Abstract
Kabuki syndrome (KS) is one of the classical, clinically well-known multiple anomalies/mental retardation syndromes, mainly characterized by a very distinctive facial appearance in combination with additional clinical signs such as developmental delay, short stature, persistent fingerpads, and urogenital tract anomalies. In our study, we sequenced all 54 coding exons of the recently identified MLL2 gene in 34 patients with Kabuki syndrome. We identified 18 distinct mutations in 19 patients, 11 of 12 tested de novo. Mutations were located all over the gene and included three nonsense mutations, two splice-site mutations, six small deletions or insertions, and seven missense mutations. We compared frequencies of clinical symptoms in MLL2 mutation carriers versus non-carriers. MLL2 mutation carriers significantly more often presented with short stature and renal anomalies (p = 0.026 and 0.031, respectively), and in addition, MLL2 carriers obviously showed more frequently a typical facial gestalt (17/19) compared with non-carriers (9/15), although this result was not statistically significant (p = 0.1). Mutation-negative patients were subsequently tested for mutations in ten functional candidate genes (e.g. MLL, ASC2, ASH2L, and WDR5), but no convincing causative mutations could be found. Our results indicate that MLL2 is the major gene for Kabuki syndrome with a wide spectrum of de novo mutations and strongly suggest further genetic heterogeneity.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Adam MP, Hudgins L (2005) Kabuki syndrome: a review. Clin Genet 67:209–219
Armstrong L, Abd El Moneim A, Aleck K, Aughton DJ, Baumann C, Braddock SR, Gillessen-Kaesbach G, Graham JM Jr, Grebe TA, Gripp KW, Hall BD, Hennekam R, Hunter A, Keppler-Noreuil K, Lacombe D, Lin AE, Ming JE, Kokitsu-Nakata NM, Nikkel SM, Philip N, Raas-Rothschild A, Sommer A, Verloes A, Walter C, Wieczorek D, Williams MS, Zackai E, Allanson JE (2005) Further delineation of Kabuki syndrome in 48 well-defined new individuals. Am J Med Genet A 132A:265–272
Chang PY, Hom RA, Musselman CA, Zhu L, Kuo A, Gozani O, Kutateladze TG, Cleary ML (2010) Binding of the MLL PHD3 finger to histone H3K4me3 is required for MLL-dependent gene transcription. J Mol Biol 400:137–144
Choufani S, Shuman C, Weksberg R (2010) Beckwith-Wiedemann syndrome. Am J Med Genet C Semin Med Genet 154C:343–354
Dodé C, Hardelin JP (2010) Clinical genetics of Kallmann syndrome. Ann Endocrinol (Paris) 71:149–157
Eggermann T, Begemann M, Spengler S, Schröder C, Kordass U, Binder G (2010) Genetic and epigenetic findings in Silver-Russel syndrome. Pediatr Endocrinol Rev 8:86–93
Fan Z, Yamaza T, Lee JS, Yu J, Wang S, Fan G, Shi S, Wang CY (2009) BCOR regulates mesenchymal stem cell function by epigenetic mechanisms. Nat Cell Biol 11:1002–1009
Francis J, Antzelevitch C (2005) Brugada syndrome. Int J Cardiol 101:173–178
Gibney ER, Nolan CM (2010) Epigenetics and gene expression. Heredity 105:4–13
Gilissen C, Arts HH, Hoischen A, Spruijt L, Mans DA, Arts P, van Lier B, Steehouwer M, van Reeuwijk J, Kant SG, Roepman R, Knoers NV, Veltman JA, Brunner HG (2010) Exome sequencing identifies WDR35 variants involved in Sensenbrenner syndrome. Am J Hum Genet 87:418–423
Ho HH, Eaves LC (1997) Kabuki make-up (Niikawa-Kuroki) syndrome: cognitive abilities and autistic features. Dev Med Child Neurol 39:487–490
Hoischen A, van Bon BW, Gilissen C, Arts P, van Lier B, Steehouwer M, de Vries P, de Reuver R, Wieskamp N, Mortier G, Devriendt K, Amorim MZ, Revencu N, Kidd A, Barbosa M, Turner A, Smith J, Oley C, Henderson A, Hayes IM, Thompson EM, Brunner HG, de Vries BB, Veltman JA (2010) De novo mutations of SETBP1 cause Schinzel-Giedion syndrome. Nat Genet 42:483–485
Issaeva I, Zonis Y, Rozovskaia T, Orlovsky K, Croce CM, Nakamura T, Mazo A, Eisenbach L, Canaani E (2007) Knockdown of ALR (MLL2) reveals ALR target genes and leads to alterations in cell adhesion and growth. Mol Cell Biol 27:1889–1903
Kalay E, Yigit G, Aslan Y, Brown KE, Pohl E, Bicknell LS, Kayserili H, Li Y, Tüysüz B, Nürnberg G, Kiess W, Koegl M, Baessmann I, Buruk K, Toraman B, Kayipmaz S, Kul S, Ikbal M, Turner DJ, Taylor MS, Aerts J, Scott C, Milstein K, Dollfus H, Wieczorek D, Brunner HG, Hurles M, Jackson AP, Rauch A, Nürnberg P, Karagüzel A, Wollnik B (2011) CEP152 is a genome maintenance protein disrupted in Seckel syndrome. Nat Genet 43:23–26
Kuroki Y, Suzuki Y, Chyo H, Hata A, Matsui I (1981) A new malformation syndrome of long palpebral fissures, large ears, depressed nasal tip, and skeletal anomalies associated with postnatal dwarfism and mental retardation. J Pediatr 99:570–573
Matsumoto N, Niikawa N (2003) Kabuki make-up syndrome: a review. Am J Med Genet 11:57–65
Ng SB, Buckingham KJ, Lee C, Bigham AW, Tabor HK, Dent KM, Huff CD, Shannon PT, Jabs EW, Nickerson DA, Shendure J, Bamshad MJ (2010a) Exome sequencing identifies the cause of a mendelian disorder. Nat Genet 42:30–35
Ng SB, Bigham AW, Buckingham KJ, Hannibal MC, McMillin MJ, Gildersleeve HI, Beck AE, Tabor HK, Cooper GM, Mefford HC, Lee C, Turner EH, Smith JD, Rieder MJ, Yoshiura K, Matsumoto N, Ohta T, Niikawa N, Nickerson DA, Bamshad MJ, Shendure J (2010b) Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome. Nat Genet 42:790–793
Niikawa N, Matsuura N, Fukushima Y, Ohsawa T, Kajiim T (1981) Kabuki make-up syndrome: a syndrome of mental retardation, unusual facies, large and protruding ears, and postnatal growth deficiency. J Pediatr 99:565–569
Niikawa N, Kuroki Y, Kajii T et al (1988) Kabuki makeup (Niikawa-Kuroki) syndrome: a study of 62 patients. Am J Med Genet 31:565–589
Paulussen AD, Stegmann AP, Blok MJ, Tserpelis D, Posma-Velter C, Detisch Y, Smeets EE, Wagemans A, Schrander JJ, van den Boogaard MJ, van der Smagt J, van Haeringen A, Stolte-Dijkstra I, Kerstjens-Frederikse WS, Mancini GM, Wessels MW, Hennekam RC, Vreeburg M, Geraedts J, de Ravel T, Fryns JP, Smeets HJ, Devriendt K, Schrander-Stumpel CT (2011) MLL2 mutation spectrum in 45 patients with Kabuki syndrome. Hum Mutat 32:E2018–E2025
Utine GE, Alanay Y, Aktaş D, Boduroğlu K, Alikaşifoğlu M, Tunçbilek E (2008) Kabuki syndrome and trisomy 10p. Genet Couns 19:291–300
Acknowledgments
We thank all family members who participated in this study and Karin Boss for critically reading the manuscript. This work was supported by the German Federal Ministry of Education and Research (BMBF) by grant number 01GM0880 (SKELNET) and 01GM0801 (E-RARE network CRANIRARE) to BW and 01GM0802 (E-RARE network CRANIRARE) to DW.
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Below is the link to the electronic supplementary material.
439_2011_1004_MOESM1_ESM.ppt
MLL2 mutations identified in patients with Kabuki syndrome. Electropherograms of identified heterozygous MLL2 mutations compared to wild-type sequences. The last-row cell of the right-most column shows the MLL variant identified in patient K1772 (PPT 555 kb)
Rights and permissions
About this article
Cite this article
Li, Y., Bögershausen, N., Alanay, Y. et al. A mutation screen in patients with Kabuki syndrome. Hum Genet 130, 715–724 (2011). https://doi.org/10.1007/s00439-011-1004-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00439-011-1004-y