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Kabuki syndrome: novel pathogenic variants, new phenotypes and review of literature

  • Huakun Shangguan
  • Chang Su
  • Qian Ouyang
  • Bingyan Cao
  • Jian Wang
  • Chunxiu GongEmail author
  • Ruimin ChenEmail author
Open Access
Research
Part of the following topical collections:
  1. Rare Diseases in Asia
  2. Clinical genetics and genomics

Abstract

Objective

This study describes 5 novel variants of 7 KMT2D/KDM6A gene and summarizes the clinical manifestations and the mutational spectrum of 47 Chinese Kabuki syndrome (KS) patients.

Methods

Blood samples were collected for whole-exome sequencing (WES) for 7 patients and their parents if available. Phenotypic and genotypic spectra of 40 previously published unrelated Chinese KS patients were summarized.

Result

Genetic sequencing identified six KMT2D variants (c.3926delC, c.5845delC, c.6595delT, c.12630delG, c.16294C > T, and c.16442delG) and one KDM6A variant (c.2668-2671del). Of them, 4 variants (c.3926delC, c.5845delC, c.12630delG, and c.16442delG) in KMT2D gene and the variant (c.2668-2671del) in KDM6A gene were novel. Combining with previously published Chinese KS cases, the patients presented with five cardinal manifestations including facial dysmorphism, intellectual disability, growth retardation, fingertip pads and skeletal abnormalities. In addition, 29.5% (5/17) patients had brain abnormalities, such as hydrocephalus, cerebellar vermis dysplasia, thin pituitary and white matter myelination delay, corpus callosum hypoplasia and Dandy-Walker malformation.

Conclusion

In this report, five novel variants in KMT2D/KDM6A genes are described. A subset of Chinese KS patients presented with brain abnormalities that were not previously reported. Our study expands the mutational and phenotypic spectra of KS.

Keywords

Kabuki syndrome KMT2D KDM6A Chinese patients Brain abnormalities 

Abbreviations

ACMG/AMP

American College of Medical Genetics and Genomics and the Association for Molecular Pathology

KDM6A

lysine (K)-specific methylase 6A

KMT2D

lysine (K)-specific methyltransferase 2D

KS

Kabuki syndrome

WES

whole-exome sequencing

Introduction

Kabuki syndrome (KS, OMIM#147920) is a rare syndrome with multiple congenital anomalies. It was first reported by Japanese researchers Kuroki and Niikawa [1, 2]. KS is a heterogeneous condition, two causative genes having been identified so far. The causative gene of KS was identified in 2010 when Bögershausen et al. [3] reported de novo heterozygous variants in KMT2D gene, which is located on chromosome 12q13. Later, in 2012, variants in the KDM6A gene, which is located on chromosome Xp11.23, were identified as another causative gene for KS [4].

Consistent features of KS included distinctive facial dysmorphism (long palpebral fissures, depressed nasal tip and large ears), short stature, intellectual disability, skeletal abnormalities and dermatoglypic abnormalities. Other recurrent features such as congenital cardiac anomalies, ureter malformation and hip joint dislocation had been reported in non-Chinese KS patients [5]. In addition, uncommon features had also been reported. Topcu et al. reported perisylvian cortical dysplasia in a KS patient from Turkey [6]. However, there is little information about brain abnormalities in KS patients.

Herein, we analyzed 7 patients, and identified 7 deleterious KMT2D/KDM6A variants including 6 truncating and 1 missense variants. Of them, 5 variants were novel. To date, 40 sporadic Chinese KS patients had been reported [7, 8, 9, 10, 11, 12, 13, 14, 15]. We evaluated the phenotype spectra of all Chinese KS patients and paid particular attention to the brain abnormalities among a total of 47 unrelated Chinese KS patients.

Subjects and methods

Subjects

Seven patients with clinical presentation of Kabuki syndrome were enrolled from Fuzhou Children’s Hospital of Fujian and Beijing Children’s Hospital, China. This study was approved by the Ethics Committee of Fuzhou Children’s Hospital of Fujian, and written informed consents were obtained from the participants’ legal guardians.

Whole-exome sequencing and variants interpretation

Genomic DNA was extracted from peripheral blood leukocytes of each patient. Blood samples from the parents were also collected if available. The whole-exome sequencing (WES) was performed at Shanghai Children’s Medical Center and MyGenostics, Beijing, China. An adaptor-ligated library was prepared using SureSelect Human All Exon Kit (Agilent Technologies, Santa Clara, America) according to the manufacturer’s protocol. Target regions were sequenced on an Illumina Hiseq X Ten System (Illumina, San Diego, America). Paired end reads were aligned to the GRCh37/hg19 human reference sequence. BAM files were generated by Picard and sequence variants were called by Genome Analysis Toolkit (GATK) Haplotype Caller.

Variants were annotated by TGex and putative pathogenic variants detected in the patients by WES were validated by Sanger sequencing. Variants were classified following the ACMG/AMP standards and guidelines [16].

Results

Clinical manifestations of seven Chinese patients with KS

We enrolled 7 patients with clinical diagnosis of KS (three males and four females). The age of initial diagnosis ranged from 7 days to 3.2 years. These patients exhibited a diverse phenotype. The clinical features of the seven Chinese patients are listed in Table 1. The main characteristics were as following: facial dysmorphism (n = 7), cardiac abnormalities (n = 6), intellectual disability (n = 5), short stature (n = 4), skeletal abnormalities (n = 3), hearing impairment (n = 3) and dermatoglypic abnormalities (n = 2).
Table 1

Phenotypic summary of Chinese KS patients

Patient

1

2

3

4

5

6

7

Literature (N = 40)

Chinese cohort (N = 47)

Non-Chinese cohort (N = 86) (Ref. 17)

Gender

Female

Female

Male

Female

Male

Male

Female

   

Age of diagnosis

1.3 yrs

11 Months

5 Months

7d

7 yrs

2.6 Months

3.2 yrs

   

Growth

 Short stature

+

+

+

+

23

57.4%

57%

Neurological abnormalities

 Intellectual disability

+

+

NA

+

+

+

32

80.4%

90%

 Seizures

4

8.5%

15%

 Cerebellar vermis dysplasia

1

2.1%

 

 Corpus callosum hypoplasia

1

2.1%

 

 Dany-Walker malformation

1

2.1%

 

 Thinning of pituitary

+

0

2.1%

 

 Delay myelination of cerebral

+

0

2.1%

 

 Hydrocephalus

1

2.1%

 

Craniofacial features

 Microcephaly

+

+

3

10.6%

41%

 Micrognathia

3

6.3%

39%

 High forehead and hairline

+

0

2.1%

 

 Low hairline

+

2

6.3%

 

 Hypertelorism

+

+

8

21.2%

 

 Epicanthus

+

8

19.1%

 

 Long palpebral fissures

+

+

+

15

38.2%

99%

 Strabismus

1

2.1%

37%

 Eversion of lateral third of lower eyelids

+

+

+

+

14

38.2%

87%

 Long eyelashes

+

+

9

23.9%

 

 Arched eyebrows

+

+

2

8.7%

 

 Sparse eyebrows

+

+

18

42.5%

 

 Depressed nasal tip

+

+

+

+

29

70.2%

80%

 Wide nasal bridge

+

+

+

7

21.9%

 

 A displastic ear

+

3

8.7%

 

 Large ears

+

+

+

29

68.0%

79%

 High-arched/cleft palate

+

+

+

24

57.4%

66%

 Thin upper vermillion

+

+

+

2

10.6%

76%

 Abnormal dentition

5

10.6%

51%

Congenital heart defect

+

+

+

+

+

+

14

42.6%

42%

 Aortic coartation

+

1

4.3%

 

 Atrial septal defect

+

+

+

+

6

21.7%

 

 Ventricular septal defects

+

+

+

+

6

21.7%

 

 Patent ductus arteriosus

+

+

1

6.5%

 

 Patent foramen ovale

+

+

+

+

+

5

21.7%

 

 Aortic arch dysplasia

+

0

2.2%

 

Internal organ problem

 Feeding difficulties

+

3

8.5%

 

 Anal atresia

+

3

8.5%

 

 Bilateral inguinal hernia

2

4.2%

 

 Splenomegaly

+

1

4.2%

 

 Cryptorchidism

1

2.%

 

 Hearing impairment

+

+

+

13

34.0%

25%

 Otitis media

+

12

27.6%

 

 Cholesteatoma

+

2

6.4%

 

 Cochlear dysplasia

+

0

2.1%

 

 Renal/ureter malformation

+

+

+

2

10.6%

40%

Musculoskeletal features

 Hip joint dislocation

+

+

9

23.4%

26%

 Right diaphyseal femoral fracture

+

0

2.1%

 

 Fifth finger clinodactyly

+

22

48.9%

84%

 Absent palmer transverse crease

+

5

12.7%

 

 Fingertip pads

+

24

53.2%

89%

Endocrine

 Hypoglycemia

+

+

2

8.5%

7–8%

 Early breast development

 

+

1

4.2%

28%

Pathogenic variants in KMT2D and KDM6A

By WES, we identified six variants (c.3926delC/p.P1309Qfs*21, c.5845delC/p.Q1949Sfs*98, c.6595delT/p.Y2199Ifs*65, c.12630delG/p.Q4210fs*5, c.16294C > T/p.R5432W and c.16442delG/p.C5481Lfs*6) in exon 12, 27, 31, 39, 51 and 52 of KMT2D gene (NM_003482.3), respectively, and one variant (c.2668-2671del) in exon 18 of KDM6A gene (NM_021140.3). The variants identified (c.5845delC, c.2668-2671del and c.12630delG) in 3 patients were confirmed by Sanger sequencing, and they were absent from their parents. The other 4 patients’ parental DNA were not available for genetic testing. Four variants (c.3926delC, c.5845delC, c.12630delG and c.16442delG in KMT2D gene, and the variant in KDM6A gene) were novel. Those 6 frameshift variants were predicted to lead to nonsense-mediated decay of mRNA. These null variants can all be classified as pathogenic according to the ACMG/AMP standards and guidelines (c.3926delC, c.5845delC, c.6595delT, c.12630delG, c.16442delG and c.2668-2671del). The remaining missense variant c.16294C > T; p.R5432W in KMT2D gene has been previously reported [17]. The variant c.16294C > T; p.R5432W was predicted to be deleterious by multiple in silico software, including SIFT (damaging), PolyPhen-2 (probably damaging), MutationTaster (disease causing), PROVEAN (deleterious), and CADD (damaging). Therefore, it can be considered to be likely pathogenic.

Phenotypic spectrum of 47 Chinese KS patients

Forty Chinese patients had been previously reported with KMT2D/KDM6A mutations. With the new 7 patients adding, we summarized the phenotypic features of a total of 47 Chinese KS patients (Table 1). The major clinical signs were as following: facial dysmorphisms (47/47; 100%), intellectual disability (36/45; 80%), short stature (27/47; 57.4%) patients, fingertip pads (25/47; 53.1%), finger clinodactyly (23/47; 48.9%), 5th finger clinodactyly (23/47; 48.9%), congenital cardiac anomalies (20/47; 42.5%) and hip joint dislocation (11/47; 23.4%). Additionally, brain imaging datasets were available for 17 patients and five patients (5/17, 29.4%) exhibited disparate brain anomalies.

Discussion

The genotypic spectrum of 47 Chinese KS patients (23 females, 24 males, 3 are sibs), including 42 KMT2D variants and 3 KDM6A variants were summarized (Table 2). Of the 42 KMT2D variants, there are 1 splicing, 1 non-frameshift indel, 10 nonsense, 13 frameshift and 17 missense variants. All of the nonsense and frameshift variants were categorized as pathogenic because the protein structure was significantly altered. We used silico prediction models including PolyPhen-2, PROVEAN, MutationTaster to analyze the missense variants. Two missense variants (c.7130C > T and c.11638C > A) are predicted to be benign, neutral or polymorphism by at least two of the three silico prediction models. The pathogenicity of the two variants (c.7130C > T and c.11638C > A) was inconclusive and could potentially be non-pathogenic according ACMG/AMP standards and guidelines. The p.R5432W variant was most common, observed in 3 unrelated patients (P2, P28 and P46), which may be a hot spot for KMT2D gene variation in Chinese Patients. Thirty four KMT2D variants and 3 KDM6A variants were confirmed by Sanger sequencing. Of them, 2 variants (c.16273C > A and c.7130 C > T) in KMT2D gene were inherited from their respective biological father, and 1 variant (c.335-1G > T) in KDM6A were inherited from mother, whereas the other 34 variants were de novo.
Table 2

Genotypic summary of Chinese KS patients

Case ID

Literature

Genes involve

Mutation

Preticted protein changes

Type of mutation

Inheritance

Exon

Pathogenic classification

1

This study

KMT2D

c.5845delC

p.Q1949Sfs*98

Frameshift del

De novo

27

Pathogenic

2

KMT2D

c.16294C > T

p.R5432W

Missense

NA

51

Likely Pathogenic

3

KDM6A

c.2668-2671del

p.N891Vfs*27

Frameshift del

De novo

18

Pathogenic

4

KMT2D

c.6595delT

p.Y2199Ifs*65

Frameshift del

NA

31

Pathogenic

5

KMT2D

c.16442delG

p.C5481Lfs*6

Frameshift del

NA

52

Pathogenic

6

KMT2D

c.3926delC

p.P1309Qfs*21

Frameshift del

NA

12

Pathogenic

7

KMT2D

c.12630delG

p.Q4210fs*5

Frameshift del

De novo

39

Pathogenic

8

[7] Liu S, et al. BMC Med Genet. 2015, 16:26.

KMT2D

c.12199C > T

p.P4067Sr

Missense

De novo

39

Likely Pathogenic

c.16295G > A

p.R5432Q

Missense

De novo

51

Likely Pathogenic

9

KMT2D

c.4664C > T

p.S1555F

Missense

De novo

17

Likely Pathogenic

10

KMT2D

c.8639 T > C

p.L2880P

Missense

De novo

34

Likely Pathogenic

11

KMT2D

c.3095delT

p.L1032Rfs24X

Frameshift del

NA

11

Pathogenic

12

KMT2D

c.96C > G

p.D32E

Missense

De novo

2

Likely Pathogenic

13

KMT2D

c.4395dupC

p.K1466Qfs25X

Frameshift del

NA

15

Pathogenic

14

KMT2D

c.11638C > Aa

p.L3880 M

Missense

NA

39

Uncertain significance

15

KMT2D

c.4140 T > A

p.C1370X

Nonsense

NA

14

Pathogenic

c.11718-11723delGCAACA

 

Non-Frameshift indel

NA

39

Likely Pathogenic

16

[8] Yang P, et al. Am J Med Genet A. 2016, 170 (6): 1613–21.

KDM6A

exon1-2del

 

Frameshift del

De novo

 

Pathogenic

17

[9] Wu BB, et al. Chin J Evid Based Pediatr. 2017, 12 (2):135–9.

KMT2D

c.12697C > T

p.Q4233X

Nonsense

De novo

39

Pathogenic

c.12696C > T

p.Q4232H

Missense

De novo

39

Pathogenic

18

KMT2D

c.3495delC

p.P1165Lfs*47

Frameshift del

De novo

11

Pathogenic

19

KMT2D

c.10881delT

p.L3627Rfs*31

Frameshift del

De novo

39

Pathogenic

20

KMT2D

c.16498C > T

p.R5500W

Missense

NA

53

Likely Pathogenic

21

KMT2D

c.12560G > A

p.G4187E

Missense

NA

39

Likely Pathogenic

22

KMT2D

c.16273G > A

p.E5425K

Missense

NA

51

Likely Pathogenic

23

[10] JUN LU, et al. MOLECULAR MEDICINE REPORTS. 2016, 14: 3641–3645.

KMT2D

c.4485C > A

p.Y1495S

Missense

De novo

16

Pathogenic

24

[11] Chengqi Xin, BMC Medical Genetics. 2018, 19:31

KMT2D

c.5235delA

p.A1746Lfs*39

Frameshift del

De novo

22

Pathogenic

25

KMT2D

c.7048G > A

p.Q2350*

Frameshift del

De novo

31

Pathogenic

26

[12] Ju-Li Lin, et al. Clinical Genetics, 2015, 88 (3): 255–260.

KMT2D

c.12307C > T

p.Q4013X

Nonsense

De novo

38

Pathogenic

27

KMT2D

c.3754C > T

p.R1252X

Nonsense

De novo

11

Pathogenic

28

KMT2D

c.16294C > T

p.R5432W

Nonsense

De novo

51

Likely Pathogenic

29

KMT2D

c.5993A > G

p.Y1998C

Missense

De novo

28

Likely

Pathogenic

30

KMT2D

c.16273G > A

p. E5425K

Missense

Father

51

Likely Pathogenic

31

KMT2D

c.16273G > A

p. E5425K

Missense

Father

51

Likely Pathogenic

32

KMT2D

c.16273G > A

p. E5425K

Missense

Father

51

Likely Pathogenic

33

KMT2D

c.8743C > T

p.R2915X

Nonsense

De novo

34

Pathogenic

34

KMT2D

c.5269C > T

p.R1757X

Nonsense

De novo

22

Pathogenic

35

KMT2D

c.16273G > A

p.E5425K

Missense

De novo

51

Likely

Pathogenic

36

KMT2D

c.7650-1delCT

p.P2550Rfs2604X

Frameshift del

De novo

31

Pathogenic

37

KMT2D

c.16135C > T

p.Q5379X

Nonsense

De novo

51

Pathogenic

38

KMT2D

c.15326G > T

p.C5109F

Missense

De novo

48

Pathogenic

39

KMT2D

c.16498C > T

p.R5500W

Missense

De novo

53

Pathogenic

40

[13] LI Jieling, ea. al. J Clin Pediatr. 2018, 1 (36): 53–56.

KMT2D

c.7130C > Ta

p.P2377L

Missense

Father

31

Uncertain significance

41

KMT2D

IVS9 + 2 T > G

 

Splice mutation

De novo

 

Pathogenic

42

[14] Wang Hongmei, et al. Chin J Pediatr. 2018, 56 (11): 846–849.

KMT2D

c.11770C > T

p.Q3924X

Nonsense

De novo

39

Pathogenic

43

KMT2D

c.13033A > T

p.K4345X

Nonsense

De novo

39

Pathogenic

44

KMT2D

c.1763C > G

p.S588X

Nonsense

De novo

10

Pathogenic

45

KMT2D

c.5848delT

p.S1950Pfs*97

Frameshift

De novo

27

Pathogenic

46

KMT2D

c.16294C > T

p.R5432W

Missense

De novo

51

Likely

Pathogenic

47

[15] Guo Z,et al. BMC Med. Genet. 2018, 12 03;19 (1).

KDM6A

c.335-1G > T

 

Splice site mutation

mother

 

Likely Pathogenic

aNo sufficient evidence supporting it’s pathogenicity *Denotes a frameshift change as the first affected amino acid

A phenotypic comparison between the 47 Chinese patients and a cohort of 86 patients from other populations was showed in Table 1. It was reported that the long palpebral fissures were observed in 99% of non-Chinese KS patients, and the eversion of lateral third of lower eyelids 87% [17]. The Chinese patients showed a significantly lower frequency (38.2% for both features). While a lack of clinical acuity in recognizing these features by clinicians could account for some differences, we think it may more likely reflecting the ethnicity difference in feature presentations. Additionally, The Chinese patients had higher frequency of hearing impairment but lower frequency of microcephaly, micrognathia, strabismus, abnormal dentition, fifth finger clinodactyly and fingertip pads. The frequencies of other phenotypes including short stature, intellectual disability, cardiac defects, large eras, hypoglycemia and high-arched/cleft palate were consistent with previously reported [17].

KMT2D/KDM6A affects genes and biological processes globally. The clinical consequence of KMT2D/KDM6A gene mutations also seems to have a global effect on development and growth, both craniofacial, cardiac, neural and musculoskeletal (presented with short stature) tissue [18]. Across the board, the Chinese KS patients had typical facial features. These dysmorphic features included long palpebral fissures, depressed nasal tip and large ears (most prominent from the profile), similar to the KS patients from other ethnicities, indicating a consistent and highly penetrant facial dysphormic profile across populations.

Thirty-one Chinese patients presented with intellectual disability, most were mildly affected. Mehmet et al. [19] reported one and Parisi et al. [20] reported three KS patients with autism spectrum disorder, yet none of the Chinese KS patients exhibited autistic features or significant behavioral issues. Various structural brain anomalies had been infrequently described in KS patients. Topcu et al. reported perisylvian cortical dysplasia [6]. Cedrik et al. reported two patients presented with holoprosencephaly [21]. Furthermore, based on MRI, significantly decreased grey matter volume in the bilateral hippocampus and dentate gyrus have been described in KS patients [22]. We found the brain abnormalities including thinning of pituitary and myelination of cerebral white matter in Chinese KS patients, which were not previously reported in KS patients. We also found that hydrocephalus, corpus callosum hypoplasia and Dandy-Walker malformation which had been reported previously both in Chinese patients and other populations [7, 15]. In addition, cerebellar vermis dysplasia was initially reported in Chinese patients [11]. These observations suggested a strong association between various brain abnormalities and KS. Further study is needed to explore the clinical consequences of these brain abnormalities.

Conclusions

We described five novel variants that are causal for the seven KS Chinese patients, and confirmed that the Chinese KS presented with typical clinical phenotypes as previously reported in non-Chinese patients, but of variable feature prevalence. We also pointed out that brain structural abnormalities including thinning of pituitary and delay myelination of cerebral white matter may be part of KS phenotype that warrant further investigation.

Notes

Acknowledgments

The authors offer their sincere thanks to all the participants and their families who participated in the clinical trial.

Authors’ contributions

HS and CS conducted the data analysis and interpretation and wrote the manuscript. JW, CG and RC contributed to the study design and helped to analyze data and revise the first draft. QO and BC assisted to conduct data analysis. All authors read and approved the final manuscript.

Funding

This work was sponsored by the grants from the Key Clinical Special Discipline Construction Program of Fuzhou, Fujian, P.R.C (No:201610191) and The Basic and Clinical Research of Rare Disease (No: ZD-2019-01).

Ethics approval and consent to participate

This study was approved by the Ethics Committee of Fuzhou Children’s Hospital of Fujian, and written informed consents were obtained from the participants’ legal guardians.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

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© The Author(s). 2019

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors and Affiliations

  1. 1.Department of Endocrinology, Fuzhou Children’s Hospital of FujianFujian Medical University Teaching HospitalFuzhouChina
  2. 2.Department of Endocrinolgy, Genetics and Metabolism, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s HealthBeijingChina
  3. 3.Department of Molecular Genetic Diagnostics, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of MedicineShanghaiChina

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