Genetic and Phenotypic Spectrum of KMT2D Variants in Taiwanese Case Series of Kabuki Syndrome

doi:10.3390/diagnostics14161815

. 2024 Aug 20;14(16):1815.

doi: 10.3390/diagnostics14161815.

Genetic and Phenotypic Spectrum of KMT2D Variants in Taiwanese Case Series of Kabuki Syndrome

Chung-Lin Lee^{1

2

3

4

5}, Chih-Kuang Chuang^{6

7}, Ming-Ren Chen¹, Ju-Li Lin⁸, Huei-Ching Chiu¹, Ya-Hui Chang^{1

3}, Yuan-Rong Tu⁶, Yun-Ting Lo³, Hsiang-Yu Lin^{1

3

4

5

6

9}, Shuan-Pei Lin^{1

3

4

6

10}

Affiliations

¹ Department of Pediatrics, MacKay Memorial Hospital, Taipei 10449, Taiwan.
² Institute of Clinical Medicine, National Yang-Ming Chiao-Tung University, Taipei 112304, Taiwan.
³ Department of Rare Disease Center, MacKay Memorial Hospital, Taipei 10449, Taiwan.
⁴ Department of Medicine, Mackay Medical College, New Taipei City 25245, Taiwan.
⁵ Department of Nursing, Mackay Junior College of Medicine, Nursing and Management, Taipei 112021, Taiwan.
⁶ Division of Genetics and Metabolism, Department of Medical Research, MacKay Memorial Hospital, Taipei 10449, Taiwan.
⁷ College of Medicine, Fu-Jen Catholic University, New Taipei City 24205, Taiwan.
⁸ Division of Endocrine & Medical Genetics, Department of Pediatrics, Chang Gung Children's Medical Center, Chang Gung Memorial Hospital, Taoyuan 33378, Taiwan.
⁹ Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 40402, Taiwan.
¹⁰ Department of Infant and Child Care, National Taipei University of Nursing and Health Sciences, Taipei 11219, Taiwan.

PMID: 39202303
PMCID: PMC11353766
DOI: 10.3390/diagnostics14161815

Genetic and Phenotypic Spectrum of KMT2D Variants in Taiwanese Case Series of Kabuki Syndrome

Chung-Lin Lee et al. Diagnostics (Basel). 2024.

. 2024 Aug 20;14(16):1815.

doi: 10.3390/diagnostics14161815.

Authors

Affiliations

¹ Department of Pediatrics, MacKay Memorial Hospital, Taipei 10449, Taiwan.
² Institute of Clinical Medicine, National Yang-Ming Chiao-Tung University, Taipei 112304, Taiwan.
³ Department of Rare Disease Center, MacKay Memorial Hospital, Taipei 10449, Taiwan.
⁴ Department of Medicine, Mackay Medical College, New Taipei City 25245, Taiwan.
⁵ Department of Nursing, Mackay Junior College of Medicine, Nursing and Management, Taipei 112021, Taiwan.
⁶ Division of Genetics and Metabolism, Department of Medical Research, MacKay Memorial Hospital, Taipei 10449, Taiwan.
⁷ College of Medicine, Fu-Jen Catholic University, New Taipei City 24205, Taiwan.
⁸ Division of Endocrine & Medical Genetics, Department of Pediatrics, Chang Gung Children's Medical Center, Chang Gung Memorial Hospital, Taoyuan 33378, Taiwan.
⁹ Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 40402, Taiwan.
¹⁰ Department of Infant and Child Care, National Taipei University of Nursing and Health Sciences, Taipei 11219, Taiwan.

PMID: 39202303
PMCID: PMC11353766
DOI: 10.3390/diagnostics14161815

Abstract

Kabuki syndrome (KS) is a rare genetic disorder characterized by distinct facial features, intellectual disability, and multiple congenital anomalies. We conducted a comprehensive analysis of the genetic and phenotypic spectrum of KS in a Taiwanese patient group of 23 patients. KMT2D variants were found in 22 individuals, with missense (26.1%), nonsense (21.7%), and frameshift (17.4%) variants being the most prevalent. One patient had a KMT2D variant of uncertain significance. The most common clinical characteristics included distinct facial features (100%), intellectual disability (100%), developmental delay (95.7%), speech delay (78.3%), hypotonia (69.6%), congenital heart abnormalities (69.6%), and recurrent infections (65.2%). Other abnormalities included hearing loss (39.1%), seizures (26.1%), cleft palate (26.1%), and renal anomalies (21.7%). This study broadens the mutational and phenotypic spectrum of KS in the Taiwanese population, highlighting the importance of comprehensive genetic testing and multidisciplinary clinical evaluations for diagnosis and treatment.

Keywords: KMT2D; Kabuki syndrome; Taiwan; phenotypic heterogeneity.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

**Figure 1**
(a) The prevalence of *KMT2D* variants (16 variants) in Taiwanese patients with Kabuki syndrome. The bar graph illustrates the distribution of *KMT2D* variants in the study patient group. (b) Distribution of the pathogenicity classifications of *KMT2D* variants (16 variants) identified in the Taiwanese patient group. The pie chart illustrates the number of variants classified as pathogenic, likely pathogenic, and variants of uncertain significance (VUS). (c) Distribution of the different types of *KMT2D* variants (16 variants) identified in the Taiwanese patient group. The pie chart illustrates the proportion of missense, nonsense, frameshift, in-frame deletion, splicing, and gross deletion variants.

See this image and copyright information in PMC

References

1. Adam M.P., Banka S., Bjornsson H.T., Bodurtha J., Chudley A.E., Harris J., Kawame H., Lanpher B.C., Lindsley A.W., Merla G., et al. Kabuki syndrome: International consensus diagnostic criteria. J. Med. Genet. 2019;56:89–95. doi: 10.1136/jmedgenet-2018-105625. - DOI - PubMed
1. Usluer E., Sayın G.Y., Güneş N., Kasap B., Tüysüz B. Investigation of genetic and phenotypic heterogeneity in 37 Turkish patients with Kabuki and Kabuki-like phenotype. Am. J. Med. Genet. A. 2022;188:2976–2987. doi: 10.1002/ajmg.a.62944. - DOI - PubMed
1. 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;31:565–589. doi: 10.1002/ajmg.1320310312. - DOI - PubMed
1. 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;99:565–569. doi: 10.1016/S0022-3476(81)80255-7. - DOI - PubMed
1. Ng S.B., Bigham A.W., Buckingham K.J., Hannibal M.C., McMillin M.J., Gildersleeve H.I., Beck A.E., Tabor H.K., Cooper G.M., Mefford H.C., et al. Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome. Nat. Genet. 2010;42:790–793. doi: 10.1038/ng.646. - DOI - PMC - PubMed

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[1] Adam M.P., Banka S., Bjornsson H.T., Bodurtha J., Chudley A.E., Harris J., Kawame H., Lanpher B.C., Lindsley A.W., Merla G., et al. Kabuki syndrome: International consensus diagnostic criteria. J. Med. Genet. 2019;56:89–95. doi: 10.1136/jmedgenet-2018-105625. - DOI - PubMed

[2] Adam M.P., Banka S., Bjornsson H.T., Bodurtha J., Chudley A.E., Harris J., Kawame H., Lanpher B.C., Lindsley A.W., Merla G., et al. Kabuki syndrome: International consensus diagnostic criteria. J. Med. Genet. 2019;56:89–95. doi: 10.1136/jmedgenet-2018-105625. - DOI - PubMed

[3] Usluer E., Sayın G.Y., Güneş N., Kasap B., Tüysüz B. Investigation of genetic and phenotypic heterogeneity in 37 Turkish patients with Kabuki and Kabuki-like phenotype. Am. J. Med. Genet. A. 2022;188:2976–2987. doi: 10.1002/ajmg.a.62944. - DOI - PubMed

[4] Usluer E., Sayın G.Y., Güneş N., Kasap B., Tüysüz B. Investigation of genetic and phenotypic heterogeneity in 37 Turkish patients with Kabuki and Kabuki-like phenotype. Am. J. Med. Genet. A. 2022;188:2976–2987. doi: 10.1002/ajmg.a.62944. - DOI - PubMed

[5] 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;31:565–589. doi: 10.1002/ajmg.1320310312. - DOI - PubMed

[6] 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;31:565–589. doi: 10.1002/ajmg.1320310312. - DOI - PubMed

[7] 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;99:565–569. doi: 10.1016/S0022-3476(81)80255-7. - DOI - PubMed

[8] 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;99:565–569. doi: 10.1016/S0022-3476(81)80255-7. - DOI - PubMed

[9] Ng S.B., Bigham A.W., Buckingham K.J., Hannibal M.C., McMillin M.J., Gildersleeve H.I., Beck A.E., Tabor H.K., Cooper G.M., Mefford H.C., et al. Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome. Nat. Genet. 2010;42:790–793. doi: 10.1038/ng.646. - DOI - PMC - PubMed

[10] Ng S.B., Bigham A.W., Buckingham K.J., Hannibal M.C., McMillin M.J., Gildersleeve H.I., Beck A.E., Tabor H.K., Cooper G.M., Mefford H.C., et al. Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome. Nat. Genet. 2010;42:790–793. doi: 10.1038/ng.646. - DOI - PMC - PubMed

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Genetic and Phenotypic Spectrum of KMT2D Variants in Taiwanese Case Series of Kabuki Syndrome

Affiliations

Genetic and Phenotypic Spectrum of KMT2D Variants in Taiwanese Case Series of Kabuki Syndrome

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Abstract

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