Update of the genotype and phenotype of KMT2D and KDM6A by genetic screening of 100 patients with clinically suspected Kabuki syndrome.
Abnormalities, Multiple
/ epidemiology
Adolescent
Adult
DNA-Binding Proteins
/ genetics
Face
/ abnormalities
Female
Genetic Heterogeneity
Genetic Predisposition to Disease
Genetic Testing
/ methods
Genotype
Hematologic Diseases
/ complications
Histone Demethylases
/ genetics
Humans
Male
Mutation
Neoplasm Proteins
/ genetics
Phenotype
Uterine Cervical Neoplasms
/ complications
Vestibular Diseases
/ complications
Young Adult
Kabuki syndrome
blended phenotype
deep splicing variant
malignancy
mosaicism
Journal
American journal of medical genetics. Part A
ISSN: 1552-4833
Titre abrégé: Am J Med Genet A
Pays: United States
ID NLM: 101235741
Informations de publication
Date de publication:
10 2020
10 2020
Historique:
received:
26
03
2020
revised:
05
06
2020
accepted:
23
06
2020
pubmed:
18
8
2020
medline:
2
6
2021
entrez:
18
8
2020
Statut:
ppublish
Résumé
Kabuki syndrome is characterized by a variable degree of intellectual disability, characteristic facial features, and complications in various organs. Many variants have been identified in two causative genes, that is, lysine methyltransferase 2D (KMT2D) and lysine demethylase 6A (KDM6A). In this study, we present the results of genetic screening of 100 patients with a suspected diagnosis of Kabuki syndrome in our center from July 2010 to June 2018. We identified 76 variants (43 novel) in KMT2D and 4 variants (3 novel) in KDM6A as pathogenic or likely pathogenic. Rare variants included a deep splicing variant (c.14000-8C>G) confirmed by RNA sequencing and an 18% mosaicism level for a KMT2D mutation. We also characterized a case with a blended phenotype consisting of Kabuki syndrome, osteogenesis imperfecta, and 16p13.11 microdeletion. We summarized the clinical phenotypes of 44 patients including a patient who developed cervical cancer of unknown origin at 16 years of age. This study presents important details of patients with Kabuki syndrome including rare clinical cases and expands our genetic understanding of this syndrome, which will help clinicians and researchers better manage and understand patients with Kabuki syndrome they may encounter.
Identifiants
pubmed: 32803813
doi: 10.1002/ajmg.a.61793
doi:
Substances chimiques
DNA-Binding Proteins
0
KMT2D protein, human
0
Neoplasm Proteins
0
Histone Demethylases
EC 1.14.11.-
KDM6A protein, human
EC 1.14.11.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2333-2344Informations de copyright
© 2020 Wiley Periodicals LLC.
Références
Adam, M. P., Banka, S., Bjornsson, H. T., Bodamer, O., Chudley, A. E., Harris, J., … Niikawa, N. (2019). Kabuki syndrome: International consensus diagnostic criteria. Journal of Medical Genetics, 56(2), 89-95. https://doi.org/10.1136/jmedgenet-2018-105625
Aref-Eshghi, E., Rodenhiser, D. I., Schenkel, L. C., Lin, H., Skinner, C., Ainsworth, P., … Sadikovic, B. (2018). Genomic DNA Methylation Signatures Enable Concurrent Diagnosis and Clinical Genetic Variant Classification in Neurodevelopmental Syndromes. The American Journal of Human Genetics, 102(1), 156-174. http://dx.doi.org/10.1016/j.ajhg.2017.12.008.
Banka, S., Howard, E., Bunstone, S., Chandler, K. E., Kerr, B., Lachlan, K., … Donnai, D. (2013). MLL2 mosaic mutations and intragenic deletion-duplications in patients with kabuki syndrome. Clinical Genetics, 83(5), 467-471. https://doi.org/10.1111/j.1399-0004.2012.01955.x
Banka, S., Veeramachaneni, R., Reardon, W., Howard, E., Bunstone, S., Ragge, N., … Donnai, D. (2012). How genetically heterogeneous is kabuki syndrome: MLL2 testing in 116 patients, review and analyses of mutation and phenotypic spectrum. European Journal of Human Genetics, 20(4), 381-388. https://doi.org/10.1038/ejhg.2011.220
Bögershausen, N., Gatinois, V., Riehmer, V., Kayserili, H., Becker, J., Thoenes, M., … Wollnik, B. (2016). Mutation update for kabuki syndrome genes KMT2D and KDM6A and further delineation of X-linked kabuki syndrome subtype 2. Human Mutation, 37(9), 847-864. https://doi.org/10.1002/humu.23026
Casanova, M., Selicorni, A., & Ferrari, A. (2011). Cancer predisposition in children with kabuki syndrome. American Journal of Medical Genetics, Part A, 155(6), 1504-1504. https://doi.org/10.1002/ajmg.a.33711
Cocciadiferro, D., Augello, B., De Nittis, P., Zhang, J., Mandriani, B., Malerba, N., … Merla, G. (2018). Dissecting KMT2D missense mutations in kabuki syndrome patients. Human Molecular Genetics, 27(21), 3651-3668. https://doi.org/10.1093/hmg/ddy241
Dentici, M. L., Di Pede, A., Lepri, F. R., Gnazzo, M., Lombardi, M. H., Auriti, C., … Dallapiccola, B. (2015). Kabuki syndrome: clinical and molecular diagnosis in the first year of life. Archives of Disease in Childhood, 100(2), 158-164. http://dx.doi.org/10.1136/archdischild-2013-305858.
Digilio, M. C., Gnazzo, M., Lepri, F., Dentici, M. L., Pisaneschi, E., Baban, A., … Dallapiccola, B. (2017). Congenital heart defects in molecularly proven kabuki syndrome patients. American Journal of Medical Genetics, Part A, 173(11), 2912-2922. https://doi.org/10.1002/ajmg.a.38417
Enomoto, Y., Tsurusaki, Y., Harada, N., Aida, N., & Kurosawa, K. (2018). Novel AMER1 frameshift mutation in a girl with osteopathia striata with cranial sclerosis. Congenital Anomalies, 10069, 145-146. https://doi.org/10.1111/cga.12258
Faundes, V., Malone, G., Newman, W. G., & Banka, S. (2019). A comparative analysis of KMT2D missense variants in Kabuki syndrome, cancers and the general population. Journal of Human Genetics, 64, 161-170. https://doi.org/10.1038/s10038-018-0536-6
Frans, G., Meyts, I., Devriendt, K., Liston, A., Vermeulen, F., & Bossuyt, X. (2016). Mild humoral immunodeficiency in a patient with X-linked Kabuki syndrome. American Journal of Medical Genetics Part A, 170(3), 801-803. http://dx.doi.org/10.1002/ajmg.a.37499.
Hannes, F. D., Sharp, A. J., Mefford, H. C., De Ravel, T., Ruivenkamp, C. A., Breuning, M. H., … Vermeesch, J. R. (2009). Recurrent reciprocal deletions and duplications of 16p13.11: The deletion is a risk factor for MR/MCA while the duplication may be a rare benign variant. Journal of Medical Genetics, 46, 223-232. https://doi.org/10.1136/jmg.2007.055202
Hannibal, M. C., Buckingham, K. J., Ng, S. B., Ming, J. E., Anita, E., Mcmillin, M. J., … Naritomi, K. (2011). Spectrum of MLL2 (ALR) mutations in 110 cases of kabuki syndrome. American Journal of Medical Genetics, Part A, 155(7), 1511-1516. https://doi.org/10.1002/ajmg.a.34074
Ijichi, O., Kawakami, K., Matsuda, Y., Ikarimoto, N., Miyata, K., Takamatsu, H., & Tokunaga, M. (1996). A case of kabuki make-up syndrome with EBV+ Burkitt's lymphoma. Pediatrics International, 38(1), 66-68. https://doi.org/10.1111/j.1442-200X.1996.tb03439.x
Karaca, E., Posey, J. E., Coban Akdemir, Z., Pehlivan, D., Harel, T., Jhangiani, S. N., … Lupski, J. R. (2018). Phenotypic expansion illuminates multilocus pathogenic variation. Genetics in Medicine, 20(12), 1528-1537. https://doi.org/10.1038/gim.2018.33
Karagianni, P., Lambropoulos, V., Stergidou, D., Fryssira, H., Chatziioannidis, I., & Spyridakis, I. (2016). Recurrent giant cell fibroblastoma: Malignancy predisposition in kabuki syndrome revisited. American Journal of Medical Genetics, Part A, 170(5), 1333-1338. https://doi.org/10.1002/ajmg.a.37584
Kokitsu-Nakata, N. M., Petrin, A. L., Heard, J. P., Vendramini-Pittoli, S., Henkle, L. E., dos Santos, D. V. C., … Richieri-Costa, A. (2012). Analysis ofMLL2gene in the first Brazilian family with Kabuki syndrome. American Journal of Medical Genetics Part A, 158A(8), 2003-2008. http://dx.doi.org/10.1002/ajmg.a.35454.
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. The Journal of Pediatrics, 99(4), 570-573. https://doi.org/10.1016/S0022-3476(81)80256-9
Lederer, D., Grisart, B., Digilio, M. C., Benoit, V., Crespin, M., Ghariani, S. C., … Verellen-Dumoulin, C. (2012). Deletion of KDM6A, a histone demethylase interacting with MLL2, in three patients with kabuki syndrome. American Journal of Human Genetics, 90(1), 119-124. https://doi.org/10.1016/j.ajhg.2011.11.021
Lepri, F. R., Cocciadiferro, D., Augello, B., Alfieri, P., Pes, V., Vancini, A., … Merla, G. (2017). Clinical and neurobehavioral features of three novel kabuki syndrome patients with mosaic KMT2D mutations and a review of literature. International Journal of Molecular Sciences, 19(1), 82. https://doi.org/10.3390/ijms19010082
Liu, S., Hong, X., Shen, C., Shi, Q., Wang, J., Xiong, F., & Qiu, Z. (2015). Kabuki syndrome: a Chinese case series and systematic review of the spectrum of mutations. BMC Medical Genetics, 16(1). http://dx.doi.org/10.1186/s12881-015-0171-4.
Makrythanasis, P., van Bon, B. W., Steehouwer, M., Rodríguez-Santiago, B., Simpson, M., Dias, P., … Hoischen, A. (2013). MLL2mutation detection in 86 patients with Kabuki syndrome: a genotype-phenotype study. Clinical Genetics, 84(6), 539-545. http://dx.doi.org/10.1111/cge.12081.
Merks, J. H. M., Caron, H. N., & Hennekam, R. C. M. (2005). High incidence of malformation syndromes in a series of 1,073 children with cancer. American Journal of Medical Genetics, 134(A(2)), 132-143. https://doi.org/10.1002/ajmg.a.30603
Micale, L., Augello, B., Fusco, C., Selicorni, A., Loviglio, M., Silengo, M., … Merla, G. (2011). Mutation spectrum of MLL2 in a cohort of kabuki syndrome patients. Orphanet Journal of Rare Diseases, 6(1), 1-8. https://doi.org/10.1186/1750-1172-6-38
Miyake, N., Koshimizu, E., Okamoto, N., Mizuno, S., Ogata, T., Nagai, T., … Niikawa, N. (2013). MLL2 and KDM6A mutations in patients with kabuki syndrome. American Journal of Medical Genetics, Part A, 161(9), 2234-2243. https://doi.org/10.1002/ajmg.a.36072
Ng, S. B., Bigham, A. W., & Shendure, J. (2010). Exome sequencing identifies MLL2 mutations as a cause of kabuki syndrome. Nature Genetics, 42(9), 790-793. https://doi.org/10.1038/ng.646
Niikawa, N., Kuroki, Y., Kajii, T., Matsuura, N., Ishikiriyama, S., Tonoki, H., … Reynolds, J. F. (1988). Kabuki make-up (Niikawa-Kuroki) syndrome: A study of 62 patients. American Journal of Medical Genetics, 31(3), 565-589. http://dx.doi.org/10.1002/ajmg.1320310312.
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. The Journal of Pediatrics, 99(4), 565-569. https://doi.org/10.1016/S0022-3476(81)80255-7
Paulussen, A. D. C., Stegmann, A. P. A., Blok, M. J., Tserpelis, D., Posma-Velter, C., Detisch, Y., … Schrander-Stumpel, C. T. R. M. (2011). MLL2 mutation spectrum in 45 patients with kabuki syndrome. Human Mutation, 32(2), 2018-2025. https://doi.org/10.1002/humu.21416
Posey, J. E., Harel, T., Liu, P., Rosenfeld, J. A., James, R. A., Coban Akdemir, Z. H., … Lupski, J. R. (2017). Resolution of disease phenotypes resulting from multilocus genomic variation. New England Journal of Medicine, 376(1), 21-31. https://doi.org/10.1056/NEJMoa1516767
Richards, L. S., Aziz, N., Bale, S., Bick, D., Das, S. P., Gastier-Foster, J., … Rehm, H. L. (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. Genetics in Medicine, 17(5), 405-424. https://doi.org/10.1038/gim.2015.30
Roma, D., Palma, P., Capolino, R., Figà-Talamanca, L., Diomedi-Camassei, F., Lepri, F. R., … Mastronuzzi, A. (2015). Spinal ependymoma in a patient with kabuki syndrome: A case report. BMC Medical Genetics, 16(1), 1-4. https://doi.org/10.1186/s12881-015-0228-4
Scherer, S., Theile, U., Beyer, V., Ferrari, R., Kreck, C., & Rister, M. (2003). Patient with kabuki syndrome and acute leukemia. American Journal of Medical Genetics, 122A, 76-79. https://doi.org/10.1002/ajmg.a.20261
Shahdadpuri, R., O'Meara, A., O'Sullivan, M., & Reardon, W. (2008). Low-grade fibromyxoid sarcoma: Yet another malignancy associated with kabuki syndrome. Clinical Dysmorphology, 17(3), 199-202. https://doi.org/10.1097/MCD.0b013e3282f5f4e3
Tanaka, R., Takenouchi, T., Uchida, K., Sato, T., Fukushima, H., Yoshihashi, H., … Kosaki, K. (2012). Congenital corneal staphyloma as a complication of Kabuki syndrome. American Journal of Medical Genetics Part A, 158A(8), 2000-2002. http://dx.doi.org/10.1002/ajmg.a.35453.
Teranishi, H., Koga, Y., Nakashima, K., Morihana, E., Ishii, K., Sakai, Y., … Ohga, S. (2018). Cancer management in kabuki syndrome: The first case of wilms tumor and a literature review. Journal of Pediatric Hematology/Oncology, 40(5), 391-394. https://doi.org/10.1097/MPH.0000000000001111
Tumino, M., Licciardello, M., Sorge, G., Cutrupi, M. C., Di Benedetto, F., Amoroso, L., … Di Cataldo, A. (2010). Kabuki syndrome and cancer in two patients. American Journal of Medical Genetics, Part A, 152(6), 1536-1539. https://doi.org/10.1002/ajmg.a.33405
Uehara, T., Tsuchihashi, T., Yamada, M., Suzuki, H., Takenouchi, T., & Kosaki, K. (2019). CNOT2 haploinsufficiency causes a neurodevelopmental disorder with characteristic facial features. American Journal of Medical Genetics, Part A, 179(12), 2506-2509. https://doi.org/10.1002/ajmg.a.61356
Xiao, B., Qiu, W., Ji, X., Liu, X., Huang, Z., Liu, H., … Sun, Y. (2018). Marked yield of re-evaluating phenotype and exome/target sequencing data in 33 individuals with intellectual disabilities. American Journal of Medical Genetics Part A, 176(1), 107-115. http://dx.doi.org/10.1002/ajmg.a.38542.