Beyond gene-disease validity: capturing structured data on inheritance, allelic-requirement, disease-relevant variant classes, and disease mechanism for inherited cardiac conditions

Katherine S Josephs; Angharad M Roberts; Pantazis Theotokis; Roddy Walsh; Philip J Ostrowski; Matthew Edwards; Andrew Fleming; Courtney Thaxton; Jason D Roberts; Melanie Care; Wojciech Zareba; Arnon Adler; Amy C Sturm; Rafik Tadros; Valeria Novelli; Emma Owens; Lucas Bronicki; Olga Jarinova; Bert Callewaert; Stacey Peters; Tom Lumbers; Elizabeth Jordan; Babken Asatryan; Neesha Krishnan; Ray E Hershberger; C Anwar A Chahal; Andrew P Landstrom; Cynthia James; Elizabeth M McNally; Daniel P Judge; Peter van Tintelen; Arthur Wilde; Michael Gollob; Jodie Ingles; James S Ware

doi:10.1101/2023.04.03.23287612

Beyond gene-disease validity: capturing structured data on inheritance, allelic-requirement, disease-relevant variant classes, and disease mechanism for inherited cardiac conditions

Katherine S Josephs, Angharad M Roberts, Pantazis Theotokis, Roddy Walsh, Philip J Ostrowski, Matthew Edwards, Andrew Fleming, Courtney Thaxton, Jason D Roberts, Melanie Care, Wojciech Zareba, Arnon Adler, Amy C Sturm, Rafik Tadros, Valeria Novelli, Emma Owens, Lucas Bronicki, Olga Jarinova, Bert Callewaert, Stacey PetersTom Lumbers, Elizabeth Jordan, Babken Asatryan, Neesha Krishnan, Ray E Hershberger, C Anwar A Chahal, Andrew P Landstrom, Cynthia James, Elizabeth M McNally, Daniel P Judge, Peter van Tintelen, Arthur Wilde, Michael Gollob, Jodie Ingles, James S Ware

Research output: Working paper › Preprint › Academic

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Abstract

BACKGROUND: As availability of genomic testing grows, variant interpretation will increasingly be performed by genomic generalists, rather than domain-specific experts. Demand is rising for laboratories to accurately classify variants in inherited cardiac condition (ICC) genes, including as secondary findings.

METHODS: We analyse evidence for inheritance patterns, allelic requirement, disease mechanism and disease-relevant variant classes for 65 ClinGen-curated ICC gene-disease pairs. We present this information for the first time in a structured dataset, CardiacG2P, and assess application in genomic variant filtering.

RESULTS: For 36/65 gene-disease pairs, loss-of-function is not an established disease mechanism, and protein truncating variants are not known to be pathogenic. Using CardiacG2P as an initial variant filter allows for efficient variant prioritisation whilst maintaining a high sensitivity for retaining pathogenic variants compared with two other variant filtering approaches.

CONCLUSIONS: Access to evidence-based structured data representing disease mechanism and allelic requirement aids variant filtering and analysis and is pre-requisite for scalable genomic testing.

Original language	English
Publisher	medRxiv
DOIs	https://doi.org/10.1101/2023.04.03.23287612
Publication status	Published - 3 Apr 2023

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Josephs, K. S., Roberts, A. M., Theotokis, P., Walsh, R., Ostrowski, P. J., Edwards, M., Fleming, A., Thaxton, C., Roberts, J. D., Care, M., Zareba, W., Adler, A., Sturm, A. C., Tadros, R., Novelli, V., Owens, E., Bronicki, L., Jarinova, O., Callewaert, B., ... Ware, J. S. (2023). Beyond gene-disease validity: capturing structured data on inheritance, allelic-requirement, disease-relevant variant classes, and disease mechanism for inherited cardiac conditions. medRxiv. https://doi.org/10.1101/2023.04.03.23287612

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title = "Beyond gene-disease validity: capturing structured data on inheritance, allelic-requirement, disease-relevant variant classes, and disease mechanism for inherited cardiac conditions",

abstract = "BACKGROUND: As availability of genomic testing grows, variant interpretation will increasingly be performed by genomic generalists, rather than domain-specific experts. Demand is rising for laboratories to accurately classify variants in inherited cardiac condition (ICC) genes, including as secondary findings.METHODS: We analyse evidence for inheritance patterns, allelic requirement, disease mechanism and disease-relevant variant classes for 65 ClinGen-curated ICC gene-disease pairs. We present this information for the first time in a structured dataset, CardiacG2P, and assess application in genomic variant filtering.RESULTS: For 36/65 gene-disease pairs, loss-of-function is not an established disease mechanism, and protein truncating variants are not known to be pathogenic. Using CardiacG2P as an initial variant filter allows for efficient variant prioritisation whilst maintaining a high sensitivity for retaining pathogenic variants compared with two other variant filtering approaches.CONCLUSIONS: Access to evidence-based structured data representing disease mechanism and allelic requirement aids variant filtering and analysis and is pre-requisite for scalable genomic testing.",

author = "Josephs, {Katherine S} and Roberts, {Angharad M} and Pantazis Theotokis and Roddy Walsh and Ostrowski, {Philip J} and Matthew Edwards and Andrew Fleming and Courtney Thaxton and Roberts, {Jason D} and Melanie Care and Wojciech Zareba and Arnon Adler and Sturm, {Amy C} and Rafik Tadros and Valeria Novelli and Emma Owens and Lucas Bronicki and Olga Jarinova and Bert Callewaert and Stacey Peters and Tom Lumbers and Elizabeth Jordan and Babken Asatryan and Neesha Krishnan and Hershberger, {Ray E} and Chahal, {C Anwar A} and Landstrom, {Andrew P} and Cynthia James and McNally, {Elizabeth M} and Judge, {Daniel P} and {van Tintelen}, Peter and Arthur Wilde and Michael Gollob and Jodie Ingles and Ware, {James S}",

year = "2023",

month = apr,

day = "3",

doi = "10.1101/2023.04.03.23287612",

language = "English",

publisher = "medRxiv",

type = "WorkingPaper",

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Josephs, KS, Roberts, AM, Theotokis, P, Walsh, R, Ostrowski, PJ, Edwards, M, Fleming, A, Thaxton, C, Roberts, JD, Care, M, Zareba, W, Adler, A, Sturm, AC, Tadros, R, Novelli, V, Owens, E, Bronicki, L, Jarinova, O, Callewaert, B, Peters, S, Lumbers, T, Jordan, E, Asatryan, B, Krishnan, N, Hershberger, RE, Chahal, CAA, Landstrom, AP, James, C, McNally, EM, Judge, DP, van Tintelen, P, Wilde, A, Gollob, M, Ingles, J & Ware, JS 2023 'Beyond gene-disease validity: capturing structured data on inheritance, allelic-requirement, disease-relevant variant classes, and disease mechanism for inherited cardiac conditions' medRxiv. https://doi.org/10.1101/2023.04.03.23287612

TY - UNPB

T1 - Beyond gene-disease validity

T2 - capturing structured data on inheritance, allelic-requirement, disease-relevant variant classes, and disease mechanism for inherited cardiac conditions

AU - Josephs, Katherine S

AU - Roberts, Angharad M

AU - Theotokis, Pantazis

AU - Walsh, Roddy

AU - Ostrowski, Philip J

AU - Edwards, Matthew

AU - Fleming, Andrew

AU - Thaxton, Courtney

AU - Roberts, Jason D

AU - Care, Melanie

AU - Zareba, Wojciech

AU - Adler, Arnon

AU - Sturm, Amy C

AU - Tadros, Rafik

AU - Novelli, Valeria

AU - Owens, Emma

AU - Bronicki, Lucas

AU - Jarinova, Olga

AU - Callewaert, Bert

AU - Peters, Stacey

AU - Lumbers, Tom

AU - Jordan, Elizabeth

AU - Asatryan, Babken

AU - Krishnan, Neesha

AU - Hershberger, Ray E

AU - Chahal, C Anwar A

AU - Landstrom, Andrew P

AU - James, Cynthia

AU - McNally, Elizabeth M

AU - Judge, Daniel P

AU - van Tintelen, Peter

AU - Wilde, Arthur

AU - Gollob, Michael

AU - Ingles, Jodie

AU - Ware, James S

PY - 2023/4/3

Y1 - 2023/4/3

N2 - BACKGROUND: As availability of genomic testing grows, variant interpretation will increasingly be performed by genomic generalists, rather than domain-specific experts. Demand is rising for laboratories to accurately classify variants in inherited cardiac condition (ICC) genes, including as secondary findings.METHODS: We analyse evidence for inheritance patterns, allelic requirement, disease mechanism and disease-relevant variant classes for 65 ClinGen-curated ICC gene-disease pairs. We present this information for the first time in a structured dataset, CardiacG2P, and assess application in genomic variant filtering.RESULTS: For 36/65 gene-disease pairs, loss-of-function is not an established disease mechanism, and protein truncating variants are not known to be pathogenic. Using CardiacG2P as an initial variant filter allows for efficient variant prioritisation whilst maintaining a high sensitivity for retaining pathogenic variants compared with two other variant filtering approaches.CONCLUSIONS: Access to evidence-based structured data representing disease mechanism and allelic requirement aids variant filtering and analysis and is pre-requisite for scalable genomic testing.

AB - BACKGROUND: As availability of genomic testing grows, variant interpretation will increasingly be performed by genomic generalists, rather than domain-specific experts. Demand is rising for laboratories to accurately classify variants in inherited cardiac condition (ICC) genes, including as secondary findings.METHODS: We analyse evidence for inheritance patterns, allelic requirement, disease mechanism and disease-relevant variant classes for 65 ClinGen-curated ICC gene-disease pairs. We present this information for the first time in a structured dataset, CardiacG2P, and assess application in genomic variant filtering.RESULTS: For 36/65 gene-disease pairs, loss-of-function is not an established disease mechanism, and protein truncating variants are not known to be pathogenic. Using CardiacG2P as an initial variant filter allows for efficient variant prioritisation whilst maintaining a high sensitivity for retaining pathogenic variants compared with two other variant filtering approaches.CONCLUSIONS: Access to evidence-based structured data representing disease mechanism and allelic requirement aids variant filtering and analysis and is pre-requisite for scalable genomic testing.

U2 - 10.1101/2023.04.03.23287612

DO - 10.1101/2023.04.03.23287612

M3 - Preprint

C2 - 37066275

BT - Beyond gene-disease validity

PB - medRxiv

ER -

Beyond gene-disease validity: capturing structured data on inheritance, allelic-requirement, disease-relevant variant classes, and disease mechanism for inherited cardiac conditions

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