Advertisement

Human Genetics

, Volume 136, Issue 3, pp 307–320 | Cite as

Mutations in chromatin regulators functionally link Cornelia de Lange syndrome and clinically overlapping phenotypes

  • Ilaria Parenti
  • María E. Teresa-Rodrigo
  • Jelena Pozojevic
  • Sara Ruiz Gil
  • Ingrid Bader
  • Diana Braunholz
  • Nuria C. Bramswig
  • Cristina Gervasini
  • Lidia Larizza
  • Lutz Pfeiffer
  • Ferda Ozkinay
  • Feliciano Ramos
  • Benedikt Reiz
  • Olaf Rittinger
  • Tim M. Strom
  • Erwan Watrin
  • Kerstin Wendt
  • Dagmar Wieczorek
  • Bernd Wollnik
  • Carolina Baquero-Montoya
  • Juan Pié
  • Matthew A. Deardorff
  • Gabriele Gillessen-Kaesbach
  • Frank J. KaiserEmail author
Original Investigation

Abstract

The coordinated tissue-specific regulation of gene expression is essential for the proper development of all organisms. Mutations in multiple transcriptional regulators cause a group of neurodevelopmental disorders termed “transcriptomopathies” that share core phenotypical features including growth retardation, developmental delay, intellectual disability and facial dysmorphism. Cornelia de Lange syndrome (CdLS) belongs to this class of disorders and is caused by mutations in different subunits or regulators of the cohesin complex. Herein, we report on the clinical and molecular characterization of seven patients with features overlapping with CdLS who were found to carry mutations in chromatin regulators previously associated to other neurodevelopmental disorders that are frequently considered in the differential diagnosis of CdLS. The identified mutations affect the methyltransferase-encoding genes KMT2A and SETD5 and different subunits of the SWI/SNF chromatin-remodeling complex. Complementary to this, a patient with Coffin–Siris syndrome was found to carry a missense substitution in NIPBL. Our findings indicate that mutations in a variety of chromatin-associated factors result in overlapping clinical phenotypes, underscoring the genetic heterogeneity that should be considered when assessing the clinical and molecular diagnosis of neurodevelopmental syndromes. It is clear that emerging molecular mechanisms of chromatin dysregulation are central to understanding the pathogenesis of these clinically overlapping genetic disorders.

Keywords

Intellectual Disability Sister Chromatid Cohesion Cohesin Complex Missense Substitution Depressed Nasal Bridge 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgements

This work was funded by the German Federal Ministry of Education and Research (BMBF) (CHROMATIN-Net: to F.K., G.G.-K., N.C.B. and D.W.; E-Rare-2 TARGET-CdLS: to F.J.K, K.W. and E.W.), by the Spain’sMinistry of Health-ISCIII (Ref. FIS PI12-01318) (to F. J.R. and J.P.) and by the Medical Faculty of the University of Lübeck (J09-2017 to I.P.).

Compliance with ethical standards

Conflict of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study. Additional informed consent was obtained from all individual participants for whom identifying information is included in this article.

Supplementary material

439_2017_1758_MOESM1_ESM.pdf (477 kb)
Supplementary material 1 (PDF 477 kb)

References

  1. Ansari M, Poke G, Ferry Q, Williamson K, Aldridge R, Meynert AM, Bengani H, Chan CY, Kayserili H, Avci S, Hennekam RC, Lampe AK, Redeker E, Homfray T, Ross A, FalkenbergSmeland M, Mansour S, Parker MJ, Cook JA, Splitt M, Fisher RB, Fryer A, Magee AC, Wilkie A, Barnicoat A, Brady AF, Cooper NS, Mercer C, Deshpande C, Bennett CP, Pilz DT, Ruddy D, Cilliers D, Johnson DS, Josifova D, Rosser E, Thompson EM, Wakeling E, Kinning E, Stewart F, Flinter F, Girisha KM, Cox H, Firth HV, Kingston H, Wee JS, Hurst JA, Clayton-Smith J, Tolmie J, Vogt J, Tatton-Brown K, Chandler K, Prescott K, Wilson L, Behnam M, McEntagart M, Davidson R, Lynch SA, Sisodiya S, Mehta SG, McKee SA, Mohammed S, Holden S, Park SM, Holder SE, Harrison V, McConnell V, Lam WK, Green AJ, Donnai D, Bitner-Glindzicz M, Donnelly DE, Nellåker C, Taylor MS, FitzPatrick DR (2014) Genetic heterogeneity in Cornelia de Lange syndrome (CdLS) and CdLS-like phenotypes with observed and predicted levels of mosaicism. J Med Genet 51(10):659–668. doi: 10.1136/jmedgenet-2014-102573 CrossRefPubMedPubMedCentralGoogle Scholar
  2. Bramswig NC, Lüdecke HJ, Alanay Y, Albrecht B, Barthelmie A, Boduroglu K, Braunholz D, Caliebe A, Chrzanowska KH, Czeschik JC, Endele S, Graf E, Guillén-Navarro E, Kiper PÖ, López-González V, Parenti I, Pozojevic J, Utine GE, Wieland T, Kaiser FJ, Wollnik B, Strom TM, Wieczorek D (2015) Exome sequencing unravels unexpected differential diagnoses in individuals with the tentative diagnosis of Coffin–Siris and Nicolaides–Baraitser syndromes. Hum Genet 134(6):553–568. doi: 10.1007/s00439-015-1535-8 CrossRefPubMedGoogle Scholar
  3. Braunholz D, Obieglo C, Parenti I, Pozojevic J, Eckhold J, Reiz B, Braenne I, Wendt KS, Watrin E, Vodopiutz J, Rieder H, Gillessen-Kaesbach G, Kaiser FJ (2015) Hidden mutations in Cornelia de Lange syndrome limitations of Sanger sequencing in molecular diagnostics. Hum Mutat 36(1):26–29. doi: 10.1002/humu.22685 CrossRefPubMedGoogle Scholar
  4. Castronovo P, Gervasini C, Cereda A, Masciadri M, Milani D, Russo S, Selicorni A, Larizza L (2009) Premature chromatid separation is not a useful diagnostic marker for Cornelia de Lange syndrome. Chromosome Res 17(6):763–771. doi: 10.1007/s10577-009-9066-6 CrossRefPubMedGoogle Scholar
  5. Deardorff MA, Kaur M, Yaeger D, Rampuria A, Korolev S, Pie J, Gil-Rodríguez C, Arnedo M, Loeys B, Kline AD, Wilson M, Lillquist K, Siu V, Ramos FJ, Musio A, Jackson LS, Dorsett D, Krantz ID (2007) Mutations in cohesin complex members SMC3 and SMC1A cause a mild variant of Cornelia de Lange syndrome with predominant mental retardation. Am J Hum Genet 80(3):485–494. doi: 10.1086/511888 CrossRefPubMedPubMedCentralGoogle Scholar
  6. Deardorff MA, Wilde JJ, Albrecht M, Dickinson E, Tennstedt S, Braunholz D, Mönnich M, Yan Y, Xu W, Gil-Rodríguez MC, Clark D, Hakonarson H, Halbach S, Michelis LD, Rampuria A, Rossier E, Spranger S, Van Maldergem L, Lynch SA, Gillessen-Kaesbach G, Lüdecke HJ, Ramsay RG, McKay MJ, Krantz ID, Xu H, Horsfield JA, Kaiser FJ (2012a) RAD21 mutations cause a human cohesinopathy. Am J Hum Genet 90(6):1014–1027. doi: 10.1016/j.ajhg.2012.04.019 CrossRefPubMedPubMedCentralGoogle Scholar
  7. Deardorff MA, Bando M, Nakato R, Watrin E, Itoh T, Minamino M, Saitoh K, Komata M, Katou Y, Clark D, Cole KE, De Baere E, Decroos C, Di Donato N, Ernst S, Francey LJ, Gyftodimou Y, Hirashima K, Hullings M, Ishikawa Y, Jaulin C, Kaur M, Kiyono T, Lombardi PM, Magnaghi-Jaulin L, Mortier GR, Nozaki N, Petersen MB, Seimiya H, Siu VM, Suzuki Y, Takagaki K, Wilde JJ, Willems PJ, Prigent C, Gillessen-Kaesbach G, Christianson DW, Kaiser FJ, Jackson LG, Hirota T, Krantz ID, Shirahige K (2012b) HDAC8 mutations in Cornelia de Lange syndrome affect the cohesin acetylation cycle. Nature 489(7415):313–317. doi: 10.1038/nature11316 CrossRefPubMedPubMedCentralGoogle Scholar
  8. Eash D, Waggoner D, Chung J, Stevenson D, Martin CL (2005) Calibration of 6q subtelomere deletions to define genotype/phenotype correlations. Clin Genet 67(5):396–403. doi: 10.1111/j.1399-0004.2005.00424.x CrossRefPubMedGoogle Scholar
  9. Gervasini C, Russo S, Cereda A, Parenti I, Masciadri M, Azzollini J, Melis D, Aravena T, Doray B, Ferrarini A, Garavelli L, Selicorni A, Larizza L (2013) Cornelia de Lange individuals with new and recurrent SMC1A mutations enhance delineation of mutation repertoire and phenotypic spectrum. Am J Med Genet A 161A(11):2909–2919. doi: 10.1002/ajmg.a.36252 CrossRefPubMedGoogle Scholar
  10. Gillis LA, McCallum J, Kaur M, DeScipio C, Yaeger D, Mariani A, Kline AD, Li HH, Devoto M, Jackson LG, Krantz ID (2004) NIPBL mutational analysis in 120 individuals with Cornelia de Lange syndrome and evaluation of genotype-phenotype correlations. Am J Hum Genet 75(4):610–623. doi: 10.1086/424698 CrossRefPubMedPubMedCentralGoogle Scholar
  11. Gil-Rodríguez MC, Deardorff MA, Ansari M, Tan CA, Parenti I, Baquero-Montoya C, Ousager LB, Puisac B, Hernández-Marcos M, Teresa-Rodrigo ME, Marcos-Alcalde I, Wesselink JJ, Lusa-Bernal S, Bijlsma EK, Braunholz D, Bueno-Martinez I, Clark D, Cooper NS, Curry CJ, Fisher R, Fryer A, Ganesh J, Gervasini C, Gillessen-Kaesbach G, Guo Y, Hakonarson H, Hopkin RJ, Kaur M, Keating BJ, Kibaek M, Kinning E, Kleefstra T, Kline AD, Kuchinskaya E, Larizza L, Li YR, Liu X, Mariani M, Picker JD, Pié Á, Pozojevic J, Queralt E, Richer J, Roeder E, Sinha A, Scott RH, So J, Wusik KA, Wilson L, Zhang J, Gómez-Puertas P, Casale CH, Ström L, Selicorni A, Ramos FJ, Jackson LG, Krantz ID, Das S, Hennekam RC, Kaiser FJ, FitzPatrick DR, Pié J (2015) De novo heterozygous mutations in SMC3 cause a range of Cornelia de Lange syndrome-overlapping phenotypes. Hum Mutat 36(4):454–462. doi: 10.1002/humu.22761 CrossRefPubMedGoogle Scholar
  12. Grozeva D, Carss K, Spasic-Boskovic O, Parker MJ, Archer H, Firth HV, Park SM, Canham N, Holder SE, Wilson M, Hackett A, Field M, Floyd JA, UK10K Consortium,Hurles M, Raymond FL (2014) De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disability. Am J Hum Genet 94(4):618–24. doi: 10.1016/j.ajhg.2014.03.006
  13. Izumi K (2016) Disorders of transcriptional regulation: an emerging category of multiple malformation syndromes. Mol Syndromol 7(5):262–273. doi: 10.1159/000448747 CrossRefPubMedGoogle Scholar
  14. Izumi K, Nakato R, Zhang Z, Edmondson AC, Noon S, Dulik MC, Rajagopalan R, Venditti CP, Gripp K, Samanich J, Zackai EH, Deardorff MA, Clark D, Allen JL, Dorsett D, Misulovin Z, Komata M, Bando M, Kaur M, Katou Y, Shirahige K, Krantz ID (2015) Germline gain-of-function mutations in AFF4 cause a developmental syndrome functionally linking the super elongation complex and cohesin. Nat Genet 47(4):338–344. doi: 10.1038/ng.3229 CrossRefPubMedPubMedCentralGoogle Scholar
  15. Jones WD, Dafou D, McEntagart M, Woollard WJ, Elmslie FV, Holder-Espinasse M, Irving M, Saggar AK, Smithson S, Trembath RC, Deshpande C, Simpson MA (2012) De novo mutations in MLL cause Wiedemann–Steiner syndrome. Am J Hum Genet 91(2):358–364. doi: 10.1016/j.ajhg.2012.06.008 CrossRefPubMedPubMedCentralGoogle Scholar
  16. Kaiser FJ, Ansari M, Braunholz D, Concepción Gil-Rodríguez M, Decroos C, Wilde JJ, Fincher CT, Kaur M, Bando M, Amor DJ, Atwal PS, Bahlo M, Bowman CM, Bradley JJ, Brunner HG, Clark D, Del Campo M, Di Donato N, Diakumis P, Dubbs H, Dyment DA, Eckhold J, Ernst S, Ferreira JC, Francey LJ, Gehlken U, Guillén-Navarro E, Gyftodimou Y, Hall BD, Hennekam R, Hudgins L, Hullings M, Hunter JM, Yntema H, Innes AM, Kline AD, Krumina Z, Lee H, Leppig K, Lynch SA, Mallozzi MB, Mannini L, McKee S, Mehta SG, Micule I; Care4Rare Canada Consortium., Mohammed S, Moran E, Mortier GR, Moser JA, Noon SE, Nozaki N, Nunes L, Pappas JG, Penney LS, Pérez-Aytés A, Petersen MB, Puisac B, Revencu N, Roeder E, Saitta S, Scheuerle AE, Schindeler KL, Siu VM, Stark Z, Strom SP, Thiese H, Vater I, Willems P, Williamson K, Wilson LC; University of Washington Center for Mendelian Genomics., Hakonarson H, Quintero-Rivera F, Wierzba J, Musio A, Gillessen-Kaesbach G, Ramos FJ, Jackson LG, Shirahige K, Pié J, Christianson DW, Krantz ID, Fitzpatrick DR, Deardorff MA (2014) Loss-of-function HDAC8 mutations cause a phenotypic spectrum of Cornelia de Lange syndrome-like features, ocular hypertelorism, large fontanelle and X-linked inheritance. Hum Mol Genet 23(11):2888–2900. doi:  10.1093/hmg/ddu002
  17. Krantz ID, McCallum J, DeScipio C, Kaur M, Gillis LA, Yaeger D, Jukofsky L, Wasserman N, Bottani A, Morris CA, Nowaczyk MJ, Toriello H, Bamshad MJ, Carey JC, Rappaport E, Kawauchi S, Lander AD, Calof AL, Li HH, Devoto M, Jackson LG (2004) Cornelia de Lange syndrome is caused by mutations in NIPBL, the human homolog of Drosophila melanogaster Nipped-B. Nat Genet 36(6):631–635. doi: 10.1038/ng1364 CrossRefPubMedPubMedCentralGoogle Scholar
  18. Kuechler A, Zink AM, Wieland T, Lüdecke HJ, Cremer K, Salviati L, Magini P, Najafi K, Zweier C, Czeschik JC, Aretz S, Endele S, Tamburrino F, Pinato C, Clementi M, Gundlach J, Maylahn C, Mazzanti L, Wohlleber E, Schwarzmayr T, Kariminejad R, Schlessinger A, Wieczorek D, Strom TM, Novarino G, Engels H (2015) Loss-of-function variants of SETD5 cause intellectual disability and the core phenotype of microdeletion 3p25.3 syndrome. Eur J Hum Genet 23(6):753–760. doi: 10.1038/ejhg.2014.165 CrossRefPubMedGoogle Scholar
  19. Li H, Durbin R (2010) Fast and accurate long-read alignment with Burrows–Wheeler transform. Bioinformatics 26:589–595. doi: 10.1093/bioinformatics/btp698 CrossRefPubMedPubMedCentralGoogle Scholar
  20. Liu J, Krantz ID (2009) Cornelia de Lange syndrome, cohesin, and beyond. Clin Genet 76(4):303–314. doi: 10.1111/j.1399-0004.2009.01271.x CrossRefPubMedPubMedCentralGoogle Scholar
  21. Lopez-Serra L, Kelly G, Patel H, Stewart A, Uhlmann F (2014) The Scc2–Scc4 complex acts in sister chromatid cohesion and transcriptional regulation by maintaining nucleosome-free regions. Nat Genet 46(10):1147–1151. doi: 10.1038/ng.3080 CrossRefPubMedPubMedCentralGoogle Scholar
  22. Mehta GD, Kumar R, Srivastava S, Ghosh SK (2013) Cohesin: functions beyond sister chromatid cohesion. FEBS Lett 587(15):2299–2312. doi: 10.1016/j.febslet.2013.06.035 CrossRefPubMedGoogle Scholar
  23. Michelson M, Ben-Sasson A, Vinkler C, Leshinsky-Silver E, Netzer I, Frumkin A, Kivity S, Lerman-Sagie T, Lev D (2012) Delineation of the interstitial 6q25 microdeletion syndrome: refinement of the critical causative region. Am J Med Genet A 158A(6):1395–1399. doi: 10.1002/ajmg.a.35361 CrossRefPubMedGoogle Scholar
  24. Musio A, Selicorni A, Focarelli ML, Gervasini C, Milani D, Russo S, Vezzoni P, Larizza L (2006) X-linked Cornelia de Lange syndrome owing to SMC1L1 mutations. Nat Genet 38(5):528–530. doi: 10.1038/ng1779 CrossRefPubMedGoogle Scholar
  25. Nagamani SC, Erez A, Eng C, Ou Z, Chinault C, Workman L, Coldwell J, Stankiewicz P, Patel A, Lupski JR, Cheung SW (2009) Interstitial deletion of 6q25.2-q25.3: a novel microdeletion syndrome associated with microcephaly, developmental delay, dysmorphic features and hearing loss. Eur J Hum Genet 17(5):573–581. doi: 10.1038/ejhg.2008.220 CrossRefPubMedGoogle Scholar
  26. Parenti I, Gervasini C, Pozojevic J, Graul-Neumann L, Azzollini J, Braunholz D, Watrin E, Wendt KS, Cereda A, Cittaro D, Gillessen-Kaesbach G, Lazarevic D, Mariani M, Russo S, Werner R, Krawitz P, Larizza L, Selicorni A, Kaiser FJ (2016a) Broadening of cohesinopathies: exome sequencing identifies mutations in ANKRD11 in two patients with Cornelia de Lange-overlapping phenotype. Clin Genet 89(1):74–81. doi: 10.1111/cge.12564 CrossRefPubMedGoogle Scholar
  27. Parenti I, Gervasini C, Pozojevic J, Wendt KS, Watrin E, Azzollini J, Braunholz D, Buiting K, Cereda A, Engels H, Garavelli L, Glazar R, Graffmann B, Larizza L, Lüdecke HJ, Mariani M, Masciadri M, Pié J, Ramos FJ, Russo S, Selicorni A, Stefanova M, Strom TM, Werner R, Wierzba J, Zampino G, Gillessen-Kaesbach G, Wieczorek D, Kaiser FJ (2016b) Expanding the clinical spectrum of the ‘HDAC8-phenotype’—implications for molecular diagnostics, counseling and risk prediction. Clin Genet 89(5):564–573. doi: 10.1111/cge.12717 CrossRefPubMedGoogle Scholar
  28. Pié J, Gil-Rodríguez MC, Ciero M, López-Viñas E, Ribate MP, Arnedo M, Deardorff MA, Puisac B, Legarreta J, de Karam JC, Rubio E, Bueno I, Baldellou A, Calvo MT, Casals N, Olivares JL, Losada A, Hegardt FG, Krantz ID, Gómez-Puertas P, Ramos FJ (2010) Mutations and variants in the cohesion factor genes NIPBL, SMC1A, and SMC3 in a cohort of 30 unrelated patients with Cornelia de Lange syndrome. Am J Med Genet A 152A(4):924–929. doi: 10.1002/ajmg.a.33348 CrossRefPubMedPubMedCentralGoogle Scholar
  29. Roelfsema JH, White SJ, Ariyürek Y, Bartholdi D, Niedrist D, Papadia F, Bacino CA, den Dunnen JT, van Ommen GJ, Breuning MH, Hennekam RC, Peters DJ (2005) Genetic heterogeneity in Rubinstein–Taybi syndrome: mutations in both the CBP and EP300 genes cause disease. Am J Hum Genet 76(4):572–580. doi: 10.1086/429130 CrossRefPubMedPubMedCentralGoogle Scholar
  30. Ronzoni L, Tagliaferri F, Tucci A, Baccarin M, Esposito S, Milani D (2016) Interstitial 6q25 microdeletion syndrome: ARID1B is the key gene. Am J Med Genet A170(5):1257–1261. doi: 10.1002/ajmg.a.37553 CrossRefGoogle Scholar
  31. Santen GW, Aten E, Sun Y, Almomani R, Gilissen C, Nielsen M, Kant SG, Snoeck IN, Peeters EA, Hilhorst-Hofstee Y, Wessels MW, den Hollander NS, Ruivenkamp CA, van Ommen GJ, Breuning MH, den Dunnen JT, van Haeringen A, Kriek M (2012) Mutations in SWI/SNF chromatin remodeling complex gene ARID1B cause Coffin–Siris syndrome. Nat Genet 44(4):379–380. doi: 10.1038/ng.2217 CrossRefPubMedGoogle Scholar
  32. Selicorni A, Russo S, Gervasini C, Castronovo P, Milani D, Cavalleri F, Bentivegna A, Masciadri M, Domi A, Divizia MT, Sforzini C, Tarantino E, Memo L, Scarano G, Larizza L (2007) Clinical score of 62 Italian patients with Cornelia de Lange syndrome and correlations with the presence and type of NIPBL mutation. Clin Genet 72(2):98–108. doi: 10.1111/j.1399-0004.2007.00832.x CrossRefPubMedGoogle Scholar
  33. Sirmaci A, Spiliopoulos M, Brancati F, Powell E, Duman D, Abrams A, Bademci G, Agolini E, Guo S, Konuk B, Kavaz A, Blanton S, Digilio MC, Dallapiccola B, Young J, Zuchner S, Tekin M (2011) Mutations in ANKRD11 cause KBG syndrome, characterized by intellectual disability, skeletal malformations, and macrodontia. Am J Hum Genet 89(2):289–294. doi: 10.1016/j.ajhg.2011.06.007 CrossRefPubMedPubMedCentralGoogle Scholar
  34. Szczałuba K, Brzezinska M, Kot J, Rydzanicz M, Walczak A, Stawiński P, Werner B, Płoski R (2016) SETD5 loss-of-function mutation as a likely cause of a familial syndromic intellectual disability with variable phenotypic expression. Am J Med Genet A170(9):2322–2327. doi: 10.1002/ajmg.a.37832 CrossRefGoogle Scholar
  35. Tang L, Nogales E, Ciferri C (2010) Structure and function of SWI/SNF chromatin remodeling complexes and mechanistic implications for transcription. Prog Biophys Mol Biol 102(2–3):122–128. doi: 10.1016/j.pbiomolbio.2010.05.001 CrossRefPubMedPubMedCentralGoogle Scholar
  36. Tonkin ET, Wang TJ, Lisgo S, Bamshad MJ, Strachan T (2004) NIPBL, encoding a homolog of fungal Scc2-type sister chromatid cohesion proteins and fly Nipped-B, is mutated in Cornelia de Lange syndrome. Nat Genet 36(6):636–641. doi: 10.1038/ng1363 CrossRefPubMedGoogle Scholar
  37. Tsurusaki Y, Okamoto N, Ohashi H, Kosho T, Imai Y, Hibi-Ko Y, Kaname T, Naritomi K, Kawame H, Wakui K, Fukushima Y, Homma T, Kato M, Hiraki Y, Yamagata T, Yano S, Mizuno S, Sakazume S, Ishii T, Nagai T, Shiina M, Ogata K, Ohta T, Niikawa N, Miyatake S, Okada I, Mizuguchi T, Doi H, Saitsu H, Miyake N, Matsumoto N (2012) Mutations affecting components of the SWI/SNF complex cause Coffin–Siris syndrome. Nat Genet 44(4):376–378. doi: 10.1038/ng.2219 CrossRefPubMedGoogle Scholar
  38. Wieczorek D, Bögershausen N, Beleggia F, Steiner-Haldenstätt S, Pohl E, Li Y, Milz E, Martin M, Thiele H, Altmüller J, Alanay Y, Kayserili H, Klein-Hitpass L, Böhringer S, Wollstein A, Albrecht B, Boduroglu K, Caliebe A, Chrzanowska K, Cogulu O, Cristofoli F, Czeschik JC, Devriendt K, Dotti MT, Elcioglu N, Gener B, Goecke TO, Krajewska-Walasek M, Guillén-Navarro E, Hayek J, Houge G, Kilic E, Simsek-Kiper PÖ, López-González V, Kuechler A, Lyonnet S, Mari F, Marozza A, Mathieu Dramard M, Mikat B, Morin G, Morice-Picard F, Ozkinay F, Rauch A, Renieri A, Tinschert S, Utine GE, Vilain C, Vivarelli R, Zweier C, Nürnberg P, Rahmann S, Vermeesch J, Lüdecke HJ, Zeschnigk M, Wollnik B (2013) A comprehensive molecular study on Coffin–Siris and Nicolaides–Baraitser syndromes identifies a broad molecular and clinical spectrum converging on altered chromatin remodeling. Hum Mol Genet 22(25):5121–5135. doi: 10.1093/hmg/ddt366 CrossRefPubMedGoogle Scholar
  39. Woods SA, Robinson HB, Kohler LJ, Agamanolis D, Sterbenz G, Khalifa M (2014) Exome sequencing identifies a novel EP300 frame shift mutation in a patient with features that overlap Cornelia de Lange syndrome. Am J Med GenetA 164A(1):251–258. doi: 10.1002/ajmg.a.36237 CrossRefGoogle Scholar
  40. Yuan B, Pehlivan D, Karaca E, Patel N, Charng WL, Gambin T, Gonzaga-Jauregui C, Sutton VR, Yesil G, Bozdogan ST, Tos T, Koparir A, Koparir E, Beck CR, Gu S, Aslan H, Yuregir OO, Al Rubeaan K, Alnaqeb D, Alshammari MJ, Bayram Y, Atik MM, Aydin H, Geckinli BB, Seven M, Ulucan H, Fenercioglu E, Ozen M, Jhangiani S, Muzny DM, Boerwinkle E, Tuysuz B, Alkuraya FS, Gibbs RA, Lupski JR (2015) Global transcriptional disturbances underlie Cornelia de Lange syndrome and related phenotypes. J Clin Invest 125(2):636–651. doi: 10.1172/JCI77435 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Ilaria Parenti
    • 1
  • María E. Teresa-Rodrigo
    • 2
    • 3
  • Jelena Pozojevic
    • 1
  • Sara Ruiz Gil
    • 1
  • Ingrid Bader
    • 4
  • Diana Braunholz
    • 1
    • 5
  • Nuria C. Bramswig
    • 6
  • Cristina Gervasini
    • 7
  • Lidia Larizza
    • 8
  • Lutz Pfeiffer
    • 9
  • Ferda Ozkinay
    • 10
    • 11
  • Feliciano Ramos
    • 2
    • 12
  • Benedikt Reiz
    • 13
  • Olaf Rittinger
    • 4
  • Tim M. Strom
    • 14
    • 15
  • Erwan Watrin
    • 16
  • Kerstin Wendt
    • 17
  • Dagmar Wieczorek
    • 18
  • Bernd Wollnik
    • 19
  • Carolina Baquero-Montoya
    • 20
  • Juan Pié
    • 2
    • 3
  • Matthew A. Deardorff
    • 21
    • 22
  • Gabriele Gillessen-Kaesbach
    • 23
  • Frank J. Kaiser
    • 1
    Email author
  1. 1.Sektion für Funktionelle Genetik am Institut für Humangenetik LübeckUniversität zu LübeckLübeckGermany
  2. 2.Unit of Clinical Genetics and Functional Genomics, Department of Pharmacology-Physiology, School of MedicineUniversity of ZaragozaZaragozaSpain
  3. 3.Unit of Clinical Genetics and Functional Genomics, Department of Paediatrics, School of MedicineUniversity of ZaragozaZaragozaSpain
  4. 4.Clinical Genetics Unit, Children’s HospitalParacelsus Medical UniversitySalzburgAustria
  5. 5.German Cancer Consortium (DKTK), Deutsches Krebsforschungszentrum (DKFZ), Partner Site BerlinCharité University Hospital BerlinBerlinGermany
  6. 6.Institut für Humangenetik, Universitätsklinikum EssenUniversität Duisburg-EssenEssenGermany
  7. 7.Medical Genetics, Department of Health SciencesUniversità degli Studi di MilanoMilanItaly
  8. 8.Laboratory of Medical Cytogenetics and Molecular GeneticsIRCCS Istituto Auxologico ItalianoMilanItaly
  9. 9.Arztpraxis Medizinische Genetik im Medizin Zentrum Lichtenberg-MZLBerlinGermany
  10. 10.Department of Medical Genetics, Faculty of MedicineEge UniversityIzmirTurkey
  11. 11.Division of Pediatric Genetics, Department of Pediatrics, Faculty of MedicineEge UniversityIzmirTurkey
  12. 12.Clinical Genetics Unit, Service of Paediatrics, Hospital “Lozano Blesa” Medical SchoolUniversity of ZaragozaZaragozaSpain
  13. 13.Institut für Integrative und Experimentelle GenomikUniversität zu LübeckLübeckGermany
  14. 14.Institute of Human GeneticsTechnische Universität MünchenMünchenGermany
  15. 15.German Research Center for Environmental Health, Institute of Human GeneticsHelmholtz Zentrum MünchenNeuherbergGermany
  16. 16.Faculté de MédecineInstitut de Génétique et Développement de RennesRennesFrance
  17. 17.Department of Cell BiologyErasmus MCRotterdamThe Netherlands
  18. 18.Institut für Humangenetik, Universitätsklinikum DüsseldorfHeinrich-Heine-Universität DüsseldorfDüsseldorfGermany
  19. 19.Institut für HumangenetikUniversität GöttingenGöttingenGermany
  20. 20.Department of PediatricsHospital Pablo Tobon UribeMedellínColombia
  21. 21.Division of Human Genetics and Molecular BiologyThe Children’s Hospital of PhiladelphiaPhiladelphiaUSA
  22. 22.Department of Pediatrics, Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaUSA
  23. 23.Institut für Humangenetik LübeckUniversität zu LübeckLübeckGermany

Personalised recommendations