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Human Genetics

, Volume 138, Issue 3, pp 257–269 | Cite as

Exploring by whole exome sequencing patients with initial diagnosis of Rubinstein–Taybi syndrome: the interconnections of epigenetic machinery disorders

  • Gloria Negri
  • Pamela Magini
  • Donatella Milani
  • Milena Crippa
  • Elisa Biamino
  • Maria Piccione
  • Stefano Sotgiu
  • Chiara Perrìa
  • Giuseppina Vitiello
  • Marina Frontali
  • Antonella Boni
  • Elisabetta Di Fede
  • Maria Chiara Gandini
  • Elisa Adele Colombo
  • Michael J. Bamshad
  • Deborah A. Nickerson
  • Joshua D. Smith
  • Italia Loddo
  • Palma Finelli
  • Marco Seri
  • Tommaso Pippucci
  • Lidia Larizza
  • Cristina GervasiniEmail author
Original Investigation

Abstract

Rubinstein–Taybi syndrome (RSTS) is an autosomal-dominant neurodevelopmental disease affecting 1:125,000 newborns characterized by intellectual disability, growth retardation, facial dysmorphisms and skeletal abnormalities. RSTS is caused by mutations in genes encoding for writers of the epigenetic machinery: CREBBP (~ 60%) or its homologous EP300 (~ 10%). No causative mutation is identified in up to 30% of patients. We performed whole-exome sequencing (WES) on eight RSTS-like individuals who had normal high-resolution array CGH testing and were CREBBP- and EP300-mutation -negative, to identify the molecular cause. In four cases, we identified putatively causal variants in three genes (ASXL1, KMT2D and KMT2A) encoding members of the epigenetic machinery known to be associated with the Bohring–Opitz, Kabuki and Wiedemann–Steiner syndromes. Each variant is novel, de novo, fulfills the ACMG criteria and is predicted to result in loss-of-function leading to haploinsufficiency of the epi-gene. In two of the remaining cases, homozygous/compound heterozygous variants in XYLT2 and PLCB4 genes, respectively, associated with spondyloocular and auriculocondylar 2 syndromes and in the latter an additional candidate variant in XRN2, a gene yet unrelated to any disease, were detected, but their pathogenicity remains uncertain. These results underscore the broad clinical spectrum of Mendelian disorders of the epigenetic apparatus and the high rate of WES disclosure of the genetic basis in cases which may pose a challenge for phenotype encompassing distinct syndromes. The overlapping features of distinct intellectual disability syndromes reflect common pathogenic molecular mechanisms affecting the complex regulation of balance between open and closed chromatin.

Notes

Acknowledgements

We thank the patients’ families for participating in this study. CG thanks the Italian Association of Rubinstein–Taybi patients “RTS Una Vita Speciale ONLUS” for its support and Dr. Giordano, Dr. Ficcadenti, Dr. Cavaliere, Dr. Vitiello for providing clinical data of patients #76, #88, #118 and #169, respectively. This work was supported by University of Milan young researcher grant to CG (Dotazione d’Ateneo linea 2 del piano di sostegno alla ricerca), by Associazione “RTS Una Vita Speciale ONLUS” (project #DigiRare) to CG and by a Ministry of Health grant to Istituto Auxologico Italiano IRCCS (08C623_2016) to PF.

Author contributions

TP and CG: conceived the project. DM, EB, MP, SS, CP, GV, MF, AB, MS: contributed to patient recruitment and/or provided biological samples. GN, PM, EDF, EAC, MCG, IL, PF: contributed to molecular analyses. UWCMG, MJB, DAN, JDS: performed bioinformatics analyses. PM, GN, CG, TP: performed data analysis and interpretation. GN, LL, TP and CG: wrote the manuscript. All authors: approved the manuscript.

Supplementary material

439_2019_1985_MOESM1_ESM.docx (18 kb)
Supplemental Table S1: list of mutations so far described for ASXL1 gene (DOCX 17 KB)
439_2019_1985_MOESM2_ESM.docx (34 kb)
Supplemental Table S2: list of mutations so far described for KMT2D gene (DOCX 34 KB)
439_2019_1985_MOESM3_ESM.docx (17 kb)
Supplemental Table S3: list of mutations so far described for KMT2A gene (DOCX 17 KB)
439_2019_1985_MOESM4_ESM.docx (15 kb)
Supplemental Table S4: variants detected in RSTS-like patients with unclear pathogenetic role. Position and type of the pathogenic variants are indicated (DOCX 15 KB)
439_2019_1985_MOESM5_ESM.docx (16 kb)
Supplemental Table S5: Clinical signs of patients #76, #88, #118 and #169 compared to typical features of RSTS (DOCX 16 KB)
439_2019_1985_MOESM6_ESM.docx (39 kb)
Supplementary material 6 (DOCX 39 KB)
439_2019_1985_MOESM7_ESM.tif (248 kb)
Supplemental Fig. S1: Gene distribution of described ASXL1, KMT2A and KMT2D mutations. Colored rectangles represent the main protein domains. Dashed lines indicate start and stop codons. Known mutations are depicted as red = truncating, blue = missense, green = inframe indel. Intragenic positions of variants identified in the present work are indicated in black. GPviz software was used to visualize mutations (TIF 248 KB)

References

  1. Aggarwal A, Rodriguez-Buritica DF, Northrup H (2017) Wiedemann–Steiner syndrome: novel pathogenic variant and review of literature. Eur J Med Genet 60:285–288.  https://doi.org/10.1016/j.ejmg.2017.03.006 CrossRefGoogle Scholar
  2. Allis CD, Jenuwein T (2016) The molecular hallmarks of epigenetic control. Nat Rev Genet 17:487–500.  https://doi.org/10.1038/nrg.2016.59 CrossRefGoogle Scholar
  3. Arunachal G, Danda S, Omprakash S, Kumar S (2016) A novel de-novo frameshift mutation of the ASXL1 gene in a classic case of Bohring–Opitz syndrome. Clin Dysmorphol 25:101–105.  https://doi.org/10.1097/MCD.0000000000000126 CrossRefGoogle Scholar
  4. Baer S, Afenjar A, Smol T, Piton A, Gérard B, Alembik Y, Bienvenu T, Boursier G, Boute O, Colson C, Cordier MP, Cormier-Daire V, Delobel B, Doco-Fenzy M, Duban-Bedu B, Fradin M, Geneviève D, Goldenberg A, Grelet M, Haye D, Heron D, Isidor B, Keren B, Lacombe D, Lèbre AS, Lesca G, Masurel A, Mathieu-Dramard M, Nava C, Pasquier L, Petit A, Philip N, Piard J, Rondeau S, Saugier-Veber P, Sukno S, Thevenon J, Van-Gils J, Vincent-Delorme C, Willems M, Schaefer E, Morin G (2018) Wiedemann–Steiner syndrome as a major cause of syndromic intellectual disability: a study of 33 French cases. Clin Genet 94:141–152.  https://doi.org/10.1111/cge.13254 CrossRefGoogle Scholar
  5. Bjornsson HT (2015) The Mendelian disorders of the epigenetic machinery. Genome Res 25:1473–1481.  https://doi.org/10.1101/gr.190629.115 CrossRefGoogle Scholar
  6. Bohring A, Silengo M, Lerone M, Superneau DW, Spaich C, Braddock SR, Poss A, Opitz JM (1999) Severe end of Opitz trigonocephaly (C) syndrome or new syndrome? Am J Med Genet 85:438–446.  https://doi.org/10.1002/(SICI)1096-8628(19990827)85:5%3C438::AID-AJMG2%3E3.0.CO;2-A CrossRefGoogle Scholar
  7. Breuning MH, Dauwerse HG, Fugazza G, Saris JJ, Spruit L, Wijnen H, Tommerup N, van der Hagen CB, Imaizumi K, Kuroki Y, van den Boogaard MJ, de Pater JM, Mariman EC, Hamel BC, Himmelbauer H, Frischauf AM, Stallings R, Beverstock GC, van Ommen GJ, Hennekam RC (1993) Rubinstein-Taybi syndrome caused by submicroscopic deletions within 16p13.3. Am J Hum Genet 52:249–254Google Scholar
  8. Dauwerse JG, van Belzen M, van Haeringen A, van Santen G, van de Lans C, Rahikkala E, Garavelli L, Breuning M, Hennekam R, Peters D (2016) Analysis of mutations within the intron20 splice donor site of CREBBP in patients with and without classical RSTS. Eur J Hum Genet 24:1639–1643.  https://doi.org/10.1038/ejhg.2016.47 CrossRefGoogle Scholar
  9. Fahrner JA, Bjornsson HT (2014) The Mendelian disorders of the epigenetic machinery. Mendelian disorders of the epigenetic machinery: tipping the balance of chromatin states. Annu Rev Genom Hum Genet 15:269–293.  https://doi.org/10.1146/annurev-genom-090613-094245 CrossRefGoogle Scholar
  10. Fergelot P, Van Belzen M, Van Gils J, Afenjar A, Armour CM, Arveiler B, Beets L, Burglen L, Busa T, Collet M, Deforges J, de Vries BB, Dominguez Garrido E, Dorison N, Dupont J, Francannet C, Garciá-Minaúr S, Gabau Vila E, Gebre-Medhin S, Gener Querol B, Geneviève D, Gérard M, Gervasini CG, Goldenberg A, Josifova D, Lachlan K, Maas S, Maranda B, Moilanen JS, Nordgren A, Parent P, Rankin J, Reardon W, Rio M, Roume J, Shaw A, Smigiel R, Sojo A, Solomon B, Stembalska A, Stumpel C, Suarez F, Terhal P, Thomas S, Touraine R, Verloes A, Vincent-Delorme C, Wincent J, Peters DJ, Bartsch O, Larizza L, Lacombe D, Hennekam RC (2016) Phenotype and genotype in 52 patients with Rubinstein-Taybi syndrome caused by EP300 mutations. Am J Med Genet A 170:3069–3082.  https://doi.org/10.1002/ajmg.a.37940 CrossRefGoogle Scholar
  11. Hamilton MJ, Newbury-Ecob R, Holder-Espinasse M, Yau S, Lillis S, Hurst JA, Clement E, Reardon W, Joss S, Hobson E, Blyth M, Al-Shehhi M, Lynch SA, Suri M, DDD Study (2016) Rubinstein-Taybi syndrome type 2: report of nine new cases that extend the phenotypic and genotypic spectrum. Clin Dysmorphol 25:135–145.  https://doi.org/10.1097/MCD.0000000000000143 CrossRefGoogle Scholar
  12. Jin B, Tao Q, Peng J, Soo HM, Wu W, Ying J, Fields CR, Delmas AL, Liu X, Qiu J, Robertson KD (2008) DNA methyltransferase 3B (DNMT3B) mutations in ICF syndrome lead to altered epigenetic modifications and aberrant expression of genes regulating development, neurogenesis and immune function. Hum Mol Genet 17:690–709.  https://doi.org/10.1093/hmg/ddm341 CrossRefGoogle Scholar
  13. Koboldt DC, Zhang Q, Larson DE, Shen D, McLellan MD, Lin L, Miller CA, Mardis ER, Ding L, Wilson RK (2012) VarScan 2: somatic mutation and copy number alteration discovery in cancer by exome sequencing. Genome Res 22:568–576.  https://doi.org/10.1101/gr.129684.111 CrossRefGoogle Scholar
  14. Lacombe D, Saura R, Taine L, Battin J (1992) Confirmation of assignment of a locus for Rubinstein-Taybi syndrome gene to 16p13.3. Am J Med Genet 44:126–128.  https://doi.org/10.1002/ajmg.1320440134 CrossRefGoogle Scholar
  15. López M, Seidel V, Santibáñez P, Cervera-Acedo C, Castro-de Castro P, Domínguez-Garrido E (2016) First case report of inherited Rubinstein–Taybi syndrome associated with a novel EP300 variant. BMC Med Genet 17:97.  https://doi.org/10.1186/s12881-016-0361-8 CrossRefGoogle Scholar
  16. Masuda K, Akiyama K, Arakawa M, Nishi E, Kitazawa N, Higuchi T, Katou Y, Shirahige K, Izumi K (2015) Exome sequencing identification of EP300 mutation in a proband with coloboma and imperforate anus: possible expansion of the phenotypic spectrum of Rubinstein–Taybi syndrome. Mol Syndromol 6:99–103.  https://doi.org/10.1159/000375542 CrossRefGoogle Scholar
  17. Menke LA, van Belzen MJ, Alders M, Cristofolik F, DDD Study, Ehmke N, Fergelot P, Foster A, Gerkes EH, Hoffer MJ, Horn D, Kant SG, Lacombe D, Leon E, Maas SM, Melis D, Muto V, Park SM, Peeters H, Peters DJ, Pfundt R, van Ravenswaaij-Arts CM, Tartaglia M, Hennekam RC (2016) CREBBP mutations in individuals without Rubinstein–Taybi syndrome phenotype. Am J Med Genet A 170:2681–2693.  https://doi.org/10.1002/ajmg.a.37800 CrossRefGoogle Scholar
  18. Menke LA, DDD study, Gardeitchik T, Hammond P, Heimdal KR, Houge G, Hufnagel SB, Ji J, Johansson S, Kant SG, Kinning E, Leon EL, Newbury-Ecob R, Paolacci S, Pfundt R, Ragge NK, Rinne T, Ruivenkamp C, Saitta SC, Sun Y, Tartaglia M, Terhal PA, van Essen AJ, Vigeland MD, Xiao B, Hennekam RC (2018) Further delineation of an entity caused by CREBBP and EP300 mutations but not resembling Rubinstein–Taybi syndrome. Am J Med Genet A 176:862–876.  https://doi.org/10.1002/ajmg.a.38626 CrossRefGoogle Scholar
  19. Negri G, Milani D, Colapietro P, Forzano F, Della Monica M, Rusconi D, Consonni L, Caffi LG, Finelli P, Scarano G, Magnani C, Selicorni A, Spena S, Larizza L, Gervasini C (2015) Clinical and molecular characterization of Rubinstein–Taybi syndrome patients carrying distinct novel mutations of the EP300 gene. Clin Genet 87:148–154.  https://doi.org/10.1111/cge.12348 CrossRefGoogle Scholar
  20. Negri G, Magini P, Milani D, Colapietro P, Rusconi D, Scarano E, Bonati MT, Priolo M, Crippa M, Mazzanti L, Wischmeijer A, Tamburrino F, Pippucci T, Finelli P, Larizza L, Gervasini C (2016) From whole gene deletion to point mutations of EP300-positive Rubinstein–Taybi Patients: new insights into the mutational spectrum and peculiar clinical hallmarks. Hum Mutat 37:175–183.  https://doi.org/10.1002/humu.22922 CrossRefGoogle Scholar
  21. Niikawa N, Matsuura N, Fukushima Y, Ohsawa T, Kajii T (1981) Kabuki make-up syndrome: a syndrome of mental retardation, unusual facies, large and protruding ears, and postnatal growth deficiency. J Pediatr 99:565–569CrossRefGoogle Scholar
  22. 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 (2016) Broadening of cohesinopathies: exome sequencing identifies mutations in ANKRD11 in two patients with Cornelia de Lange-overlapping phenotype. Clin Genet 89:74–81.  https://doi.org/10.1111/cge.12564 CrossRefGoogle Scholar
  23. Ramu A, Noordam MJ, Schwartz RS, Wuster A, Hurles ME, Cartwright RA, Conrad DF (2013) DeNovoGear: de novo indel and point mutation discovery and phasing. Nat Methods 10:985–987.  https://doi.org/10.1038/nmeth.2611 CrossRefGoogle Scholar
  24. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, ACMG Laboratory Quality Assurance Committee (2015) 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 17:405–424.  https://doi.org/10.1038/gim.2015.30 CrossRefGoogle Scholar
  25. Rubinstein JH, Taybi H (1963) Broad thumbs and toes and facial abnormalities. A possible mental retardation syndrome. Am J Dis Child 105:588–608.  https://doi.org/10.1001/archpedi.1963.02080040590010 CrossRefGoogle Scholar
  26. Rusconi D, Negri G, Colapietro P, Picinelli C, Milani D, Spena S, Magnani C, Silengo MC, Sorasio L, Curtisova V, Cavaliere ML, Prontera P, Stangoni G, Ferrero GB, Biamino E, Fischetto R, Piccione M, Gasparini P, Salviati L, Selicorni A, Finelli P, Larizza L, Gervasini C (2015) Characterization of 14 novel deletions underlying Rubinstein–Taybi syndrome: an update of the CREBBP deletion repertoire. Hum Genet 134:613–626.  https://doi.org/10.1007/s00439-015-1542-9 CrossRefGoogle Scholar
  27. Schott DA, Blok MJ, Gerver WJ, Devriendt K, Zimmermann LJ, Stumpel CT (2016) Growth pattern in Kabuki syndrome with a KMT2D mutation. Am J Med Genet A 170:3172–3179.  https://doi.org/10.1002/ajmg.a.37930 CrossRefGoogle Scholar
  28. Sellars EA, Sullivan BR, Schaefer GB (2016) Whole exome sequencing reveals EP300 mutation in mildly affected female: expansion of the spectrum. Clin Case Rep 4:696–698.  https://doi.org/10.1002/ccr3.598 CrossRefGoogle Scholar
  29. 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 89:289–294.  https://doi.org/10.1016/j.ajhg.2011.06.007 CrossRefGoogle Scholar
  30. Smith E, Lin C, Shilatifard A (2011) The super elongation complex (SEC) and MLL in development and disease. Genes Dev 25:661–672.  https://doi.org/10.1101/gad.2015411 CrossRefGoogle Scholar
  31. Sobreira N, Brucato M, Zhang L, Ladd-Acosta C, Ongaco C, Romm J, Doheny KF, Mingroni-Netto RC, Bertola D, Kim CA, Perez AB, Melaragno MI, Valle D, Meloni VA, Bjornsson HT (2017) Patients with a Kabuki syndrome phenotype demonstrate DNA methylation abnormalities. Eur J Hum Genet 25:1335–1344.  https://doi.org/10.1038/s41431-017-0023-0 CrossRefGoogle Scholar
  32. Spena S, Gervasini C, Milani D (2015a) Ultra-rare syndromes: the example of Rubinstein–Taybi syndrome. J Pediatr Genet 4:177–186.  https://doi.org/10.1055/s-0035-1564571 CrossRefGoogle Scholar
  33. Spena S, Milani D, Rusconi D, Negri G, Colapietro P, Elcioglu N, Bedeschi F, Pilotta A, Spaccini L, Ficcadenti A, Magnani C, Scarano G, Selicorni A, Larizza L, Gervasini C (2015b) Insights into genotype-phenotype correlations from CREBBP point mutation screening in a cohort of 46 Rubinstein–Taybi syndrome patients. Clin Genet 88:431–440.  https://doi.org/10.1111/cge.12537 CrossRefGoogle Scholar
  34. Tucker JF, Ohle C, Schermann G, Bendrin K, Zhang W, Fischer T, Zhang K (2016) A novel epigenetic silencing pathway involving the highly conserved 5′–3′ exoribonuclease Dhp1/Rat1/Xrn2 in Schizosaccharomyces pombe. PLoS Genet 12:e1005873.  https://doi.org/10.1371/journal.pgen.1005873 CrossRefGoogle Scholar
  35. Van der Auwera GA, Carneiro MO, Hartl C, Poplin R, Del Angel G, Levy-Moonshine A, Jordan T, Shakir K, Roazen D, Thibault J, Banks E, Garimella KV, Altshuler D, Gabriel S, DePristo MA (2013) From FastQ data to high confidence variant calls: the Genome Analysis Toolkit best practices pipeline. Curr Protoc Bioinform 43:11.10.1–33.  https://doi.org/10.1002/0471250953.bi1110s43 Google Scholar
  36. Wiedemann HR, Kunze J, Grosse FR, Dibbern H (1989) A syndrome of abnormal facies, short stature, and psychomotor retardation. In: Atlas of clinical syndromes: a visual aid to diagnosis for clinicians and practicing physicians, 2nd edn. Wolfe Publishing Ltd, London, pp 198–199Google Scholar
  37. Wincent J, Luthman A, van Belzen M, van der Lans C, Albert J, Nordgren A, Anderlid BM (2015) CREBBP and EP300 mutational spectrum and clinical presentations in a cohort of Swedish patients with Rubinstein–Taybi syndrome. Mol Genet Genom Med 4:39–45.  https://doi.org/10.1002/mgg3.177 CrossRefGoogle Scholar
  38. 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 Genet A 164A:251–258.  https://doi.org/10.1002/ajmg.a.36237 CrossRefGoogle Scholar
  39. 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 125:636–651.  https://doi.org/10.1172/JCI77435 CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Gloria Negri
    • 1
  • Pamela Magini
    • 2
  • Donatella Milani
    • 3
  • Milena Crippa
    • 4
    • 5
  • Elisa Biamino
    • 6
  • Maria Piccione
    • 7
  • Stefano Sotgiu
    • 8
  • Chiara Perrìa
    • 8
  • Giuseppina Vitiello
    • 9
  • Marina Frontali
    • 10
  • Antonella Boni
    • 11
  • Elisabetta Di Fede
    • 1
  • Maria Chiara Gandini
    • 1
  • Elisa Adele Colombo
    • 1
  • Michael J. Bamshad
    • 12
  • Deborah A. Nickerson
    • 12
  • Joshua D. Smith
    • 12
  • Italia Loddo
    • 13
  • Palma Finelli
    • 4
    • 5
  • Marco Seri
    • 2
  • Tommaso Pippucci
    • 2
  • Lidia Larizza
    • 4
  • Cristina Gervasini
    • 1
    Email author
  1. 1.Genetica Medica, Dipartimento di Scienze della SaluteUniversità degli Studi di MilanoMilanItaly
  2. 2.U.O. Genetica Medica, Policlinico S. Orsola-MalpighiAzienda Ospedaliero-Universitaria di BolognaBolognaItaly
  3. 3.Unità di Pediatria ad alta Intensità di Cura, Fondazione IRCCS Ca’ GrandaMilanItaly
  4. 4.Medical Cytogenetics and Molecular Genetics LaboratoryIRCCS Istituto Auxologico ItalianoMilanItaly
  5. 5.Department of Medical Biotechnology and Translational MedicineUniversità degli Studi di MilanoMilanItaly
  6. 6.Dipartimento di PediatriaUniversità di TorinoTurinItaly
  7. 7.Dipartimento Materno InfantileAzienda Ospedali Riuniti Villa Sofia Cervello, Università di PalermoPalermoItaly
  8. 8.Dipartimento di Medicina Clinica e Sperimentale, U.O.C. Neuropsichiatria InfantileA.O.U. di SassariSassariItaly
  9. 9.Dipartimento di Medicina Traslazionale, Sezione di PediatriaUniversità Federico IINaplesItaly
  10. 10.Istituto di Farmacologia Traslazionale CNRRomeItaly
  11. 11.IRCCS Istituto delle Scienze Neurologiche di Bologna UOC Neuropsichiatria Infantile, Ospedale BellariaBolognaItaly
  12. 12.Department of Genome Sciences, Center for Mendelian GenomicsUniversity of WashingtonSeattleUSA
  13. 13.Dipartimento di Medicina di Laboratorio e Biotecnologie AvanzateIRCCS ISMETTPalermoItaly

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