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

doi:10.1016/j.xhgg.2021.100075

. 2021 Dec 3;3(1):100075.

doi: 10.1016/j.xhgg.2021.100075. eCollection 2022 Jan 13.

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

Michael A Levy¹, Haley McConkey¹, Jennifer Kerkhof¹, Mouna Barat-Houari², Sara Bargiacchi³, Elisa Biamino⁴, María Palomares Bralo⁵, Gerarda Cappuccio^{6

7}, Andrea Ciolfi⁸, Angus Clarke⁹, Barbara R DuPont¹⁰, Mariet W Elting¹¹, Laurence Faivre^{12

13}, Timothy Fee¹⁰, Robin S Fletcher¹⁰, Florian Cherik^{14

15}, Aidin Foroutan¹⁶, Michael J Friez¹⁰, Cristina Gervasini¹⁷, Sadegheh Haghshenas¹⁶, Benjamin A Hilton¹⁰, Zandra Jenkins¹⁸, Simranpreet Kaur¹⁹, Suzanne Lewis²⁰, Raymond J Louie¹⁰, Silvia Maitz²¹, Donatella Milani²², Angela T Morgan²³, Renske Oegema²⁴, Elsebet Østergaard^{25

26}, Nathalie Ruiz Pallares², Maria Piccione²⁷, Simone Pizzi⁸, Astrid S Plomp²⁸, Cathryn Poulton²⁹, Jack Reilly¹⁶, Raissa Relator¹, Rocio Rius^{30

31}, Stephen Robertson¹⁸, Kathleen Rooney^{1

16}, Justine Rousseau³², Gijs W E Santen³³, Fernando Santos-Simarro⁵, Josephine Schijns³⁴, Gabriella Maria Squeo³⁵, Miya St John²³, Christel Thauvin-Robinet^{12

13

36

37}, Giovanna Traficante³, Pleuntje J van der Sluijs³³, Samantha A Vergano^{38

39}, Niels Vos⁴⁰, Kellie K Walden¹⁰, Dimitar Azmanov⁴¹, Tugce Balci^{42

43}, Siddharth Banka^{44

45}, Jozef Gecz^{46

47}, Peter Henneman²⁸, Jennifer A Lee¹⁰, Marcel M A M Mannens²⁸, Tony Roscioli^{48

49

50

51}, Victoria Siu^{42

43}, David J Amor²³, Gareth Baynam^{29

29

52}, Eric G Bend⁵³, Kym Boycott^{54

55}, Nicola Brunetti-Pierri^{6

7}, Philippe M Campeau³², John Christodoulou¹⁹, David Dyment⁵⁶, Natacha Esber⁵⁷, Jill A Fahrner⁵⁸, Mark D Fleming⁵⁹, David Genevieve¹⁵, Kristin D Kerrnohan^{54

60}, Alisdair McNeill⁶¹, Leonie A Menke³⁴, Giuseppe Merla^{35

62}, Paolo Prontera⁶³, Cheryl Rockman-Greenberg⁶⁴, Charles Schwartz¹⁰, Steven A Skinner¹⁰, Roger E Stevenson¹⁰, Antonio Vitobello^{12

36}, Marco Tartaglia⁸, Marielle Alders²⁸, Matthew L Tedder¹⁰, Bekim Sadikovic^{1

16}

Affiliations

¹ Verspeeten Clinical Genome Centre; London Health Sciences Centre, London, ON N6A 5W9, Canada.
² Autoinflammatory and Rare Diseases Unit, Medical Genetic Department for Rare Diseases and Personalized Medicine, CHU Montpellier, Montpellier, France.
³ Medical Genetics Unit, "A. Meyer" Children's Hospital of Florence, Florence, Italy.
⁴ Department of Pediatrics, University of Turin, Turin, Italy.
⁵ Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, IdiPAZ, CIBERER, ISCIII, Madrid, Spain.
⁶ Department of Translational Medicine, Federico II University of Naples, Naples, Italy.
⁷ Telethon Institute of Genetics and Medicine, Pozzuoli, Italy.
⁸ Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy.
⁹ Cardiff University School of Medicine, Cardiff, UK.
¹⁰ Greenwood Genetic Center, Greenwood, SC 29646, USA.
¹¹ Department of Clinical Genetics, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
¹² INSERM-Université de Bourgogne UMR1231 GAD « Génétique Des Anomalies du Développement », FHU-TRANSLAD, UFR Des Sciences de Santé, Dijon, France.
¹³ Centre de Référence Maladies Rares «Anomalies du Développement et Syndromes Malformatifs », Centre de Génétique, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France.
¹⁴ Genetic medical center, CHU Clermont Ferrand, France.
¹⁵ Montpellier University, Reference Center for Rare Disease, Medical Genetic Department for Rare Disease and Personalize Medicine, Inserm Unit 1183, CHU Montpellier, Montpellier, France.
¹⁶ Department of Pathology and Laboratory Medicine, Western University, London, ON N6A 3K7, Canada.
¹⁷ Division of Medical Genetics, Department of Health Sciences, Università degli Studi di Milano, Milan, Italy.
¹⁸ Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.
¹⁹ Brain and Mitochondrial Research Group, Murdoch Children's Research Institute and Department of Paediatrics, University of Melbourne, Melbourne, Australia.
²⁰ BC Children's and Women's Hospital and Department of Medical Genetics, Faculty of Medicine, University of British Columbia, Vancouver, Canada.
²¹ Clinical Pediatric Genetics Unit, Pediatrics Clinics, MBBM Foundation, Hospital San Gerardo, Monza, Italy.
²² Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
²³ Murdoch Children's Research Institute and Department of Paediatrics, University of Melbourne, Melbourne, Australia.
²⁴ Department of Genetics, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
²⁵ Department of Clinical Genetics, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.
²⁶ Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
²⁷ Medical Genetics Unit Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy.
²⁸ Amsterdam UMC, University of Amsterdam, Department of Human Genetics, Amsterdam Reproduction and Development Research Institute, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands.
²⁹ Undiagnosed Diseases Program, Genetic Services of Western Australia, King Edward Memorial Hospital, Perth, Australia.
³⁰ Brain and Mitochondrial Research Group, Murdoch Children's Research Institute, Melbourne, Australia.
³¹ Department of Paediatrics, University of Melbourne, Melbourne, Australia.
³² CHU Sainte-Justine Research Center, University of Montreal, Montreal, QC H3T 1C5, Canada.
³³ Department of Clinical Genetics, LUMC, Leiden, the Netherlands.
³⁴ Department of Pediatrics, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.
³⁵ Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, Italy.
³⁶ Unité Fonctionnelle d'Innovation Diagnostique des Maladies Rares, FHU-TRANSLAD, France Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement (TRANSLAD), Centre Hospitalier Universitaire Dijon Bourgogne, CHU Dijon Bourgogne, Dijon, France.
³⁷ Centre de Référence Déficiences Intellectuelles de Causes Rares, Hôpital D'Enfants, CHU Dijon Bourgogne, 21000 Dijon, France.
³⁸ Division of Medical Genetics and Metabolism, Children's Hospital of The King's Daughters, Norfolk, VA, USA.
³⁹ Department of Pediatrics, Eastern Virginia Medical School, Norfolk, VA, USA.
⁴⁰ Department of Clinical Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam Reproduction and Development Research Institute, Meibergdreef 9, Amsterdam, the Netherlands.
⁴¹ Department of Diagnostic Genomics, PathWest Laboratory Medicine, QEII Medical Centre, Perth, Australia.
⁴² Department of Pediatrics, Division of Medical Genetics, Western University, London, ON N6A 3K7, Canada.
⁴³ Medical Genetics Program of Southwestern Ontario, London Health Sciences Centre and Children's Health Research Institute, London, ON N6A5W9, Canada.
⁴⁴ Division of Evolution, Infection & Genomics, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.
⁴⁵ Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester, UK.
⁴⁶ School of Medicine, Robinson Research Institute, University of Adelaide, Adelaide, SA 5005, Australia.
⁴⁷ South Australian Health and Medical Research Institute, Adelaide, SA 5005, Australia.
⁴⁸ Neuroscience Research Australia (NeuRA), Sydney, Australia.
⁴⁹ Prince of Wales Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia.
⁵⁰ New South Wales Health Pathology Randwick Genomics, Prince of Wales Hospital, Sydney, Australia.
⁵¹ Centre for Clinical Genetics, Sydney Children's Hospital, Sydney, Australia.
⁵² Division of Paediatrics and Telethon Kids Institute, Faculty of Health and Medical Sciences, Perth, Australia.
⁵³ PreventionGenetics, Marshfield, WI, USA.
⁵⁴ Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, Canada.
⁵⁵ Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada.
⁵⁶ Children's Hospital of Eastern Ontario, Ottawa, Canada.
⁵⁷ KAT6A Foundation.
⁵⁸ Departments of Genetic Medicine and Pediatrics, Johns Hopkins University, Baltimore, MD 21205, USA.
⁵⁹ Department of Pathology, Boston Children's Hospital, Boston, MA, USA.
⁶⁰ Newborn Screening Ontario, Children's Hospital of Eastern Ontario, Ottawa, Canada.
⁶¹ Department of Neuroscience, University of Sheffield, Sheffield Children's Hospital NHS Foundation Trust, Sheffield, UK.
⁶² Laboratory of Regulatory and Functional Genomics, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo (Foggia), Italy.
⁶³ Medical Genetics Unit, University of Perugia Hospital SM della Misericordia, Perugia, Italy.
⁶⁴ Department of Pediatrics and Child Health, Rady Faculty of Health Sciences, University of Manitoba and Program in Genetics and Metabolism, Shared Health MB, Winnipeg, MB, Canada.

PMID: 35047860
PMCID: PMC8756545
DOI: 10.1016/j.xhgg.2021.100075

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

Michael A Levy et al. HGG Adv. 2021.

. 2021 Dec 3;3(1):100075.

doi: 10.1016/j.xhgg.2021.100075. eCollection 2022 Jan 13.

Authors

Affiliations

¹ Verspeeten Clinical Genome Centre; London Health Sciences Centre, London, ON N6A 5W9, Canada.
² Autoinflammatory and Rare Diseases Unit, Medical Genetic Department for Rare Diseases and Personalized Medicine, CHU Montpellier, Montpellier, France.
³ Medical Genetics Unit, "A. Meyer" Children's Hospital of Florence, Florence, Italy.
⁴ Department of Pediatrics, University of Turin, Turin, Italy.
⁵ Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, IdiPAZ, CIBERER, ISCIII, Madrid, Spain.
⁶ Department of Translational Medicine, Federico II University of Naples, Naples, Italy.
⁷ Telethon Institute of Genetics and Medicine, Pozzuoli, Italy.
⁸ Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy.
⁹ Cardiff University School of Medicine, Cardiff, UK.
¹⁰ Greenwood Genetic Center, Greenwood, SC 29646, USA.
¹¹ Department of Clinical Genetics, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
¹² INSERM-Université de Bourgogne UMR1231 GAD « Génétique Des Anomalies du Développement », FHU-TRANSLAD, UFR Des Sciences de Santé, Dijon, France.
¹³ Centre de Référence Maladies Rares «Anomalies du Développement et Syndromes Malformatifs », Centre de Génétique, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France.
¹⁴ Genetic medical center, CHU Clermont Ferrand, France.
¹⁵ Montpellier University, Reference Center for Rare Disease, Medical Genetic Department for Rare Disease and Personalize Medicine, Inserm Unit 1183, CHU Montpellier, Montpellier, France.
¹⁶ Department of Pathology and Laboratory Medicine, Western University, London, ON N6A 3K7, Canada.
¹⁷ Division of Medical Genetics, Department of Health Sciences, Università degli Studi di Milano, Milan, Italy.
¹⁸ Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.
¹⁹ Brain and Mitochondrial Research Group, Murdoch Children's Research Institute and Department of Paediatrics, University of Melbourne, Melbourne, Australia.
²⁰ BC Children's and Women's Hospital and Department of Medical Genetics, Faculty of Medicine, University of British Columbia, Vancouver, Canada.
²¹ Clinical Pediatric Genetics Unit, Pediatrics Clinics, MBBM Foundation, Hospital San Gerardo, Monza, Italy.
²² Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
²³ Murdoch Children's Research Institute and Department of Paediatrics, University of Melbourne, Melbourne, Australia.
²⁴ Department of Genetics, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
²⁵ Department of Clinical Genetics, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.
²⁶ Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
²⁷ Medical Genetics Unit Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy.
²⁸ Amsterdam UMC, University of Amsterdam, Department of Human Genetics, Amsterdam Reproduction and Development Research Institute, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands.
²⁹ Undiagnosed Diseases Program, Genetic Services of Western Australia, King Edward Memorial Hospital, Perth, Australia.
³⁰ Brain and Mitochondrial Research Group, Murdoch Children's Research Institute, Melbourne, Australia.
³¹ Department of Paediatrics, University of Melbourne, Melbourne, Australia.
³² CHU Sainte-Justine Research Center, University of Montreal, Montreal, QC H3T 1C5, Canada.
³³ Department of Clinical Genetics, LUMC, Leiden, the Netherlands.
³⁴ Department of Pediatrics, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.
³⁵ Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, Italy.
³⁶ Unité Fonctionnelle d'Innovation Diagnostique des Maladies Rares, FHU-TRANSLAD, France Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement (TRANSLAD), Centre Hospitalier Universitaire Dijon Bourgogne, CHU Dijon Bourgogne, Dijon, France.
³⁷ Centre de Référence Déficiences Intellectuelles de Causes Rares, Hôpital D'Enfants, CHU Dijon Bourgogne, 21000 Dijon, France.
³⁸ Division of Medical Genetics and Metabolism, Children's Hospital of The King's Daughters, Norfolk, VA, USA.
³⁹ Department of Pediatrics, Eastern Virginia Medical School, Norfolk, VA, USA.
⁴⁰ Department of Clinical Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam Reproduction and Development Research Institute, Meibergdreef 9, Amsterdam, the Netherlands.
⁴¹ Department of Diagnostic Genomics, PathWest Laboratory Medicine, QEII Medical Centre, Perth, Australia.
⁴² Department of Pediatrics, Division of Medical Genetics, Western University, London, ON N6A 3K7, Canada.
⁴³ Medical Genetics Program of Southwestern Ontario, London Health Sciences Centre and Children's Health Research Institute, London, ON N6A5W9, Canada.
⁴⁴ Division of Evolution, Infection & Genomics, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.
⁴⁵ Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester, UK.
⁴⁶ School of Medicine, Robinson Research Institute, University of Adelaide, Adelaide, SA 5005, Australia.
⁴⁷ South Australian Health and Medical Research Institute, Adelaide, SA 5005, Australia.
⁴⁸ Neuroscience Research Australia (NeuRA), Sydney, Australia.
⁴⁹ Prince of Wales Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia.
⁵⁰ New South Wales Health Pathology Randwick Genomics, Prince of Wales Hospital, Sydney, Australia.
⁵¹ Centre for Clinical Genetics, Sydney Children's Hospital, Sydney, Australia.
⁵² Division of Paediatrics and Telethon Kids Institute, Faculty of Health and Medical Sciences, Perth, Australia.
⁵³ PreventionGenetics, Marshfield, WI, USA.
⁵⁴ Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, Canada.
⁵⁵ Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada.
⁵⁶ Children's Hospital of Eastern Ontario, Ottawa, Canada.
⁵⁷ KAT6A Foundation.
⁵⁸ Departments of Genetic Medicine and Pediatrics, Johns Hopkins University, Baltimore, MD 21205, USA.
⁵⁹ Department of Pathology, Boston Children's Hospital, Boston, MA, USA.
⁶⁰ Newborn Screening Ontario, Children's Hospital of Eastern Ontario, Ottawa, Canada.
⁶¹ Department of Neuroscience, University of Sheffield, Sheffield Children's Hospital NHS Foundation Trust, Sheffield, UK.
⁶² Laboratory of Regulatory and Functional Genomics, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo (Foggia), Italy.
⁶³ Medical Genetics Unit, University of Perugia Hospital SM della Misericordia, Perugia, Italy.
⁶⁴ Department of Pediatrics and Child Health, Rady Faculty of Health Sciences, University of Manitoba and Program in Genetics and Metabolism, Shared Health MB, Winnipeg, MB, Canada.

PMID: 35047860
PMCID: PMC8756545
DOI: 10.1016/j.xhgg.2021.100075

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.

Keywords: Clinical diagnostics; DNA methylation; Epigenetics; Episignatures; Neurodevelopmental disorders.

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing interests.

Figures

**Figure 1**
Methylation differences of probes used for episignatures Methylation differences between cases and controls for the microarray probes that make up each episignature for the newly identified and previously reported episignatures. Red lines indicate mean methylation for each episignature. Asterisk indicates new episignatures and/or those that have not previously been included in the multiclass classifier.

**Figure 2**
Gene region- or variant-specific sub-signatures (A) The last exon of *ARID1A* and *ARID1B* shown with the location of seven variants in the c.6200 region colored by whether they match the c.6200 episignature or not. (B and C) MDS (B) and hierarchical clustering (C) plots of the seven samples showing that the four central samples have a matching episignature, while the outer three cluster with controls. For hierarchical clustering plots, each row represents one microarray probe, and each column represents one sample. (D) Gene diagram of *SMARCA4* (NM_001128849.1) showing the location of the three c.2656A>G variants in exon 19 (red arrowhead). The five horizontal gray bars indicate the locations of protein domains: QLQ, HSA, helicase ATP-binding, helicase C-terminal, and bromodomain. (E and F) MDS (E) and hierarchical clustering (F) showing that the three CSS4 samples with the above variant cluster separately from controls and from other BAFopathy samples. (G) Protein diagram of CREBBP/EP300 showing the location of protein domains (gray boxes) and intrinsically disordered (ID) domains (numbered). (H and I) MDS (H) and hierarchical clustering (I) showing the MKHK_ID4 samples clustering separately from controls and from other MKHK samples.

**Figure 3**
Identifying episignatures to distinguish between closely related syndromes Hierarchical clustering and MDS plots are shown for each episignature. For hierarchical clustering plots, each row represents one microarray probe, and each column represents one sample. (A and B) ARTHS probe selection using only ARTHS and control samples. (C and D) ARTHS probe selection when GTPTS and SBBYSS samples are included as controls. (E and F) The previously reported RSTS (RSTS1/RSTS2 combined) episignature. (G and H) The RSTS1 episignature generated by including RSTS2 samples as control. (I and J) the RSTS2 episignature generated by including RSTS1 samples as control.

**Figure 4**
Support vector machine-based classifiers for concurrent episignature detection (A) Each of the 19 new episignatures were evaluated using 4-fold cross-validation. For each fold, a different 25% of samples were used for testing (blue), and the remaining 75% of samples were used for training (gray). The case samples for each episignature are shown in red. The eight testing samples referenced in the text are labeled. (B) The final classifiers for all 57 episignatures. The case samples for each episignature are shown in red, and all other samples are in black. Non-case RSTS samples (for example, RSTS1 samples in the RSTS2 column) are in blue. Arrowheads indicate the two GADEVS samples with high BAFopathy scores.

**Figure 5**
Screening unresolved cases Samples with MVP scores greater than 0.5 were further assessed by unsupervised clustering plots. Hierarchical clustering and MDS plots are shown for each case. For hierarchical clustering plots, each row represents one microarray probe, and each column represents one sample. (A) Sample Unresolved_1, a previously unresolved case that matches the MKHK_ID4 episignature. (B) Sample Unresolved_2, a previously unresolved case that matches the LLS episignature. (C) Sample Unresolved_3, a previously unresolved case that matches the VCFS episignature.

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References

1. Nguengang Wakap S., Lambert D.M., Olry A., Rodwell C., Gueydan C., Lanneau V., Murphy D., Le Cam Y., Rath A. Estimating cumulative point prevalence of rare diseases: analysis of the Orphanet database. Eur. J. Hum. Genet. 2020;28:165–173. - PMC - PubMed
1. Baird P.A., Anderson T.W., Newcombe H.B., Lowry R.B. Genetic disorders in children and young adults: a population study. Am. J. Hum. Genet. 1988;42:677–693. - PMC - PubMed
1. Kvarnung M., Nordgren A. Intellectual disability & rare disorders: A diagnostic challenge. Adv. Exp. Med. Biol. 2017;1031:39–54. - PubMed
1. Schwarze K., Buchanan J., Taylor J.C., Wordsworth S. Are whole-exome and whole-genome sequencing approaches cost-effective? A systematic review of the literature. Gen. Med. 2018;20:1122–1130. - PubMed
1. Eisenberger T., Neuhaus C., Khan A.O., Decker C., Preising M.N., Friedburg C., Bieg A., Gliem M., Charbel Issa P., Holz F.G., et al. Increasing the yield in targeted next-generation sequencing by implicating CNV analysis, non-coding exons and the overall variant load: the example of retinal dystrophies. PLoS One. 2013;8:e78496. - PMC - PubMed

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[1] Nguengang Wakap S., Lambert D.M., Olry A., Rodwell C., Gueydan C., Lanneau V., Murphy D., Le Cam Y., Rath A. Estimating cumulative point prevalence of rare diseases: analysis of the Orphanet database. Eur. J. Hum. Genet. 2020;28:165–173. - PMC - PubMed

[2] Nguengang Wakap S., Lambert D.M., Olry A., Rodwell C., Gueydan C., Lanneau V., Murphy D., Le Cam Y., Rath A. Estimating cumulative point prevalence of rare diseases: analysis of the Orphanet database. Eur. J. Hum. Genet. 2020;28:165–173. - PMC - PubMed

[3] Baird P.A., Anderson T.W., Newcombe H.B., Lowry R.B. Genetic disorders in children and young adults: a population study. Am. J. Hum. Genet. 1988;42:677–693. - PMC - PubMed

[4] Baird P.A., Anderson T.W., Newcombe H.B., Lowry R.B. Genetic disorders in children and young adults: a population study. Am. J. Hum. Genet. 1988;42:677–693. - PMC - PubMed

[5] Kvarnung M., Nordgren A. Intellectual disability & rare disorders: A diagnostic challenge. Adv. Exp. Med. Biol. 2017;1031:39–54. - PubMed

[6] Kvarnung M., Nordgren A. Intellectual disability & rare disorders: A diagnostic challenge. Adv. Exp. Med. Biol. 2017;1031:39–54. - PubMed

[7] Schwarze K., Buchanan J., Taylor J.C., Wordsworth S. Are whole-exome and whole-genome sequencing approaches cost-effective? A systematic review of the literature. Gen. Med. 2018;20:1122–1130. - PubMed

[8] Schwarze K., Buchanan J., Taylor J.C., Wordsworth S. Are whole-exome and whole-genome sequencing approaches cost-effective? A systematic review of the literature. Gen. Med. 2018;20:1122–1130. - PubMed

[9] Eisenberger T., Neuhaus C., Khan A.O., Decker C., Preising M.N., Friedburg C., Bieg A., Gliem M., Charbel Issa P., Holz F.G., et al. Increasing the yield in targeted next-generation sequencing by implicating CNV analysis, non-coding exons and the overall variant load: the example of retinal dystrophies. PLoS One. 2013;8:e78496. - PMC - PubMed

[10] Eisenberger T., Neuhaus C., Khan A.O., Decker C., Preising M.N., Friedburg C., Bieg A., Gliem M., Charbel Issa P., Holz F.G., et al. Increasing the yield in targeted next-generation sequencing by implicating CNV analysis, non-coding exons and the overall variant load: the example of retinal dystrophies. PLoS One. 2013;8:e78496. - PMC - PubMed

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

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

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