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; 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 Ostergaard; 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; Leonie A. Menke; 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

doi: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, 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. HiltonZandra Jenkins, Simranpreet Kaur, Suzanne Lewis, Raymond J. Louie, Silvia Maitz, Donatella Milani, Angela T. Morgan, Renske Oegema, Elsebet Ostergaard, 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, Leonie A. Menke, 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^*

^*Corresponding author for this work

Research output: Contribution to journal › Journal article › Research › peer-review

90 Citations (Scopus)

11 Downloads (Pure)

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
Article number	100075
Journal	Human Genetics and Genomics Advances
Volume	3
Issue number	1
Number of pages	18
ISSN	2666-2477
DOIs	https://doi.org/10.1016/j.xhgg.2021.100075
Publication status	Published - 13 Jan 2022

Keywords

INTELLECTUAL DISABILITY
COFFIN-SIRIS
SIGNATURE
MUTATIONS
VARIANTS
COMPLEX
DOMAIN

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10.1016/j.xhgg.2021.100075Licence: CC BY-NC-ND

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Levy, M. A., McConkey, H., Kerkhof, J., Barat-Houari, M., Bargiacchi, S., Biamino, E., 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., Haghshenas, S., ... Sadikovic, B. (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

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

In: Human Genetics and Genomics Advances, Vol. 3, No. 1, 100075, 13.01.2022.

Research output: Contribution to journal › Journal article › Research › peer-review

Levy, MA, McConkey, H, Kerkhof, J, Barat-Houari, M, Bargiacchi, S, Biamino, E, 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, Ostergaard, 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, Menke, LA, Merla, G, Prontera, P, Rockman-Greenberg, C, Schwartz, C, Skinner, SA, Stevenson, RE, Vitobello, A, Tartaglia, M, Alders, M, Tedder, ML & Sadikovic, B 2022, 'Novel diagnostic DNA methylation episignatures expand and refine the epigenetic landscapes of Mendelian disorders', Human Genetics and Genomics Advances, vol. 3, no. 1, 100075. https://doi.org/10.1016/j.xhgg.2021.100075

Levy, Michael A. ; McConkey, Haley ; Kerkhof, Jennifer ; Barat-Houari, Mouna ; Bargiacchi, Sara ; Biamino, Elisa ; Cappuccio, Gerarda ; Ciolfi, Andrea ; Clarke, Angus ; DuPont, Barbara R. ; Elting, Mariet W. ; Faivre, Laurence ; Fee, Timothy ; Fletcher, Robin S. ; Cherik, Florian ; Foroutan, Aidin ; Friez, Michael J. ; Gervasini, Cristina ; Haghshenas, Sadegheh ; Hilton, Benjamin A. ; Jenkins, Zandra ; Kaur, Simranpreet ; Lewis, Suzanne ; Louie, Raymond J. ; Maitz, Silvia ; Milani, Donatella ; Morgan, Angela T. ; Oegema, Renske ; Ostergaard, Elsebet ; Pallares, Nathalie Ruiz ; Piccione, Maria ; Pizzi, Simone ; Plomp, Astrid S. ; Poulton, Cathryn ; Reilly, Jack ; Relator, Raissa ; Rius, Rocio ; Robertson, Stephen ; Rooney, Kathleen ; Rousseau, Justine ; Santen, Gijs W. E. ; Santos-Simarro, Fernando ; Schijns, Josephine ; Squeo, Gabriella Maria ; St John, Miya ; Thauvin-Robinet, Christel ; Traficante, Giovanna ; van der Sluijs, Pleuntje J. ; Vergano, Samantha A. ; Vos, Niels ; Walden, Kellie K. ; Azmanov, Dimitar ; Balci, Tugce ; Banka, Siddharth ; Gecz, Jozef ; Henneman, Peter ; Lee, Jennifer A. ; Mannens, Marcel M. A. M. ; Roscioli, Tony ; Siu, Victoria ; Amor, David J. ; Baynam, Gareth ; Bend, Eric G. ; Boycott, Kym ; Brunetti-Pierri, Nicola ; Campeau, Philippe M. ; Christodoulou, John ; Dyment, David ; Esber, Natacha ; Fahrner, Jill A. ; Fleming, Mark D. ; Genevieve, David ; Kerrnohan, Kristin D. ; McNeill, Alisdair ; Menke, Leonie A. ; Merla, Giuseppe ; Prontera, Paolo ; Rockman-Greenberg, Cheryl ; Schwartz, Charles ; Skinner, Steven A. ; Stevenson, Roger E. ; Vitobello, Antonio ; Tartaglia, Marco ; Alders, Marielle ; Tedder, Matthew L. ; Sadikovic, Bekim. / Novel diagnostic DNA methylation episignatures expand and refine the epigenetic landscapes of Mendelian disorders. In: Human Genetics and Genomics Advances. 2022 ; Vol. 3, No. 1.

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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.",

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year = "2022",

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day = "13",

doi = "10.1016/j.xhgg.2021.100075",

language = "English",

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journal = "Human Genetics and Genomics Advances",

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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 - 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 - Ostergaard, 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 - Menke, Leonie A.

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

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.

KW - INTELLECTUAL DISABILITY

KW - COFFIN-SIRIS

KW - SIGNATURE

KW - MUTATIONS

KW - VARIANTS

KW - COMPLEX

KW - DOMAIN

U2 - 10.1016/j.xhgg.2021.100075

DO - 10.1016/j.xhgg.2021.100075

M3 - Journal article

C2 - 35047860

VL - 3

JO - Human Genetics and Genomics Advances

JF - Human Genetics and Genomics Advances

SN - 2666-2477

IS - 1

M1 - 100075

ER -