This is a preprint.

It has not yet been peer reviewed by a journal.

The National Library of Medicine is running a pilot to include preprints that result from research funded by NIH in PMC and PubMed.

[Preprint]. 2023 Jan 13:2023.01.12.523654.

doi: 10.1101/2023.01.12.523654.

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

Stephanie A Felker¹, James Mj Lawlor¹, Susan M Hiatt¹, Michelle L Thompson¹, Donald R Latner¹, Candice R Finnila¹, Kevin M Bowling², Zachary T Bonnstetter¹, Katherine E Bonini³, Nicole R Kelly⁴, Whitley V Kelley¹, Anna Ce Hurst⁵, Melissa A Kelly⁶, Ghunwa Nakouzi⁶, Laura G Hendon⁷, E Martina Bebin⁸, Eimear E Kenny^{3

9

10}, Gregory M Cooper¹

Affiliations

¹ HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA 35806.
² Washington University School of Medicine, Saint Louis, MO, USA 63110.
³ Institute for Genomic Health, Icahn School of Medicine at Mount Sinai. New York, NY, USA 10029.
⁴ Department of Pediatrics, Division of Pediatric Genetic Medicine, Children's Hospital at Montefiore/Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY, USA 10467.
⁵ University of Alabama in Birmingham, Birmingham, AL, USA 35294.
⁶ HudsonAlpha Clinical Services Lab, Huntsville, AL, USA.
⁷ University of Mississippi Medical Center, Jackson, MS, 39216.
⁸ Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, USA 35294.
⁹ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA 10029.
¹⁰ Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA 10029.

PMID: 36711854
PMCID: PMC9882217
DOI: 10.1101/2023.01.12.523654

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

Stephanie A Felker et al. bioRxiv. 2023.

[Preprint]. 2023 Jan 13:2023.01.12.523654.

doi: 10.1101/2023.01.12.523654.

Authors

Affiliations

¹ HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA 35806.
² Washington University School of Medicine, Saint Louis, MO, USA 63110.
³ Institute for Genomic Health, Icahn School of Medicine at Mount Sinai. New York, NY, USA 10029.
⁴ Department of Pediatrics, Division of Pediatric Genetic Medicine, Children's Hospital at Montefiore/Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY, USA 10467.
⁵ University of Alabama in Birmingham, Birmingham, AL, USA 35294.
⁶ HudsonAlpha Clinical Services Lab, Huntsville, AL, USA.
⁷ University of Mississippi Medical Center, Jackson, MS, 39216.
⁸ Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, USA 35294.
⁹ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA 10029.
¹⁰ Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA 10029.

PMID: 36711854
PMCID: PMC9882217
DOI: 10.1101/2023.01.12.523654

Update in

Poison exon annotations improve the yield of clinically relevant variants in genomic diagnostic testing.
Felker SA, Lawlor JMJ, Hiatt SM, Thompson ML, Latner DR, Finnila CR, Bowling KM, Bonnstetter ZT, Bonini KE, Kelly NR, Kelley WV, Hurst ACE, Rashid S, Kelly MA, Nakouzi G, Hendon LG, Bebin EM, Kenny EE, Cooper GM. Felker SA, et al. Genet Med. 2023 Aug;25(8):100884. doi: 10.1016/j.gim.2023.100884. Epub 2023 May 6. Genet Med. 2023. PMID: 37161864 Free PMC article.

Abstract

Purpose: Neurodevelopmental disorders (NDDs) often result from rare genetic variation, but genomic testing yield for NDDs remains around 50%, suggesting some clinically relevant rare variants may be missed by standard analyses. Here we analyze "poison exons" (PEs) which, while often absent from standard gene annotations, are alternative exons whose inclusion results in a premature termination codon. Variants that alter PE inclusion can lead to loss-of-function and may be highly penetrant contributors to disease.

Methods: We curated published RNA-seq data from developing mouse cortex to define 1,937 PE regions conserved between humans and mice and potentially relevant to NDDs. We then analyzed variants found by genome sequencing in multiple NDD cohorts.

Results: Across 2,999 probands, we found six clinically relevant variants in PE regions that were previously overlooked. Five of these variants are in genes that are part of the sodium voltage-gated channel alpha subunit family ( SCN1A, SCN2A , and SCN8A ), 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 were observed in probands with features consistent with those reported for the associated gene.

Conclusion: With only a minimal increase in variant analysis burden (most probands had zero or one candidate PE variants in a known NDD gene, with an average of 0.77 per proband), annotation of PEs can improve diagnostic yield for NDDs and likely other congenital conditions.

PubMed Disclaimer

Conflict of interest statement

CONFLICT OF INTEREST

Disclosure: Dr. 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 competing interests.

Figures

**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.. 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

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 Jan 18]. Available from: https://decipher.sanger.ac.uk
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. 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. 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

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

This is a preprint.

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

Affiliations

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

Authors

Affiliations

Update in

Abstract

Conflict of interest statement

Figures

References

Publication types

Grants and funding

LinkOut - more resources

Full Text Sources