Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Aug;25(8):100884.
doi: 10.1016/j.gim.2023.100884. Epub 2023 May 6.

Poison exon annotations improve the yield of clinically relevant variants in genomic diagnostic testing

Stephanie A Felker  1 , James M J Lawlor  1 , Susan M Hiatt  1 , Michelle L Thompson  1 , Donald R Latner  1 , Candice R Finnila  1 , Kevin M Bowling  2 , Zachary T Bonnstetter  1 , Katherine E Bonini  3 , Nicole R Kelly  4 , Whitley V Kelley  1 , Anna C E Hurst  5 , Salman Rashid  5 , Melissa A Kelly  6 , Ghunwa Nakouzi  6 , Laura G Hendon  7 , E Martina Bebin  8 , Eimear E Kenny  9 , Gregory M Cooper  10
Affiliations

Poison exon annotations improve the yield of clinically relevant variants in genomic diagnostic testing

Stephanie A Felker et al. Genet Med. 2023 Aug.

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: Alternative splicing; Neurodevelopmental disorders; Nonsense-mediated decay; Poison exon; Voltage-gated sodium channels.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest Eimear E. Kenny received personal fees from Illumina, 23andMe, and Regeneron Pharmaceuticals and serves as a scientific advisory board member for Encompass Bio, Foresite Labs, and Galateo Bio. All other authors declare no conflicts of interest.

Figures

Figure 1.
Figure 1.. Extracting Clinically Relevant Poison Exons from Conserved Cassette Exons in Mouse Cortex.
Graphic depiction of the methodology implemented to filter differentially spliced cassette exons in mouse cortex to find poison exons relevant to human neurodevelopmental disease. Poison exons are depicted in orange, and canonical exons are depicted in gray.
Figure 2.
Figure 2.. Variants found within introns containing poison exons in neurodevelopmental disease cohorts.
Scale representations of the introns and canonical exons (gray), poison exons (orange), and alternatively spliced canonical exons (blue) in which variants were found. GERP scores are plotted below each and GERP conserved elements are noted (maroon bars).
See this image and copyright information in PMC

Update of

References

    1. Ropers HH. Genetics of intellectual disability. Curr Opin Genet Dev. 2008;18(3):241–50. doi: 10.1016/j.gde.2008.07.008 - DOI - PubMed
    1. DECIPHER (DatabasE of genomiC varIation and Phenotype in Humans using Ensembl Resources) GRCh37, mapping the clinical genome [Internet] Cambridge: Wellcome Trust Sanger Institute; c2017. [cited 2022 Mar 9]. Available from: https://decipher.sanger.ac.uk
    1. Childerhose JE, Rich C, East KM, Kelley WV, Simmons S, Finnila CR, Bowling K, Amaral M, Hiatt SM, Thompson M, Gray DE, Lawlor JMJ, Myers RM, Barsh GS, Lose EJ, Bebin ME, Cooper GM, Brothers KB. The Therapeutic Odyssey: Positioning Genomic Sequencing in the Search for a Child's Best Possible Life. AJOB Empir Bioeth. 2021;12(3):179–189. doi: 10.1080/23294515.2021.1907475 - DOI - PMC - PubMed
    1. Chong JX, Buckingham KJ, Jhangiani SN, Boehm C, Sobreira N, Smith JD, Harrell TM, McMillin MJ, Wiszniewski W, Gambin T, Coban Akdemir ZH, Doheny K, Scott AF, Avramopoulos D, Chakravarti A, Hoover-Fong J, Mathews D, Witmer PD, Ling H, Hetrick K, Watkins L, Patterson KE, Reinier F, Blue E, Muzny D, Kircher M, Bilguvar K, López-Giráldez F, Sutton VR, Tabor HK, Leal SM, Gunel M, Mane S, Gibbs RA, Boerwinkle E, Hamosh A, Shendure J, Lupski JR, Lifton RP, Valle D, Nickerson DA; Centers for Mendelian Genomics, Bamshad MJ. The Genetic Basis of Mendelian Phenotypes: Discoveries, Challenges, and Opportunities. Am J Hum Genet. 2015. Aug 6;97(2):199–215. doi: 10.1016/j.ajhg.2015.06.009. Epub 2015 Jul 9. - DOI - PMC - PubMed
    1. Srivastava S, Love-Nichols JA, Dies KA, Ledbetter DH, Martin CL, Chung WK, Firth HV, Frazier T, Hansen RL, Prock L, Brunner H, Hoang N, Scherer SW, Sahin M, Miller DT; NDD Exome Scoping Review Work Group. Meta-analysis and multidisciplinary consensus statement: exome sequencing is a first-tier clinical diagnostic test for individuals with neurodevelopmental disorders. Genet Med. 2019;21(11 ):2413–2421. doi: 10.1038/s41436-019-0554-6. - DOI - PMC - PubMed

Publication types