg.2016.04.011
- Identifying rare, medically relevant variation via population-based genomic screening in Alabama: opportunities and pitfalls.Genet Med. 2021; 23: 280-288https://doi.org/10.1038/s41436-020-00976-z
- Pharmacogenetic predictors of cannabidiol response and tolerability in treatment-resistant epilepsy.Clin Pharmacol Ther. 2021; 110: 1368-1380https://doi.org/10.1002/cpt.2408
- Applying the Clinician-reported Genetic testing Utility Index (C-GUIDE) to genome sequencing: further evidence of validity.Eur J Hum Genet. 2022; 30: 1423-1431https://doi.org/10.1038/s41431-022-01192-w
- The clinical sequencing evidence-generating research consortium: integrating genomic sequencing in diverse and medically underserved populations.Am J Hum Genet. 2018; 103: 319-327https://doi.org/10.1016/j.ajhg.2018.08.007
- Inverting the model of genomics data sharing with the NHGRI Genomic Data Science Analysis, Visualization, and Informatics Lab-space.Cell Genom. 2022; 2100085https://doi.org/10.1016/j.xgen.2021.100085
- Somalier: rapid relatedness estimation for cancer and germline studies using efficient genome sketches.Genome Med. 2020; 12: 62https://doi.org/10.1186/s13073-020-00761-2
- Robust relationship inference in genome-wide association studies.Bioinformatics. 2010; 26: 2867-2873https://doi.org/10.1093/bioinformatics/btq559
- Sentieon DNASeq variant calling workflow demonstrates strong computational performance and accuracy.Front Genet. 2019; 10: 736https://doi.org/10.3389/fgene.2019.00736
- Strelka2: fast and accurate calling of germline and somatic variants.Nat Methods. 2018; 15: 591-594https://doi.org/10.1038/s41592-018-0051-x
- Detection of mosaic variants using genome sequencing in a diverse pediatric cohort.Am J Med Genet A. 2023; 191: 699-710https://doi.org/10.1002/ajmg.a.63062
- Lessons learned and recommendations for data coordination in collaborative research: the CSER consortium experience.HGG Adv. 2022; 3100120https://doi.org/10.1016/j.xhgg.2022.100120
- Twelve years of SAMtools and BCFtools.GigaScience. 2021; 10: giab008https://doi.org/10.1093/gigascience/giab008
- The Ensembl variant effect predictor.Genome Biol. 2016; 17: 122https://doi.org/10.1186/s13059-016-0974-4
- CADD-Splice-improving genome-wide variant effect prediction using deep learning-derived splice scores.Genome Med. 2021; 13: 31https://doi.org/10.1186/s13073-021-00835-9
- Identifying a high fraction of the human genome to be under selective constraint using GERP++.PLoS Comput Biol. 2010; 6e1001025https://doi.org/10.1371/journal.pcbi.1001025
- The mutational constraint spectrum quantified from variation in 141,456 humans.Nature. 2020; 581: 434-443https://doi.org/10.1038/s41586-020-2308-7
- Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program.Nature. 2021; 590: 290-299https://doi.org/10.1038/s41586-021-03205-y
- Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.Genet Med. 2015; 17: 405-424https://doi.org/10.1038/gim.2015.30
- Recommendations for clinical interpretation of variants found in non-coding regions of the genome.Genome Med. 2022; 14: 73https://doi.org/10.1186/s13073-022-01073-3
- Recommendations for interpreting the loss of function PVS1 ACMG/AMP variant criterion.Hum Mutat. 2018; 39: 1517-1524https://doi.org/10.1002/humu.23626
- VariantValidator: accurate validation, mapping, and formatting of sequence variation descriptions.Hum Mutat. 2018; 39: 61-68https://doi.org/10.1002/humu.23348
- Idiopathic epilepsies with seizures precipitated by fever and SCN1A abnormalities.Epilepsia. 2007; 48: 1678-1685https://doi.org/10.1111/j.1528-1167.2007.01122.x
- A general framework for estimating the relative pathogenicity of human genetic variants.Nat Genet. 2014; 46: 310-315https://doi.org/10.1038/ng.2892
- Predicting splicing from primary sequence with deep learning.Cell. 2019; 176: 535-548.e24https://doi.org/10.1016/j.cell.2018.12.015
- ATtRACT-a database of RNA-binding proteins and associated motifs.Database (Oxford). 2016; 2016: baw035https://doi.org/10.1093/database/baw035
- Splicing factors PTBP1 and PTBP2 promote proliferation and migration of glioma cell lines.Brain. 2009; 132: 2277-2288https://doi.org/10.1093/brain/awp153
- Nova-1 regulates neuron-specific alternative splicing and is essential for neuronal viability.Neuron. 2000; 25: 359-371https://doi.org/10.1016/s0896-6273(00)80900-9
- Mutually exclusive splicing regulates the Nav 1.6 sodium channel function through a combinatorial mechanism that involves three distinct splicing regulatory elements and their ligands.Nucleic Acids Res. 2012; 40: 6255-6269https://doi.org/10.1093/nar/gks249
- Antisense oligonucleotides increase Scn1a expression and reduce seizures and SUDEP incidence in a mouse model of Dravet syndrome.Sci Transl Med. 2020; 12 (eaaz6100. https://doi.org/10.1126/scitranslmed.aaz6100)
Article info
Publication history
Published online: May 06, 2023
Accepted:
May 3,
2023
Received in revised form:
May 1,
2023
Received:
December 22,
2022
Identification
Copyright
© 2023 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.
