- Case report
- Open Access
- Open Peer Review
Identification of novel KMT2D mutations in two Chinese children with Kabuki syndrome: a case report and systematic literature review
- Chengqi Xin†1,
- Chun Wang†2,
- Yachen Wang1,
- Jingyuan Zhao1,
- Liang Wang1,
- Runjie Li3 and
- Jing Liu1Email authorView ORCID ID profile
© The Author(s). 2018
- Received: 15 November 2017
- Accepted: 20 February 2018
- Published: 27 February 2018
Kabuki syndrome (KS) is a rare pediatric congenital disorder with multiple congenital anomalies and intellectual disabilities, which is inherited in an autosomal dominant manner. Mutations in KMT2D and KDM6A have been proven to be the primary cause in most cases of KS.
Here we report two Chinese boys with clinical features of KS referred to our hospital for clinical diagnosis. Next-generation sequencing was performed on MiSeq to analyze the genetic mutations in both patients. In both, two novel de novo mutations in KMT2D gene (c.5235delA, p.(A1746Lfs*39) and c.7048G > A, p.(Q2350*)) were detected, both of which were subsequently confirmed by the two-generation pedigree analysis based on Sanger sequencing. A systematic literature review of previously reported mutational spectrum of KMT2D was also conducted.
Two novel de novo mutations in KMT2D gene were identified and considered to be pathogenic in both of KS patients. Our data adds information to the growing knowledge on the mutational spectrum of KS.
- Kabuki syndrome
Kabuki syndrome (KS) (OMIM#147920), also previously known as Kabuki makeup syndrome, or Niikawa-Kuroki syndrome, first reported by Japanese researchers Kuroki  and Niikawa , is a congenital disorder with multiple congenital anomalies and intellectual disabilities . The cardinal diagnostic manifestations of KS include distinctive facial features, mild-to-moderate intellectual disability, skeletal anomalies, dermatoglyphic abnormalities, and postnatal growth deficiencies . The prevalence of this syndrome is estimated to be 1/86,000–1/32,000 .
It has been proved that KS is an autosomal dominant disorder and can be mainly caused by loss-of-function in two different genes-KMT2D and KDM6A. In 2010, KMT2D (NM_003482.3, formerly known as MLL2) was identified as the first causative gene in KS patients using whole-exome sequencing , which locates on chromosome 12q13. In 2012, KDM6A (NM_021140.3) was identified as the second causative gene in three KMT2D mutation-negative KS patients , which locates on chromosome Xp11.23. These two genes belong to a family of genes called chromatin-modifying enzymes, and act together in the epigenetic control of regulating a diverse set of gene transcriptions involved in embryogenesis and development [7, 8].
Cases of KS patients have been extensively reported from different parts all over the world during past years. However, there are only few cases from China. To the best of our knowledge, only 25 sporadic KS patients have been reported in China [9–18], in which 15 cases performed genetic analysis, including 14 cases with KMT2D mutation [15, 17] and 1 case with KDM6A mutation . Here, our present study reported two novel de novo mutations of KMT2D in two young Chinese boys with KS.
This study conformed to the Tenets of the Declaration of Helsinki and was approved by the Ethics Board of the First Affiliated Hospital of Dalian Medical University. The CARE guidelines were followed in reporting our cases. Written informed consents from both patients and their parents were obtained before collecting blood samples.
Patient 2 was the second child of healthy, non-consanguineous Chinese parents. There was also no family history of genetic disorder. He was born 40 weeks of gestation by spontaneous vaginal delivery and diagnosed as neonatal hypoglycemia and intrauterine infection. At 6 months of age, he visited our hospital due to motor developmental delay. He could not stand up and sit alone. He had distinctive facial appearance, long palpebral fissures with lateral eversion of the lower eyelids, arched eyebrows with laterally thinning eyebrows, depressed nasal tip, large ears, low hairline, and lower lip concave (Fig. 1b). He also had brachydactyly and prominent finger pads especially for the fifth finger and palm with a straight line across it, and sacral dimpling (Fig. 1d and f). He had joint hypermobility and hypotonia. The examination in blood routine, urine routine and abdominal ultrasound showed no apparent abnormality. Additionally, magnetic resonance imaging of brain suggested cerebellar vermis dysplasia, and urological ultrasound indicated incomplete cryptorchidism on the left side.
Summary of clinical and genotypic features of 2 Chinese children with KS
Age at diagnosis (months)
Elongated palpebral fissures
Eversion of the lateral third of the lower eyelid
Laterally sparse eyebrows
Depressed nasal tip
Spinal column abnormalities
Single palmar crease
Clinodactyly of fifth digits
Postnatal growth deficiency
Cerebellar vermis dysplasia
Peripheral blood sample was collected from both patients and genomic DNA was then extracted from blood with a QIAamp DNA Mini Kit (catalog no. 51304, QIAGEN). Library was constructed using TruSight One Sequencing Panel (Illumina, San Diego, CA, USA, which is the largest sequencing panel available and includes 4813 clinically relevant genes), and sequenced on MiSeq platform (Illumina). The sequence was analyzed using ANNOVAR , PolyPhen2 , Mutation-Taster , and various databases, including ClinVar, dbSNP, 1000 genomes, Exome Sequencing Project 6500, and HGMD (Human Gene Mutation Data), were used in our study for screening and annotation of gene variants in accordance with the American college of medical genetics and genomics guidelines . Furthermore, confirmation of the variants found in both patients and analysis of their parental samples were done by Sanger sequencing using standard procedures.
Kabuki syndrome is a rare congenital disease that is characterized by five cardinal manifestations. Its incidence rate is approximately 1 in 32,000 individuals; however, the rate may be underestimated because of misdiagnosis and missed diagnosis. Diagnosis of KS is mainly clinical, based on a combination of distinctive dysmorphic face, intellectual disability, and multiple congenital abnormalities. Our present study reports a new case of two young Chinese boys with KS, both of which were characterized by the most striking facial appearances, skeletal anomalies, visceral anomalies and postnatal growth deficiency. More specifically in detail for both patients, we observed the typical facial appearances, including long palpebral fissures with lateral eversion of the lower eyelids, arched eyebrows with laterally thinning, depressed nasal tip, lower lip concave, and large ears (Fig. 1a-b), and skeletal anomalies, referring to brachydactyly and prominent finger pads especially for the fifth finger and sacral dimpling (Fig. 1c-f), and visceral anomalies, especially for the urogenital system, one with ectopic kidney, and the other with incomplete cryptorchidism. Specially, patient 1 showed feeding difficulty and recurrent respiratory tract infection, and his motor delay was obviously backward. In addition, he had abnormal genitourinary system, urological ultrasound indicating his ectopic kidney, and abnormal dentitions, which are less frequently observed according to previous studies. Patient 2 had cerebellar vermis dysplasia and motor delay, and his urological ultrasound indicated incomplete cryptorchidism on the left side.
In our present study, one frameshift mutation in exon 22 (c.5235delA heterozygous mutation, p.(A1746Lfs*39)) and one nonsense mutation in exon 31 (c.7048G > A heterozygous mutation, p.(Q2350*)) were identified in KMT2D using next-generation sequencing. Considering that all the patients’ parents were not found to carry KMT2D mutations, so both the patients harbored two de novo genetic mutations. In summary, we identified two novel de novo KMT2D mutations in two Chinese boys with KS, which adds information to the growing knowledge on the mutational spectrum of KS.
We thank all the patients and their families for their collaboration in the study.
This study was funded by the National Nature Science Foundation of China (Grant No. 81471308) and National Health and Family Planning Commission of China and China Food and Drug Administration (Registration No. CMR-20161129-1003).
Availability of data and materials
The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.
CX and CW contributed equally as co-first authors. JL was the corresponding author. CX, CW and YW performed the mutational analysis and literature review. JZ and LW drafted the figures and revised the manuscript. YW, RL and JL participated in the clinical diagnosis. CX, CW and JL wrote the manuscript. All authors read and approved the finial manuscript.
Ethics approval and consent to participate
This study conformed to the Tenets of the Declaration of Helsinki and was approved by the Ethics Board of the First Affiliated Hospital of Dalian Medical University (FB-KY-2016-47). Informed consent form from the patients and their parents was obtained before collecting blood samples.
Consent for publication
Written informed consent was obtained from all patients and their parents for publication of this case report and any accompanying images.
The authors declare that they have no competing interests.
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- Kuroki Y, Suzuki Y, Chyo H, Hata A, Matsui I. 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. 1981;99(4):570–3.View ArticlePubMedGoogle Scholar
- Niikawa N, Matsuura N, Fukushima Y, Ohsawa T, Kajii T. Kabuki make-up syndrome: a syndrome of mental retardation, unusual facies, large and protruding ears, and postnatal growth deficiency. J Pediatr. 1981;99(4):565–9.View ArticlePubMedGoogle Scholar
- Verhagen JM, Oostdijk W, Terwisscha van Scheltinga CE, Schalij-Delfos NE, van Bever Y. An unusual presentation of kabuki syndrome: clinical overlap with CHARGE syndrome. Eur J Med Genet. 2014;57(9):510–2.View ArticlePubMedGoogle Scholar
- Niikawa N, Kuroki Y, Kajii T, Matsuura N, Ishikiriyama S, Tonoki H, Ishikawa N, Yamada Y, Fujita M, Umemoto H, et al. Kabuki make-up (Niikawa-Kuroki) syndrome: a study of 62 patients. Am J Med Genet. 1988;31(3):565–89.View ArticlePubMedGoogle Scholar
- Ng SB, Bigham AW, Buckingham KJ, Hannibal MC, McMillin MJ, Gildersleeve HI, Beck AE, Tabor HK, Cooper GM, Mefford HC, et al. Exome sequencing identifies MLL2 mutations as a cause of kabuki syndrome. Nat Genet. 2010;42(9):790–3.View ArticlePubMedPubMed CentralGoogle Scholar
- Lederer D, Grisart B, Digilio MC, Benoit V, Crespin M, Ghariani SC, Maystadt I, Dallapiccola B, Verellen-Dumoulin C. Deletion of KDM6A, a histone demethylase interacting with MLL2, in three patients with kabuki syndrome. Am J Hum Genet. 2012;90(1):119–24.View ArticlePubMedPubMed CentralGoogle Scholar
- FitzGerald KT, Diaz MO. MLL2: A new mammalian member of the trx/MLL family of genes. Genomics. 1999;59(2):187–92.View ArticlePubMedGoogle Scholar
- Aziz A, Liu QC, Dilworth FJ. Regulating a master regulator: establishing tissue-specific gene expression in skeletal muscle. Epigenetics. 2010;5(8):691–5.View ArticlePubMedPubMed CentralGoogle Scholar
- Ma KH, Chow SN, Yau FT. Isolated adrenocorticotropin deficiency in a child with kabuki syndrome. J Pediatr Endocrinol Metab. 2005;18(6):607–9.View ArticlePubMedGoogle Scholar
- Jiang YQ, Cao YH, Sun JF. Kabuki syndrome one case report. Chin J Dermatol. 2000;33(2):132.Google Scholar
- Atar M, Lee W, O'Donnell D. Kabuki syndrome: oral and general features seen in a 2-year-old Chinese boy. Int J Paediatr Dent. 2006;16(3):222–6.View ArticlePubMedGoogle Scholar
- Yang XJ, Zeng Y, Xiong F. Kabuki syndrome case report. Zhonghua Er Ke Za Zhi. 2010;48(11):868–70.PubMedGoogle Scholar
- Huang HQ, Gong GS. Four cases of kabuki make-up syndrome. Chin J Clinicians( Electronic Edition). 2013;7(2):857–8.Google Scholar
- Lu Y, Cao KL. A case report: hearing disorder in kabuki make-up (Niikawa-Kuroki) syndrome in China. Journal of Otology. 2014;9:136–40.View ArticleGoogle Scholar
- Liu S, Hong X, Shen C, Shi Q, Wang J, Xiong F, Qiu Z. Kabuki syndrome: a Chinese case series and systematic review of the spectrum of mutations. BMC Med Genet. 2015;16:26.View ArticlePubMedPubMed CentralGoogle Scholar
- Yang P, Tan H, Xia Y, Yu Q, Wei X, Guo R, Peng Y, Chen C, Li H, Mei L, et al. De novo exonic deletion of KDM6A in a Chinese girl with kabuki syndrome: a case report and brief literature review. Am J Med Genet A. 2016;170(6):1613–21.View ArticlePubMedGoogle Scholar
- Wu BB, Su YJ, Wang HJ, Zhang P, Li L, Zhou WH. Report of 6 kabuki syndrome cases caused by KMT2D gene mutation and literature review. Chin J Evid Based Pediatr. 2017;12(2):135–9.Google Scholar
- Wang LC, Chiu I, Wang PJ, Wu MH, Wang JK, Hung Y. Kabuki make-up syndrome associated with congenital heart disease. Zhonghua Min Guo Xiao Er Ke Yi Xue Hui Za Zhi. 1994;35(1):63–9.PubMedGoogle Scholar
- Wang K, Li M, Hakonarson H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 2010;38(16):e164.View ArticlePubMedPubMed CentralGoogle Scholar
- Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR. A method and server for predicting damaging missense mutations. Nat Methods. 2010;7(4):248–9.View ArticlePubMedPubMed CentralGoogle Scholar
- Schwarz JM, Cooper DN, Schuelke M, Seelow D. MutationTaster2: mutation prediction for the deep-sequencing age. Nat Methods. 2014;11(4):361–2.View ArticlePubMedGoogle Scholar
- Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, et 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. 2015;17(5):405–24.View ArticlePubMedPubMed CentralGoogle Scholar
- Banka S, Veeramachaneni R, Reardon W, Howard E, Bunstone S, Ragge N, Parker MJ, Crow YJ, Kerr B, Kingston H, et al. How genetically heterogeneous is kabuki syndrome?: MLL2 testing in 116 patients, review and analyses of mutation and phenotypic spectrum. Eur J Hum Genet. 2012;20(4):381–8.View ArticlePubMedGoogle Scholar
- Bogershausen N, Gatinois V, Riehmer V, Kayserili H, Becker J, Thoenes M, Simsek-Kiper PO, Barat-Houari M, Elcioglu NH, Wieczorek D, et al. Mutation update for kabuki syndrome genes KMT2D and KDM6A and further delineation of X-linked kabuki syndrome subtype 2. Hum Mutat. 2016;37(9):847–64.View ArticlePubMedGoogle Scholar