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1. The detection of a strong episignature for Chung–Jansen syndrome, partially overlapping with Börjeson–Forssman–Lehmann and White–Kernohan syndromes

Author

Vos, Niels, Haghshenas, Sadegheh, van der Laan, Liselot, Russel, Perle K. M., Rooney, Kathleen, Levy, Michael A., Relator, Raissa, Kerkhof, Jennifer, McConkey, Haley, Maas, Saskia M., Vissers, Lisenka E. L. M., de Vries, Bert B. A., Pfundt, Rolph, Elting, Mariet W., van Hagen, Johanna M., Verbeek, Nienke E., Jongmans, Marjolijn C. J., Lakeman, Phillis, Rumping, Lynne, Bosch, Danielle G. M., Vitobello, Antonio, Thauvin-Robinet, Christel, Faivre, Laurence, Nambot, Sophie, Garde, Aurore, Willems, Marjolaine, Genevieve, David, Nicolas, Gaël, Busa, Tiffany, Toutain, Annick, Gérard, Marion, Bizaoui, Varoona, Isidor, Bertrand, Merla, Giuseppe, Accadia, Maria, Schwartz, Charles E., Ounap, Katrin, Hoffer, Mariëtte J. V., Nezarati, Marjan M., van den Boogaard, Marie-José H., Tedder, Matthew L., Rogers, Curtis, Brusco, Alfredo, Ferrero, Giovanni B., Spodenkiewicz, Marta, Sidlow, Richard, Mussa, Alessandro, Trajkova, Slavica, McCann, Emma, Mroczkowski, Henry J., Jansen, Sandra, Donker-Kaat, Laura, Duijkers, Floor A. M., Stuurman, Kyra E., Mannens, Marcel M. A. M., Alders, Mariëlle, Henneman, Peter, White, Susan M., Sadikovic, Bekim, and van Haelst, Mieke M.

Published
2024
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2. DNA methylation episignature and comparative epigenomic profiling of HNRNPU-related neurodevelopmental disorder

Author

Rooney, Kathleen, van der Laan, Liselot, Trajkova, Slavica, Haghshenas, Sadegheh, Relator, Raissa, Lauffer, Peter, Vos, Niels, Levy, Michael A., Brunetti-Pierri, Nicola, Terrone, Gaetano, Mignot, Cyril, Keren, Boris, de Villemeur, Thierry B., Volker-Touw, Catharina M.L., Verbeek, Nienke, van der Smagt, Jasper J., Oegema, Renske, Brusco, Alfredo, Ferrero, Giovanni B., Misra-Isrie, Mala, Hochstenbach, Ron, Alders, Mariëlle, Mannens, Marcel M.A.M., Sadikovic, Bekim, van Haelst, Mieke M., and Henneman, Peter

Published
2023
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3. The utility of obesity polygenic risk scores from research to clinical practice: A review.

Author

Jansen, Philip R., Vos, Niels, van Uhm, Jorrit, Dekkers, Ilona A., van der Meer, Rieneke, Mannens, Marcel M. A. M., and van Haelst, Mieke M.

Subjects
*GENETIC risk score, *OBESITY genetics, *HEALTH equity, *CLINICAL medicine, *MEDICAL research
Abstract

Summary: Obesity represents a major public health emergency worldwide, and its etiology is shaped by a complex interplay of environmental and genetic factors. Over the last decade, polygenic risk scores (PRS) have emerged as a promising tool to quantify an individual's genetic risk of obesity. The field of PRS in obesity genetics is rapidly evolving, shedding new lights on obesity mechanisms and holding promise for contributing to personalized prevention and treatment. Challenges persist in terms of its clinical integration, including the need for further validation in large‐scale prospective cohorts, ethical considerations, and implications for health disparities. In this review, we provide a comprehensive overview of PRS for studying the genetics of obesity, spanning from methodological nuances to clinical applications and challenges. We summarize the latest developments in the generation and refinement of PRS for obesity, including advances in methodologies for aggregating genome‐wide association study data and improving PRS predictive accuracy, and discuss limitations that need to be overcome to fully realize its potential benefits of PRS in both medicine and public health. [ABSTRACT FROM AUTHOR]

Published
2024
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5. GNB1 and obesity: Evidence for a correlation between haploinsufficiency and syndromic obesity

Author

Kleinendorst, Lotte, primary, Abawi, Ozair, additional, Vos, Niels, additional, van der Valk, Eline S., additional, Maas, Saskia M., additional, Morgan, Angela T., additional, Hildebrand, Michael S., additional, Da Silva, Jorge D., additional, Florijn, Ralph J., additional, Lauffer, Peter, additional, Visser, Jenny A., additional, van Rossum, Elisabeth F. C., additional, van den Akker, Erica L. T., additional, and van Haelst, Mieke M., additional

Published
2024
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6. The detection of a strong episignature for Chung-Jansen syndrome, partially overlapping with Börjeson-Forssman-Lehmann and White-Kernohan syndromes

Author

Genetica Klinische Genetica, Cancer, Child Health, Vos, Niels, Haghshenas, Sadegheh, van der Laan, Liselot, Russel, Perle K M, Rooney, Kathleen, Levy, Michael A, Relator, Raissa, Kerkhof, Jennifer, McConkey, Haley, Maas, Saskia M, Vissers, Lisenka E L M, de Vries, Bert B A, Pfundt, Rolph, Elting, Mariet W, van Hagen, Johanna M, Verbeek, Nienke E, Jongmans, Marjolijn C J, Lakeman, Phillis, Rumping, Lynne, Bosch, Danielle G M, Vitobello, Antonio, Thauvin-Robinet, Christel, Faivre, Laurence, Nambot, Sophie, Garde, Aurore, Willems, Marjolaine, Genevieve, David, Nicolas, Gaël, Busa, Tiffany, Toutain, Annick, Gérard, Marion, Bizaoui, Varoona, Isidor, Bertrand, Merla, Giuseppe, Accadia, Maria, Schwartz, Charles E, Ounap, Katrin, Hoffer, Mariëtte J V, Nezarati, Marjan M, van den Boogaard, Marie-José H, Tedder, Matthew L, Rogers, Curtis, Brusco, Alfredo, Ferrero, Giovanni B, Spodenkiewicz, Marta, Sidlow, Richard, Mussa, Alessandro, Trajkova, Slavica, McCann, Emma, Mroczkowski, Henry J, Jansen, Sandra, Donker-Kaat, Laura, Duijkers, Floor A M, Stuurman, Kyra E, Mannens, Marcel M A M, Alders, Mariëlle, Henneman, Peter, White, Susan M, Sadikovic, Bekim, van Haelst, Mieke M, Genetica Klinische Genetica, Cancer, Child Health, Vos, Niels, Haghshenas, Sadegheh, van der Laan, Liselot, Russel, Perle K M, Rooney, Kathleen, Levy, Michael A, Relator, Raissa, Kerkhof, Jennifer, McConkey, Haley, Maas, Saskia M, Vissers, Lisenka E L M, de Vries, Bert B A, Pfundt, Rolph, Elting, Mariet W, van Hagen, Johanna M, Verbeek, Nienke E, Jongmans, Marjolijn C J, Lakeman, Phillis, Rumping, Lynne, Bosch, Danielle G M, Vitobello, Antonio, Thauvin-Robinet, Christel, Faivre, Laurence, Nambot, Sophie, Garde, Aurore, Willems, Marjolaine, Genevieve, David, Nicolas, Gaël, Busa, Tiffany, Toutain, Annick, Gérard, Marion, Bizaoui, Varoona, Isidor, Bertrand, Merla, Giuseppe, Accadia, Maria, Schwartz, Charles E, Ounap, Katrin, Hoffer, Mariëtte J V, Nezarati, Marjan M, van den Boogaard, Marie-José H, Tedder, Matthew L, Rogers, Curtis, Brusco, Alfredo, Ferrero, Giovanni B, Spodenkiewicz, Marta, Sidlow, Richard, Mussa, Alessandro, Trajkova, Slavica, McCann, Emma, Mroczkowski, Henry J, Jansen, Sandra, Donker-Kaat, Laura, Duijkers, Floor A M, Stuurman, Kyra E, Mannens, Marcel M A M, Alders, Mariëlle, Henneman, Peter, White, Susan M, Sadikovic, Bekim, and van Haelst, Mieke M

Published
2024

7. GNB1 and obesity:Evidence for a correlation between haploinsufficiency and syndromic obesity

Author

Kleinendorst, Lotte, Abawi, Ozair, Vos, Niels, van der Valk, Eline S., Maas, Saskia M., Morgan, Angela T., Hildebrand, Michael S., Da Silva, Jorge D., Florijn, Ralph J., Lauffer, Peter, Visser, Jenny A., van Rossum, Elisabeth F.C., van den Akker, Erica L.T., van Haelst, Mieke M., Kleinendorst, Lotte, Abawi, Ozair, Vos, Niels, van der Valk, Eline S., Maas, Saskia M., Morgan, Angela T., Hildebrand, Michael S., Da Silva, Jorge D., Florijn, Ralph J., Lauffer, Peter, Visser, Jenny A., van Rossum, Elisabeth F.C., van den Akker, Erica L.T., and van Haelst, Mieke M.

Abstract

Most patients with GNB1 encephalopathy have developmental delay and/or intellectual disability, brain anomalies and seizures. Recently, two cases with GNB1 encephalopathy caused by haploinsufficiency have been reported that also show a Prader–Willi-like phenotype of childhood hypotonia and severe obesity. Here we present three new cases from our expert centre for genetic obesity in which GNB1 truncating and splice variants, probably leading to haploinsufficiency, were identified. They all have obesity, hyperphagia and intellectual deficit. The clinical cases and their weight courses are presented, together with a review of all 68 published cases with GNB1 encephalopathy. Information on weight was not mentioned in most of these articles, so we contacted authors for additional clinical information on weight status and hyperphagia. Of the 42 patients whose weight status we could determine, obesity was present in 8 patients (19%). Obesity is significantly over-represented in the group with truncating and splicing variants. In this group, we see an obesity prevalence of 75%. Since GNB1 has been linked to several key genes in the hypothalamic leptin-melanocortin pathway, which regulates satiety and energy expenditure, our data support the potential association between GNB1 haploinsufficiency and genetic obesity. We also suggest GNB1 is a candidate gene for the known obesity phenotype of the 1p36 microdeletion syndrome given this chromosomal region includes the GNB1 gene. Knowledge of an additional obesity phenotype is important for prognosis, early interventions against obesity and awareness when prescribing weight-inducing medication.

Published
2024

8. Evaluation of 100 Dutch cases with 16p11.2 deletion and duplication syndromes:from clinical manifestations towards personalized treatment options

Author

Vos, Niels, Kleinendorst, Lotte, van der Laan, Liselot, van Uhm, Jorrit, Jansen, Philip R, van Eeghen, Agnies M, Maas, Saskia M, Mannens, Marcel M A M, van Haelst, Mieke M, Vos, Niels, Kleinendorst, Lotte, van der Laan, Liselot, van Uhm, Jorrit, Jansen, Philip R, van Eeghen, Agnies M, Maas, Saskia M, Mannens, Marcel M A M, and van Haelst, Mieke M

Abstract

The 16p11.2 deletion syndrome is a clinically heterogeneous disorder, characterized by developmental delay, intellectual disability, hyperphagia, obesity, macrocephaly and psychiatric problems. Cases with 16p11.2 duplication syndrome have similar neurodevelopmental problems, but typically show a partial 'mirror phenotype' with underweight and microcephaly. Various copy number variants (CNVs) of the chromosomal 16p11.2 region have been described. Most is known about the 'typical' 16p11.2 BP4-BP5 (29.6-30.2 Mb; ~600 kb) deletions and duplications, but there are also several published cohorts with more distal 16p11.2 BP2-BP3 CNVs (28.8-29.0 Mb; ~220 kb), who exhibit clinical overlap. We assessed 100 cases with various pathogenic 16p11.2 CNVs and compared their clinical characteristics to provide more clear genotype-phenotype correlations and raise awareness of the different 16p11.2 CNVs. Neurodevelopmental and weight issues were reported in the majority of cases. Cases with distal 16p11.2 BP2-BP3 deletion showed the most severe obesity phenotype (73.7% obesity, mean BMI SDS 3.2). In addition to the more well defined typical 16p11.2 BP4-BP5 and distal 16p11.2 BP2-BP3 CNVs, we describe the clinical features of five cases with other, overlapping, 16p11.2 CNVs in more detail. Interestingly, four cases had a second genetic diagnosis and 18 cases an additional gene variant of uncertain significance, that could potentially help explain the cases' phenotypes. In conclusion, we provide an overview of our Dutch cohort of cases with various pathogenic 16p11.2 CNVs and relevant second genetic findings, that can aid in adequately recognizing, diagnosing and counseling of individuals with 16p11.2 CNVs, and describe the personalized medicine for cases with these conditions.

Published
2024

9. The utility of obesity polygenic risk scores from research to clinical practice: A review

Author

Jansen, Philip R, Vos, Niels, van Uhm, Jorrit, Dekkers, Ilona A, van der Meer, Rieneke, Mannens, Marcel M A M, van Haelst, Mieke M, Jansen, Philip R, Vos, Niels, van Uhm, Jorrit, Dekkers, Ilona A, van der Meer, Rieneke, Mannens, Marcel M A M, and van Haelst, Mieke M

Abstract

Obesity represents a major public health emergency worldwide, and its etiology is shaped by a complex interplay of environmental and genetic factors. Over the last decade, polygenic risk scores (PRS) have emerged as a promising tool to quantify an individual's genetic risk of obesity. The field of PRS in obesity genetics is rapidly evolving, shedding new lights on obesity mechanisms and holding promise for contributing to personalized prevention and treatment. Challenges persist in terms of its clinical integration, including the need for further validation in large-scale prospective cohorts, ethical considerations, and implications for health disparities. In this review, we provide a comprehensive overview of PRS for studying the genetics of obesity, spanning from methodological nuances to clinical applications and challenges. We summarize the latest developments in the generation and refinement of PRS for obesity, including advances in methodologies for aggregating genome-wide association study data and improving PRS predictive accuracy, and discuss limitations that need to be overcome to fully realize its potential benefits of PRS in both medicine and public health.

Published
2024

11. DNA methylation episignature and comparative epigenomic profiling of HNRNPU-related neurodevelopmental disorder

Author

Genetica Klinische Genetica, Circulatory Health, Brain, Child Health, Genetica Sectie Genoomdiagnostiek, Rooney, Kathleen, van der Laan, Liselot, Trajkova, Slavica, Haghshenas, Sadegheh, Relator, Raissa, Lauffer, Peter, Vos, Niels, Levy, Michael A, Brunetti-Pierri, Nicola, Terrone, Gaetano, Mignot, Cyril, Keren, Boris, Billette de Villemeur, Thierry, Volker-Touw, Catharina M L, Verbeek, Nienke, van der Smagt, Jasper J, Oegema, Renske, Brusco, Alfredo, Ferrero, Giovanni Battista, Misra-Isrie, Mala, Hochstenbach, Ron, Alders, Mariëlle, Mannens, Marcel M A M, Sadikovic, Bekim, van Haelst, Mieke M, Henneman, Peter, Genetica Klinische Genetica, Circulatory Health, Brain, Child Health, Genetica Sectie Genoomdiagnostiek, Rooney, Kathleen, van der Laan, Liselot, Trajkova, Slavica, Haghshenas, Sadegheh, Relator, Raissa, Lauffer, Peter, Vos, Niels, Levy, Michael A, Brunetti-Pierri, Nicola, Terrone, Gaetano, Mignot, Cyril, Keren, Boris, Billette de Villemeur, Thierry, Volker-Touw, Catharina M L, Verbeek, Nienke, van der Smagt, Jasper J, Oegema, Renske, Brusco, Alfredo, Ferrero, Giovanni Battista, Misra-Isrie, Mala, Hochstenbach, Ron, Alders, Mariëlle, Mannens, Marcel M A M, Sadikovic, Bekim, van Haelst, Mieke M, and Henneman, Peter

Published
2023

12. DNA methylation episignatures are sensitive and specific biomarkers for detection of patients with KAT6A/KAT6B variants

Author

Vos, Niels, Reilly, Jack, Elting, Mariet W., Campeau, Philippe M., Coman, David, Stark, Zornitza, Tan, Tiong Yang, Amor, David J., Kaur, Simran, StJohn, Miya, Morgan, Angela T., Kamien, Benjamin A., Patel, Chirag, Tedder, Matthew L., Merla, Giuseppe, Prontera, Paolo, Castori, Marco, Muru, Kai, Collins, Felicity, Christodoulou, John, Smith, Janine, Zeev, Bruria Ben, Murgia, Alessandra, Leonardi, Emanuela, Esber, Natacha, Martinez-Monseny, Antonio, Casas-Alba, Didac, Wallis, Matthew, Mannens, Marcel, Levy, Michael A., Relator, Raissa, Alders, Marielle, Sadikovic, Bekim, Human genetics, and Amsterdam Reproduction & Development (AR&D)

Abstract

Accurate diagnosis for patients living with neurodevelopmental disorders is often met with numerous challenges, related to the ambiguity of findings and lack of specificity in genetic variants leading to pathology. Genome-wide DNA methylation analysis has been used to develop highly sensitive and specific 'episignatures' as biomarkers capable of differentiating and classifying complex neurodevelopmental disorders. In this study we describe distinct episignatures for KAT6A syndrome, caused by pathogenic variants in the lysine acetyltransferase A gene (KAT6A), and for the two neurodevelopmental disorders associated with lysine acetyl transferase B (KAT6B). We demonstrate the ability of our models to differentiate between highly overlapping episignatures, increasing the ability to effectively identify and diagnose these conditions.

Published
2023

14. Functional correlation of genome‐wide DNA methylation profiles in genetic neurodevelopmental disorders

Author

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

Published
2022
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15. Novel diagnostic DNA methylation episignatures expand and refine the epigenetic landscapes of Mendelian disorders

Author

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, 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., and Sadikovic, Bekim

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.

Published
2022

16. Functional correlation of genome-wide DNA methylation profiles in genetic neurodevelopmental disorders

Author

Levy, Michael A., Relator, Raissa, McConkey, Haley, Pranckeviciene, Erinija, Kerkhof, Jennifer, Barat-Houari, Mouna, Bargiacchi, Sara, Biamino, Elisa, Palomares Bralo, María, Cappuccio, Gerarda, Ciolfi, Andrea, Clarke, Angus, DuPont, Barbara R., Elting, Mariet W., Faivre, Laurence, Fee, Timothy, Ferilli, Marco, Fletcher, Robin S., Cherick, 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, Østergaard, Elsebet, Pallares, Nathalie R., Piccione, Maria, Plomp, Astrid S., Poulton, Cathryn, Reilly, Jack, Rius, Rocio, Robertson, Stephen, Rooney, Kathleen, Rousseau, Justine, Santen, Gijs W.E., Santos-Simarro, Fernando, Schijns, Josephine, Squeo, Gabriella M., John, Miya St, Thauvin-Robinet, Christel, Traficante, Giovanna, van der Sluijs, Pleuntje J., Vergano, Samantha A., Vos, Niels, Walden, Kellie K., Azmanov, Dimitar, Balci, Tugce B., 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., Campion, Dominique, Christodoulou, John, Dyment, David, Esber, Natacha, Fahrner, Jill A., Fleming, Mark D., Genevieve, David, Heron, Delphine, Husson, Thomas, Kernohan, Kristin D., McNeill, Alisdair, Menke, Leonie A., Merla, Giuseppe, Prontera, Paolo, Rockman-Greenberg, Cheryl, Schwartz, Charles, Skinner, Steven A., Stevenson, Roger E., Vincent, Marie, Vitobello, Antonio, Tartaglia, Marco, Alders, Marielle, Tedder, Matthew L., Sadikovic, Bekim, Levy, Michael A., Relator, Raissa, McConkey, Haley, Pranckeviciene, Erinija, Kerkhof, Jennifer, Barat-Houari, Mouna, Bargiacchi, Sara, Biamino, Elisa, Palomares Bralo, María, Cappuccio, Gerarda, Ciolfi, Andrea, Clarke, Angus, DuPont, Barbara R., Elting, Mariet W., Faivre, Laurence, Fee, Timothy, Ferilli, Marco, Fletcher, Robin S., Cherick, 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, Østergaard, Elsebet, Pallares, Nathalie R., Piccione, Maria, Plomp, Astrid S., Poulton, Cathryn, Reilly, Jack, Rius, Rocio, Robertson, Stephen, Rooney, Kathleen, Rousseau, Justine, Santen, Gijs W.E., Santos-Simarro, Fernando, Schijns, Josephine, Squeo, Gabriella M., John, Miya St, Thauvin-Robinet, Christel, Traficante, Giovanna, van der Sluijs, Pleuntje J., Vergano, Samantha A., Vos, Niels, Walden, Kellie K., Azmanov, Dimitar, Balci, Tugce B., 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., Campion, Dominique, Christodoulou, John, Dyment, David, Esber, Natacha, Fahrner, Jill A., Fleming, Mark D., Genevieve, David, Heron, Delphine, Husson, Thomas, Kernohan, Kristin D., McNeill, Alisdair, Menke, Leonie A., Merla, Giuseppe, Prontera, Paolo, Rockman-Greenberg, Cheryl, Schwartz, Charles, Skinner, Steven A., Stevenson, Roger E., Vincent, Marie, Vitobello, Antonio, Tartaglia, Marco, Alders, Marielle, Tedder, Matthew L., and Sadikovic, Bekim

Abstract

An expanding range of genetic syndromes are characterized by genome-wide disruptions in DNA methylation profiles referred to as episignatures. Episignatures are distinct, highly sensitive, and specific biomarkers that have recently been applied in clinical diagnosis of genetic syndromes. Episignatures are contained within the broader disorder-specific genome-wide DNA methylation changes, which can share significant overlap among different conditions. In this study, we performed functional genomic assessment and comparison of disorder-specific and overlapping genome-wide DNA methylation changes related to 65 genetic syndromes with previously described episignatures. We demonstrate evidence of disorder-specific and recurring genome-wide differentially methylated probes (DMPs) and regions (DMRs). The overall distribution of DMPs and DMRs across the majority of the neurodevelopmental genetic syndromes analyzed showed substantial enrichment in gene promoters and CpG islands, and under-representation of the more variable intergenic regions. Analysis showed significant enrichment of the DMPs and DMRs in gene pathways and processes related to neurodevelopment, including neurogenesis, synaptic signaling and synaptic transmission. This study expands beyond the diagnostic utility of DNA methylation episignatures by demonstrating correlation between the function of the mutated genes and the consequent genomic DNA methylation profiles as a key functional element in the molecular etiology of genetic neurodevelopmental disorders.

Published
2022

17. Functional correlation of genome-wide DNA methylation profiles in genetic neurodevelopmental disorders

Author

Genetica Klinische Genetica, Brain, Child Health, Levy, Michael A, Relator, Raissa, McConkey, Haley, Pranckeviciene, Erinija, Kerkhof, Jennifer, Barat-Houari, Mouna, Bargiacchi, Sara, Biamino, Elisa, Bralo, María Palomares, Cappuccio, Gerarda, Ciolfi, Andrea, Clarke, Angus, DuPont, Barbara R, Elting, Mariet W, Faivre, Laurence, Fee, Timothy, Ferilli, Marco, Fletcher, Robin S, Cherick, 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, Østergaard, Elsebet, Pallares, Nathalie Ruiz, Piccione, Maria, Plomp, Astrid S, Poulton, Cathryn, Reilly, Jack, Rius, Rocio, Robertson, Stephen, Rooney, Kathleen, Rousseau, Justine, Santen, Gijs W E, Santos-Simarro, Fernando, Schijns, Josephine, Squeo, Gabriella Maria, John, Miya St, Thauvin-Robinet, Christel, Traficante, Giovanna, van der Sluijs, Pleuntje J, Vergano, Samantha A, Vos, Niels, Walden, Kellie K, Azmanov, Dimitar, Balci, Tugce B, 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, Campion, Dominique, Christodoulou, John, Dyment, David, Esber, Natacha, Fahrner, Jill A, Fleming, Mark D, Genevieve, David, Heron, Delphine, Husson, Thomas, Kernohan, Kristin D, McNeill, Alisdair, Menke, Leonie A, Merla, Giuseppe, Prontera, Paolo, Rockman-Greenberg, Cheryl, Schwartz, Charles, Skinner, Steven A, Stevenson, Roger E, Vincent, Marie, Vitobello, Antonio, Tartaglia, Marco, Alders, Marielle, Tedder, Matthew L, Sadikovic, Bekim, Genetica Klinische Genetica, Brain, Child Health, Levy, Michael A, Relator, Raissa, McConkey, Haley, Pranckeviciene, Erinija, Kerkhof, Jennifer, Barat-Houari, Mouna, Bargiacchi, Sara, Biamino, Elisa, Bralo, María Palomares, Cappuccio, Gerarda, Ciolfi, Andrea, Clarke, Angus, DuPont, Barbara R, Elting, Mariet W, Faivre, Laurence, Fee, Timothy, Ferilli, Marco, Fletcher, Robin S, Cherick, 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, Østergaard, Elsebet, Pallares, Nathalie Ruiz, Piccione, Maria, Plomp, Astrid S, Poulton, Cathryn, Reilly, Jack, Rius, Rocio, Robertson, Stephen, Rooney, Kathleen, Rousseau, Justine, Santen, Gijs W E, Santos-Simarro, Fernando, Schijns, Josephine, Squeo, Gabriella Maria, John, Miya St, Thauvin-Robinet, Christel, Traficante, Giovanna, van der Sluijs, Pleuntje J, Vergano, Samantha A, Vos, Niels, Walden, Kellie K, Azmanov, Dimitar, Balci, Tugce B, 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, Campion, Dominique, Christodoulou, John, Dyment, David, Esber, Natacha, Fahrner, Jill A, Fleming, Mark D, Genevieve, David, Heron, Delphine, Husson, Thomas, Kernohan, Kristin D, McNeill, Alisdair, Menke, Leonie A, Merla, Giuseppe, Prontera, Paolo, Rockman-Greenberg, Cheryl, Schwartz, Charles, Skinner, Steven A, Stevenson, Roger E, Vincent, Marie, Vitobello, Antonio, Tartaglia, Marco, Alders, Marielle, Tedder, Matthew L, and Sadikovic, Bekim

Published
2022

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

Author

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

Published
2022
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26. Celebrating the best of British.

Author

De Vos, Niels

Abstract

The article offers information on the United Kingdom Athletics (UKA) Awards Dinner with a theme "best of British" on December 5, 2009 at the National Motorcycle Museum in Solihull, England. It notes that the event aims to reflect the achievements of various individuals and hundreds of teams across the range of sports. It mentions that the event will feature several World Championships medallists including Mara Yamauchi, Simeon Williamson, and Danny Crates.

Published
2009

27. Your Say.

Author

Frost, Jack, Martineau, Mike, de Vos, Niels, and Smith, Dave

Abstract

Several letters to the editor are presented in response to issues in British athletics and articles featured in previous issues, including Wilf Paish's article on athletics coaching, Christine Ohuruogu's reinstatement and the UK Athletics Competition Review.

Published
2007

28. DNA methylation episignatures are sensitive and specific biomarkers for detection of patients with KAT6A / KAT6B variants.

Author

Vos N, Reilly J, Elting MW, Campeau PM, Coman D, Stark Z, Tan TY, Amor DJ, Kaur S, StJohn M, Morgan AT, Kamien BA, Patel C, Tedder ML, Merla G, Prontera P, Castori M, Muru K, Collins F, Christodoulou J, Smith J, Zeev BB, Murgia A, Leonardi E, Esber N, Martinez-Monseny A, Casas-Alba D, Wallis M, Mannens M, Levy MA, Relator R, Alders M, and Sadikovic B

Subjects
Humans, Biomarkers, Histone Acetyltransferases genetics, DNA Methylation, Neurodevelopmental Disorders genetics
Abstract

Accurate diagnosis for patients living with neurodevelopmental disorders is often met with numerous challenges, related to the ambiguity of findings and lack of specificity in genetic variants leading to pathology. Genome-wide DNA methylation analysis has been used to develop highly sensitive and specific 'episignatures' as biomarkers capable of differentiating and classifying complex neurodevelopmental disorders. In this study we describe distinct episignatures for KAT6A syndrome, caused by pathogenic variants in the lysine acetyltransferase A gene ( KAT6A ), and for the two neurodevelopmental disorders associated with lysine acetyl transferase B ( KAT6B ). We demonstrate the ability of our models to differentiate between highly overlapping episignatures, increasing the ability to effectively identify and diagnose these conditions.

Published
2023
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29. Novel diagnostic DNA methylation episignatures expand and refine the epigenetic landscapes of Mendelian disorders.

Author

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, Menke LA, Merla G, Prontera P, Rockman-Greenberg C, Schwartz C, Skinner SA, Stevenson RE, Vitobello A, Tartaglia M, Alders M, Tedder ML, and Sadikovic B

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., Competing Interests: The authors declare no competing interests., (© 2021 The Author(s).)

Published
2021
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