Advanced search
Publication Cover
Epigenomics Volume 15, 2023 - Issue 6
Submit an article Journal homepage
217
Views
0
CrossRef citations to date
0
Altmetric
Research Article

Dna Methylation Episignatures are Sensitive and Specific Biomarkers for Detection of Patients with Kat6A/Kat6B Variants

Niels Vos1 Department of Human Genetics, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105, AZ, Amsterdam, The NetherlandsView further author information
,
Jack Reilly2 Department of Pathology & Laboratory Medicine, Western University, London, ON, N6A 5C1, CanadaORCID Iconhttps://orcid.org/0000-0001-7150-9566View further author information
ORCID Icon,
Mariet W Elting1 Department of Human Genetics, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105, AZ, Amsterdam, The NetherlandsView further author information
,
Philippe M Campeau3 Department of Pediatrics, Sainte-Justine UHC & University of Montreal, Montreal, QC, H3T 1C5, CanadaView further author information
,
David Coman4 Department of Metabolic Medicine, Queensland Children’s Hospital, South Brisbane, QLD4101, Australia;5 School of Medicine, University of Queensland, Brisbane, QLD4072, AustraliaView further author information
,
Zornitza Stark6 Victorian Clinical Genetics Services, Murdoch Children’s Research Institute, Parkville, Victoria, 3052, Australia;7 Department of Paediatrics, University of Melbourne, Grattan Street, Parkville, Victoria, 3010, AustraliaView further author information
,
Tiong Yang Tan6 Victorian Clinical Genetics Services, Murdoch Children’s Research Institute, Parkville, Victoria, 3052, Australia;7 Department of Paediatrics, University of Melbourne, Grattan Street, Parkville, Victoria, 3010, AustraliaView further author information
,
David J Amor8 Murdoch Children’s Research Institute, Royal Children’s Hospital, Flemington Rd, ParkvilleVIC, 3052, Australia;9 University of Melbourne Department of Pediatrics, Parkville, Victoria, 3010, AustraliaView further author information
,
Simran Kaur8 Murdoch Children’s Research Institute, Royal Children’s Hospital, Flemington Rd, ParkvilleVIC, 3052, Australia;9 University of Melbourne Department of Pediatrics, Parkville, Victoria, 3010, AustraliaView further author information
,
Miya StJohn8 Murdoch Children’s Research Institute, Royal Children’s Hospital, Flemington Rd, ParkvilleVIC, 3052, Australia;9 University of Melbourne Department of Pediatrics, Parkville, Victoria, 3010, AustraliaView further author information
,
Angela T Morgan8 Murdoch Children’s Research Institute, Royal Children’s Hospital, Flemington Rd, ParkvilleVIC, 3052, Australia;9 University of Melbourne Department of Pediatrics, Parkville, Victoria, 3010, AustraliaView further author information
,
Benjamin A Kamien10 Genetics Services of Western Australia, Perth, 6008, Western AustraliaView further author information
,
Chirag Patel11 Genetic Health Queensland, Royal Brisbane & Women’s Hospital, Herston, QLD4006, AustraliaView further author information
,
Matthew L Tedder12 Greenwood Genetic Center, Greenwood, SC29646, United StatesView further author information
,
Giuseppe Merla13 Laboratory of Regulatory and Functional Genomics, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013, San Giovanni Rotondo (Foggia), Italy;14 Department of Molecular Medicine and Medical Biotechnology, University of Naples Federica II, 5 - 80131, Naples, ItalyView further author information
,
Paolo Prontera15 Medical Genetics Unit, University of Perugia Hospital SM della Misericordia, Piazza dell’Università, 1, 06123, Perugia PG, ItalyView further author information
,
Marco Castori16 Division of Medical Genetics, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013, San Giovanni Rotondo (Foggia), ItalyView further author information
,
Kai Muru17 Department of Clinical Genetics, United Laboratories, Tartu University Hospital, Riia 23b, 51010, Tartu, EstoniaView further author information
,
Felicity Collins18 Discipline of Child and Adolescent Health and Genomic Medicine, Sydney Medical School, Sydney University, Sydney, CamperdownNSW, 2050, Australia;19 Department of Clinical Genetics, Western Sydney Genetics Program, Children’s Hospital at Westmead, RandwickNSW, 2031, AustraliaView further author information
,
John Christodoulou19 Department of Clinical Genetics, Western Sydney Genetics Program, Children’s Hospital at Westmead, RandwickNSW, 2031, AustraliaView further author information
,
Janine Smith20 Sydney Children’s Hospitals Network-Westmead, RandwickNSW, 2031, Australia;21 University of Sydney, CamperdownNSW, 2006, Australia.View further author information
,
Bruria Ben Zeev22 Sackler School of Medicine Tel Aviv University, Tel Aviv, 6997801, IsraelView further author information
,
Alessandra Murgia23 Laboratory of Molecular Genetics of Neurodevelopment, Department of Women’s and Children’s Health, University of Padua, Via Giustiniani 3, 35128, Padua, ItalyView further author information
,
Emanuela Leonardi23 Laboratory of Molecular Genetics of Neurodevelopment, Department of Women’s and Children’s Health, University of Padua, Via Giustiniani 3, 35128, Padua, ItalyView further author information
,
Natacha Esber24 KAT6A Foundation, 3 Louise Dr., West Nyack, NY10994, USAView further author information
,
Antonio Martinez-Monseny25 Genetics and Molecular Medicine Department, Rare Disease Pediatric Unit, Hospital Sant Joan de Déu, 2, 08950Esplugues de Llobregat, Barcelona, SpainView further author information
,
Didac Casas-Alba25 Genetics and Molecular Medicine Department, Rare Disease Pediatric Unit, Hospital Sant Joan de Déu, 2, 08950Esplugues de Llobregat, Barcelona, SpainView further author information
,
Matthew Wallis26 Tasmanian Clinical Genetics Service, Tasmanian Health Service, Royal Hobart Hospital, Hobart, TAS7001, AustraliaView further author information
,
Marcel Mannens1 Department of Human Genetics, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105, AZ, Amsterdam, The NetherlandsORCID Iconhttps://orcid.org/0000-0001-7137-119XView further author information
ORCID Icon,
Michael A Levy27 Molecular Genetics Laboratory, Molecular Diagnostics Division, London Health Sciences Centre, London, ON, N6A 5W9, CanadaView further author information
,
Raissa Relator27 Molecular Genetics Laboratory, Molecular Diagnostics Division, London Health Sciences Centre, London, ON, N6A 5W9, CanadaView further author information
,
Marielle Alders1 Department of Human Genetics, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105, AZ, Amsterdam, The NetherlandsView further author information
&
Bekim Sadikovic27 Molecular Genetics Laboratory, Molecular Diagnostics Division, London Health Sciences Centre, London, ON, N6A 5W9, CanadaCorrespondence[email protected]
ORCID Iconhttps://orcid.org/0000-0001-6363-0016View further author information
ORCID Icon show all
Pages 351-367 | Received 01 Mar 2023, Accepted 10 May 2023, Published online: 30 May 2023

References

  • Wakap SN , LambertDM , OlryAet al. Estimating cumulative point prevalence of rare diseases: analysis of the Orphanet database. Eur. J. Hum. Genet.28, 165–173 (2020).
  • Zablotsky B , BlackLI , MaennerMJet al. Prevalence and trends of developmental disabilities among children in the United States: 2009–2017. Pediatrics144(4), e20190811 (2019).
  • Aref-Eshghi E , RodenhiserDI , SchenkelLCet al. Genomic DNA methylation signatures enable concurrent diagnosis and clinical genetic variant classification in neurodevelopmental syndromes. Am. J. Hum. Genet.102(1), 156–174 (2018).
  • Richards S , AzizN , BaleSet al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet. Med.17(5), 405–424 (2015).
  • Sadikovic B , Aref-EshghiE , LevyMA , RodenhiserD. DNA methylation signatures in Mendelian developmental disorders as a diagnostic bridge between genotype and phenotype. Epigenomics11, 563–575 (2019).
  • Skvortsova K , IovinoN , BogdanovićO. Functions and mechanisms of epigenetic inheritance in animals. Nat. Rev. Mol. Cell Biol.19(12), 774–790 (2018).
  • Costa FF . Non-coding RNAs, epigenetics and complexity. Gene410(1), 9–17 (2008).
  • Bjornsson HT . The Mendelian disorders of the epigenetic machinery. Genome Res.25(10), 1473–1481 (2015).
  • Barros-Silva D , MarquesCJ , HenriqueR , JerónimoC. Profiling DNA methylation based on next-generation sequencing approaches: new insights and clinical applications. Genes9, 429 (2018).
  • Choufani S , CytrynbaumC , ChungBHYet al. NSD1 mutations generate a genome-wide DNA methylation signature. Nat. Commun.6, 10207(2015).
  • Schenkel LC , KernohanKD , McBrideAet al. Identification of epigenetic signature associated with alpha thalassemia/mental retardation X-linked syndrome. Epigenetics Chromatin10, 1–11 (2017).
  • Aref-Eshghi E , BendEG , ColaiacovoSet al. Diagnostic utility of genome-wide DNA methylation testing in genetically unsolved individuals with suspected hereditary conditions. Am. J. Hum. Genet.104, 685–700 (2019).
  • Butcher DT , CytrynbaumC , TurinskyALet al. CHARGE and Kabuki syndromes: gene-specific DNA methylation signatures identify epigenetic mechanisms linking these clinically overlapping conditions. Am. J. Hum. Genet.100, 773–788 (2017).
  • Hood RL , SchenkelLC , NikkelSMet al. The defining DNA methylation signature of Floating-Harbor syndrome. Sci. Rep.6, 38803 (2016).
  • Schenkel LC , Aref-EshghiE , SkinnerCet al. Peripheral blood epi-signature of Claes–Jensen syndrome enables sensitive and specific identification of patients and healthy carriers with pathogenic mutations in KDM5C. Clin. Epigenetics10, 1–11 (2018).
  • Schenkel LC , SchwartzC , SkinnerCet al. Clinical validation of fragile X syndrome screening by DNA methylation array. J. Mol. Diagn.18, 834–841 (2016).
  • Li Y , ChenJA , SearsRLet al. An epigenetic signature in peripheral blood associated with the haplotype on 17q21.31, a risk factor for neurodegenerative tauopathy. PLoS Genet.2014, 10 (2014).
  • Aref-Eshghi E , SchenkelLC , LinHet al. Clinical validation of a genome-wide DNA methylation assay for molecular diagnosis of imprinting disorders. J. Mol. Diagn.19, 848–856 (2017).
  • Guastafierro T , BacaliniMG , MarcocciaAet al. Genome-wide DNA methylation analysis in blood cells from patients with Werner syndrome. Clin. Epigenetics9, 92 (2017).
  • Aref-Eshghi E , KerkhofJ , PedroVPet al. Evaluation of DNA methylation episignatures for diagnosis and phenotype correlations in 42 Mendelian neurodevelopmental disorders. Am. J. Hum. Genet.106, 356–370 (2020).
  • Bend EG , Aref-EshghiE , EvermanDBet al. Gene domain-specific DNA methylation episignatures highlight distinct molecular entities of ADNP syndrome. Clin. Epigenetics11(1), 64 (2019).
  • Sadikovic B , LevyMA , KerkhofJet al. Clinical epigenomics: genome-wide DNA methylation analysis for the diagnosis of Mendelian disorders. Genet. Med.23, 1065–1074 (2021).
  • Lee KK , WorkmanJL. Histone acetyltransferase complexes: one size doesn’t fit all. Nat. Rev. Mol. Cell Biol.8(4), 284–295 (2007).
  • Akatsuki Kimura , KazukoMatsubara , MasamiHorikoshi. A decade of histone acetylation: marking eukaryotic chromosomes with specific codes. J. Biochem.138(6), 647–662 (2005).
  • Klein BJ , LalondeME , CôtéJ , YangXJ , KutateladzeTG. Crosstalk between epigenetic readers regulates the MOZ/MORF HAT complexes. Epigenetics9(2), 186–193 (2014).
  • Arboleda VA , LeeH , DorraniNet al. De novo nonsense mutations in KAT6A, a lysine acetyl-transferase gene, cause a syndrome including microcephaly and global developmental delay. Am. J. Hum. Genet.96(3), 498–506 (2015).
  • Tham E , LindstrandA , SantaniAet al. Dominant mutations in KAT6A cause intellectual disability with recognizable syndromic features. Am. J. Hum. Genet.96(3), 507–513 (2015).
  • Kennedy J , GoudieD , BlairEet al. KAT6A syndrome: genotype–phenotype correlation in 76 patients with pathogenic KAT6A variants. Genet. Med.21(4), 850–860 (2019).
  • Su Y , LiuJ , YuB , BaR , ZhaoC. BRPF1 haploinsufficiency impairs dendritic arborization and spine formation, leading to cognitive deficits. Front Cell Neurosci.13, 249 (2019).
  • Yan K , RousseauJ , LittlejohnROet al. Mutations in the chromatin regulator gene BRPF1 cause syndromic intellectual disability and deficient histone acetylation. Am. J. Hum. Genet.100(1), 91–104 (2017).
  • Clayton-Smith J , O’SullivanJ , DalySet al. Whole-exome-sequencing identifies mutations in histone acetyltransferase gene KAT6B in individuals with the Say–Barber–Biesecker variant of Ohdo syndrome. Am. J. Hum. Genet.89(5), 675–681 (2011).
  • Kraft M , CirsteaIC , VossAKet al. Disruption of the histone acetyltransferase MYST4 leads to a Noonan syndrome-like phenotype and hyperactivated MAPK signaling in humans and mice. J. Clin. Invest.121(9), 3479–3491 (2011).
  • Wiesel-Motiuk N , AssarafYG. The key roles of the lysine acetyltransferases KAT6A and KAT6B in physiology and pathology. Drug Resist. Updat.53, 100729 (2020).
  • Aref-Eshghi E , BendEG , HoodRLet al. BAFopathies’ DNA methylation epi-signatures demonstrate diagnostic utility and functional continuum of Coffin–Siris and Nicolaides–Baraitser syndromes. Nat. Commun.9(1), 4885 (2018).
  • Aryee MJ , JaffeAE , Corrada-BravoHet al. Minfi: a flexible and comprehensive Bioconductor package for the analysis of Infinium DNA methylation microarrays. Bioinformatics30(10), 1363–1369 (2014).
  • Ritchie ME , PhipsonB , WuDet al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res.43(7), e47 (2015).
  • Houseman EA , AccomandoWP , KoestlerDCet al. DNA methylation arrays as surrogate measures of cell mixture distribution. BMC Bioinformatics13(1), 86 (2012).
  • Reinius LE , AcevedoN , JoerinkMet al. Differential DNA methylation in purified human blood cells: implications for cell lineage and studies on disease susceptibility. PLOS ONE7(7), e41361 (2012).
  • Advances in Large-Margin Classifiers . The MIT Press Published: 2000. SmolaAJ, BartlettP, SchölkopfB, SchuurmansD. doi:10.7551/mitpress/1113.001.0001 (2000).
  • Peters TJ , BuckleyMJ , StathamAL , PidsleyR , SamarasK , V LordRet al. De novo identification of differentially methylated regions in the human genome. Epigenetics Chromatin8(1), 6 (2015).
  • Levy MA , McConkeyH , KerkhofJet al. Novel diagnostic DNA methylation episignatures expand and refine the epigenetic landscapes of Mendelian disorders. HGG Adv.3(1), 100075 (2021).
  • Haghshenas S , LevyMA , KerkhofJet al. Detection of a DNA methylation signature for the intellectual developmental disorder, X-linked, syndromic, Armfield type. Int. J. Mol. Sci.22(3), 1111 (2021).
  • Aref-Eshghi E , BourqueDK , KerkhofJet al. Genome-wide DNA methylation and RNA analyses enable reclassification of two variants of uncertain significance in a patient with clinical Kabuki syndrome. Hum. Mutat.40(10), 1684–1689 (2019).
  • Aref-Eshghi E , SchenkelLC , LinHet al. The defining DNA methylation signature of Kabuki syndrome enables functional assessment of genetic variants of unknown clinical significance. Epigenetics12(11), 923–933 (2017).
  • Cappuccio , Gerardaet al. De novo SMARCA2 variants clustered outside the helicase domain cause a new recognizable syndrome with intellectual disability and blepharophimosis distinct from Nicolaides–Baraitser syndrome. Genet. Med.22(11), 1838–1850 (2020).
  • Rots , Dmitrijset al. Truncating SRCAP variants outside the Floating-Harbor syndrome locus cause a distinct neurodevelopmental disorder with a specific DNA methylation signature. Am. J. Hum. Genet.108(6), 1053–1068 (2021).
  • Cuvertino , Saraet al. A restricted spectrum of missense KMT2D variants cause a multiple malformations disorder distinct from Kabuki syndrome. Genet. Med.22(5), 867–877 (2020).
  • Blackburn , PatrickRet al. Variable expressivity of syndromic BMP4-related eye, brain, and digital anomalies: a review of the literature and description of three new cases. Eur. J. Hum. Genet.27(9), 1379–1388 (2019).
  • Reamon-Buettner SM , BorlakJ. HEY2 mutations in malformed hearts. Hum. Mutat.27(1), 118 (2006).
  • Voss AK , CollinC , DixonMP , ThomasT. MOZ and retinoic acid coordinately regulate H3K9 acetylation, Hox gene expression, and segment identity. Dev. Cell17(5), 674–686 (2009).
  • Shane C Quinonez , InnisJW. Human HOX gene disorders. Mol. Genet. Metab.111(1), 4–15 (2014).
  • Klengel T , PapeJ , BinderEB , MehtaD. The role of DNA methylation in stress-related psychiatric disorders. Neuropharmacology80, 115–132 (2014).
  • Lussier AA , BodnarTS , MingayMet al. Prenatal alcohol exposure: profiling developmental DNA methylation patterns in central and peripheral tissues. Front. Genet.9, 6102018).
  • Levy MA , RelatorR , McConkeyHet al. Functional correlation of genome-wide DNA methylation profiles in genetic neurodevelopmental disorders. Hum. Mutat.43(11), 1609–1628 (2022).

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Order Reprints Request Corporate Permissions

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

Request Academic Permissions

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.

Related research

People also read lists articles that other readers of this article have read.

Recommended articles lists articles that we recommend and is powered by our AI driven recommendation engine.

Cited by lists all citing articles based on Crossref citations.
Articles with the Crossref icon will open in a new tab.