Novel diagnostic DNA methylation episignatures expand and refine the epigenetic landscapes of Mendelian disorders

Michael A Levy; Haley McConkey; Jennifer Kerkhof; Mouna Barat-Houari; Sara Bargiacchi; Elisa Biamino; María Palomares Bralo; Gerarda Cappuccio; Andrea Ciolfi; Angus Clarke; Barbara R DuPont; Mariet W Elting; Laurence Faivre; Timothy Fee; Robin S Fletcher; Florian Cherik; Aidin Foroutan; Michael J Friez; Cristina Gervasini; Sadegheh Haghshenas; Benjamin A Hilton; Zandra Jenkins; Simranpreet Kaur; Suzanne Lewis; Raymond J Louie; Silvia Maitz; Donatella Milani; Angela T Morgan; Renske Oegema; Elsebet Østergaard; Nathalie Ruiz Pallares; Maria Piccione; Simone Pizzi; Astrid S Plomp; Cathryn Poulton; Jack Reilly; Raissa Relator; Rocio Rius; Stephen Robertson; Kathleen Rooney; Justine Rousseau; Gijs W E Santen; Fernando Santos-Simarro; Josephine Schijns; Gabriella Maria Squeo; Miya St John; Christel Thauvin-Robinet; Giovanna Traficante; Pleuntje J van der Sluijs; Samantha A Vergano; Niels Vos; Kellie K Walden; Dimitar Azmanov; Tugce Balci; Siddharth Banka; Jozef Gecz; Peter Henneman; Jennifer A Lee; Marcel M A M Mannens; Tony Roscioli; Victoria Siu; David J Amor; Gareth Baynam; Eric G Bend; Kym Boycott; Nicola Brunetti-Pierri; Philippe M Campeau; John Christodoulou; David Dyment; Natacha Esber; Jill A Fahrner; Mark D Fleming; David Genevieve; Kristin D Kerrnohan; Alisdair McNeill; Giuseppe Merla; Paolo Prontera; Cheryl Rockman-Greenberg; Charles Schwartz; Steven A Skinner; Roger E Stevenson; Antonio Vitobello; Marco Tartaglia; Marielle Alders; Matthew L Tedder; Bekim Sadikovic; Leonie A. Menke

doi:https://doi.org/10.1016/j.xhgg.2021.100075

Novel diagnostic DNA methylation episignatures expand and refine the epigenetic landscapes of Mendelian disorders

Michael A Levy, Haley McConkey, Jennifer Kerkhof, Mouna Barat-Houari, Sara Bargiacchi, Elisa Biamino, María Palomares Bralo, Gerarda Cappuccio, Andrea Ciolfi, Angus Clarke, Barbara R DuPont, Mariet W Elting, Laurence Faivre, Timothy Fee, Robin S Fletcher, Florian Cherik, Aidin Foroutan, Michael J Friez, Cristina Gervasini, Sadegheh HaghshenasBenjamin A Hilton, Zandra Jenkins, Simranpreet Kaur, Suzanne Lewis, Raymond J Louie, Silvia Maitz, Donatella Milani, Angela T Morgan, Renske Oegema, Elsebet Østergaard, Nathalie Ruiz Pallares, Maria Piccione, Simone Pizzi, Astrid S Plomp, Cathryn Poulton, Jack Reilly, Raissa Relator, Rocio Rius, Stephen Robertson, Kathleen Rooney, Justine Rousseau, Gijs W E Santen, Fernando Santos-Simarro, Josephine Schijns, Gabriella Maria Squeo, Miya St John, Christel Thauvin-Robinet, Giovanna Traficante, Pleuntje J van der Sluijs, Samantha A Vergano, Niels Vos, Kellie K Walden, Dimitar Azmanov, Tugce Balci, Siddharth Banka, Jozef Gecz, Peter Henneman, Jennifer A Lee, Marcel M A M Mannens, Tony Roscioli, Victoria Siu, David J Amor, Gareth Baynam, Eric G Bend, Kym Boycott, Nicola Brunetti-Pierri, Philippe M Campeau, John Christodoulou, David Dyment, Natacha Esber, Jill A Fahrner, Mark D Fleming, David Genevieve, Kristin D Kerrnohan, Alisdair McNeill, Giuseppe Merla, Paolo Prontera, Cheryl Rockman-Greenberg, Charles Schwartz, Steven A Skinner, Roger E Stevenson, Antonio Vitobello, Marco Tartaglia, Marielle Alders, Matthew L Tedder, Bekim Sadikovic, Leonie A. Menke

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Overlapping clinical phenotypes and an expanding breadth and complexity of genomic associations are a growing challenge in the diagnosis and clinical management of Mendelian disorders. The functional consequences and clinical impacts of genomic variation may involve unique, disorder-specific, genomic DNA methylation episignatures. In this study, we describe 19 novel episignature disorders and compare the findings alongside 38 previously established episignatures for a total of 57 episignatures associated with 65 genetic syndromes. We demonstrate increasing resolution and specificity ranging from protein complex, gene, sub-gene, protein domain, and even single nucleotide-level Mendelian episignatures. We show the power of multiclass modeling to develop highly accurate and disease-specific diagnostic classifiers. This study significantly expands the number and spectrum of disorders with detectable DNA methylation episignatures, improves the clinical diagnostic capabilities through the resolution of unsolved cases and the reclassification of variants of unknown clinical significance, and provides further insight into the molecular etiology of Mendelian conditions.

Original language	English
Pages (from-to)	100075
Journal	Human Genetics and Genomics Advances
Volume	3
Issue number	1
DOIs	https://doi.org/10.1016/j.xhgg.2021.100075
Publication status	Published - 13 Jan 2022

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https://doi.org/10.1016/j.xhgg.2021.100075

Cite this

Levy, M. A., McConkey, H., Kerkhof, J., Barat-Houari, M., Bargiacchi, S., Biamino, E., Bralo, M. P., Cappuccio, G., Ciolfi, A., Clarke, A., DuPont, B. R., Elting, M. W., Faivre, L., Fee, T., Fletcher, R. S., Cherik, F., Foroutan, A., Friez, M. J., Gervasini, C., ... Menke, L. A. (2022). Novel diagnostic DNA methylation episignatures expand and refine the epigenetic landscapes of Mendelian disorders. Human Genetics and Genomics Advances, 3(1), 100075. https://doi.org/10.1016/j.xhgg.2021.100075

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title = "Novel diagnostic DNA methylation episignatures expand and refine the epigenetic landscapes of Mendelian disorders",

abstract = "Overlapping clinical phenotypes and an expanding breadth and complexity of genomic associations are a growing challenge in the diagnosis and clinical management of Mendelian disorders. The functional consequences and clinical impacts of genomic variation may involve unique, disorder-specific, genomic DNA methylation episignatures. In this study, we describe 19 novel episignature disorders and compare the findings alongside 38 previously established episignatures for a total of 57 episignatures associated with 65 genetic syndromes. We demonstrate increasing resolution and specificity ranging from protein complex, gene, sub-gene, protein domain, and even single nucleotide-level Mendelian episignatures. We show the power of multiclass modeling to develop highly accurate and disease-specific diagnostic classifiers. This study significantly expands the number and spectrum of disorders with detectable DNA methylation episignatures, improves the clinical diagnostic capabilities through the resolution of unsolved cases and the reclassification of variants of unknown clinical significance, and provides further insight into the molecular etiology of Mendelian conditions.",

author = "Levy, {Michael A} and Haley McConkey and Jennifer Kerkhof and Mouna Barat-Houari and Sara Bargiacchi and Elisa Biamino and Bralo, {Mar{\'i}a Palomares} and Gerarda Cappuccio and Andrea Ciolfi and Angus Clarke and DuPont, {Barbara R} and Elting, {Mariet W} and Laurence Faivre and Timothy Fee and Fletcher, {Robin S} and Florian Cherik and Aidin Foroutan and Friez, {Michael J} and Cristina Gervasini and Sadegheh Haghshenas and Hilton, {Benjamin A} and Zandra Jenkins and Simranpreet Kaur and Suzanne Lewis and Louie, {Raymond J} and Silvia Maitz and Donatella Milani and Morgan, {Angela T} and Renske Oegema and Elsebet {\O}stergaard and Pallares, {Nathalie Ruiz} and Maria Piccione and Simone Pizzi and Plomp, {Astrid S} and Cathryn Poulton and Jack Reilly and Raissa Relator and Rocio Rius and Stephen Robertson and Kathleen Rooney and Justine Rousseau and Santen, {Gijs W E} and Fernando Santos-Simarro and Josephine Schijns and Squeo, {Gabriella Maria} and {St John}, Miya and Christel Thauvin-Robinet and Giovanna Traficante and {van der Sluijs}, {Pleuntje J} and Vergano, {Samantha A} and Niels Vos and Walden, {Kellie K} and Dimitar Azmanov and Tugce Balci and Siddharth Banka and Jozef Gecz and Peter Henneman and Lee, {Jennifer A} and Mannens, {Marcel M A M} and Tony Roscioli and Victoria Siu and Amor, {David J} and Gareth Baynam and Bend, {Eric G} and Kym Boycott and Nicola Brunetti-Pierri and Campeau, {Philippe M} and John Christodoulou and David Dyment and Natacha Esber and Fahrner, {Jill A} and Fleming, {Mark D} and David Genevieve and Kerrnohan, {Kristin D} and Alisdair McNeill and Giuseppe Merla and Paolo Prontera and Cheryl Rockman-Greenberg and Charles Schwartz and Skinner, {Steven A} and Stevenson, {Roger E} and Antonio Vitobello and Marco Tartaglia and Marielle Alders and Tedder, {Matthew L} and Bekim Sadikovic and Menke, {Leonie A.}",

note = "{\textcopyright} 2021 The Author(s).",

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doi = "https://doi.org/10.1016/j.xhgg.2021.100075",

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Levy, MA, McConkey, H, Kerkhof, J, Barat-Houari, M, Bargiacchi, S, Biamino, E, Bralo, MP, Cappuccio, G, Ciolfi, A, Clarke, A, DuPont, BR, Elting, MW, Faivre, L, Fee, T, Fletcher, RS, Cherik, F, Foroutan, A, Friez, MJ, Gervasini, C, Haghshenas, S, Hilton, BA, Jenkins, Z, Kaur, S, Lewis, S, Louie, RJ, Maitz, S, Milani, D, Morgan, AT, Oegema, R, Østergaard, E, Pallares, NR, Piccione, M, Pizzi, S, Plomp, AS, Poulton, C, Reilly, J, Relator, R, Rius, R, Robertson, S, Rooney, K, Rousseau, J, Santen, GWE, Santos-Simarro, F, Schijns, J, Squeo, GM, St John, M, Thauvin-Robinet, C, Traficante, G, van der Sluijs, PJ, Vergano, SA, Vos, N, Walden, KK, Azmanov, D, Balci, T, Banka, S, Gecz, J, Henneman, P, Lee, JA, Mannens, MMAM, Roscioli, T, Siu, V, Amor, DJ, Baynam, G, Bend, EG, Boycott, K, Brunetti-Pierri, N, Campeau, PM, Christodoulou, J, Dyment, D, Esber, N, Fahrner, JA, Fleming, MD, Genevieve, D, Kerrnohan, KD, McNeill, A, Merla, G, Prontera, P, Rockman-Greenberg, C, Schwartz, C, Skinner, SA, Stevenson, RE, Vitobello, A, Tartaglia, M, Alders, M, Tedder, ML, Sadikovic, B & Menke, LA 2022, 'Novel diagnostic DNA methylation episignatures expand and refine the epigenetic landscapes of Mendelian disorders', Human Genetics and Genomics Advances, vol. 3, no. 1, pp. 100075. https://doi.org/10.1016/j.xhgg.2021.100075

TY - JOUR

T1 - Novel diagnostic DNA methylation episignatures expand and refine the epigenetic landscapes of Mendelian disorders

AU - Levy, Michael A

AU - McConkey, Haley

AU - Kerkhof, Jennifer

AU - Barat-Houari, Mouna

AU - Bargiacchi, Sara

AU - Biamino, Elisa

AU - Bralo, María Palomares

AU - Cappuccio, Gerarda

AU - Ciolfi, Andrea

AU - Clarke, Angus

AU - DuPont, Barbara R

AU - Elting, Mariet W

AU - Faivre, Laurence

AU - Fee, Timothy

AU - Fletcher, Robin S

AU - Cherik, Florian

AU - Foroutan, Aidin

AU - Friez, Michael J

AU - Gervasini, Cristina

AU - Haghshenas, Sadegheh

AU - Hilton, Benjamin A

AU - Jenkins, Zandra

AU - Kaur, Simranpreet

AU - Lewis, Suzanne

AU - Louie, Raymond J

AU - Maitz, Silvia

AU - Milani, Donatella

AU - Morgan, Angela T

AU - Oegema, Renske

AU - Østergaard, Elsebet

AU - Pallares, Nathalie Ruiz

AU - Piccione, Maria

AU - Pizzi, Simone

AU - Plomp, Astrid S

AU - Poulton, Cathryn

AU - Reilly, Jack

AU - Relator, Raissa

AU - Rius, Rocio

AU - Robertson, Stephen

AU - Rooney, Kathleen

AU - Rousseau, Justine

AU - Santen, Gijs W E

AU - Santos-Simarro, Fernando

AU - Schijns, Josephine

AU - Squeo, Gabriella Maria

AU - St John, Miya

AU - Thauvin-Robinet, Christel

AU - Traficante, Giovanna

AU - van der Sluijs, Pleuntje J

AU - Vergano, Samantha A

AU - Vos, Niels

AU - Walden, Kellie K

AU - Azmanov, Dimitar

AU - Balci, Tugce

AU - Banka, Siddharth

AU - Gecz, Jozef

AU - Henneman, Peter

AU - Lee, Jennifer A

AU - Mannens, Marcel M A M

AU - Roscioli, Tony

AU - Siu, Victoria

AU - Amor, David J

AU - Baynam, Gareth

AU - Bend, Eric G

AU - Boycott, Kym

AU - Brunetti-Pierri, Nicola

AU - Campeau, Philippe M

AU - Christodoulou, John

AU - Dyment, David

AU - Esber, Natacha

AU - Fahrner, Jill A

AU - Fleming, Mark D

AU - Genevieve, David

AU - Kerrnohan, Kristin D

AU - McNeill, Alisdair

AU - Merla, Giuseppe

AU - Prontera, Paolo

AU - Rockman-Greenberg, Cheryl

AU - Schwartz, Charles

AU - Skinner, Steven A

AU - Stevenson, Roger E

AU - Vitobello, Antonio

AU - Tartaglia, Marco

AU - Alders, Marielle

AU - Tedder, Matthew L

AU - Sadikovic, Bekim

AU - Menke, Leonie A.

PY - 2022/1/13

Y1 - 2022/1/13

N2 - Overlapping clinical phenotypes and an expanding breadth and complexity of genomic associations are a growing challenge in the diagnosis and clinical management of Mendelian disorders. The functional consequences and clinical impacts of genomic variation may involve unique, disorder-specific, genomic DNA methylation episignatures. In this study, we describe 19 novel episignature disorders and compare the findings alongside 38 previously established episignatures for a total of 57 episignatures associated with 65 genetic syndromes. We demonstrate increasing resolution and specificity ranging from protein complex, gene, sub-gene, protein domain, and even single nucleotide-level Mendelian episignatures. We show the power of multiclass modeling to develop highly accurate and disease-specific diagnostic classifiers. This study significantly expands the number and spectrum of disorders with detectable DNA methylation episignatures, improves the clinical diagnostic capabilities through the resolution of unsolved cases and the reclassification of variants of unknown clinical significance, and provides further insight into the molecular etiology of Mendelian conditions.

AB - Overlapping clinical phenotypes and an expanding breadth and complexity of genomic associations are a growing challenge in the diagnosis and clinical management of Mendelian disorders. The functional consequences and clinical impacts of genomic variation may involve unique, disorder-specific, genomic DNA methylation episignatures. In this study, we describe 19 novel episignature disorders and compare the findings alongside 38 previously established episignatures for a total of 57 episignatures associated with 65 genetic syndromes. We demonstrate increasing resolution and specificity ranging from protein complex, gene, sub-gene, protein domain, and even single nucleotide-level Mendelian episignatures. We show the power of multiclass modeling to develop highly accurate and disease-specific diagnostic classifiers. This study significantly expands the number and spectrum of disorders with detectable DNA methylation episignatures, improves the clinical diagnostic capabilities through the resolution of unsolved cases and the reclassification of variants of unknown clinical significance, and provides further insight into the molecular etiology of Mendelian conditions.

U2 - https://doi.org/10.1016/j.xhgg.2021.100075

DO - https://doi.org/10.1016/j.xhgg.2021.100075

M3 - Article

C2 - 35047860

SN - 2666-2477

VL - 3

SP - 100075

JO - Human Genetics and Genomics Advances

JF - Human Genetics and Genomics Advances

IS - 1

ER -