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Journal of Peking University (Health Sciences) ›› 2021, Vol. 53 ›› Issue (1): 24-33. doi: 10.19723/j.issn.1671-167X.2021.01.005

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Detection of EDA gene mutation and phenotypic analysis in patients with hypohidrotic ectodermal dysplasia

WU Jun-yi1,YU Miao1,SUN Shi-chen1,2,FAN Zhuang-zhuang1,3,ZHENG Jing-lei1,ZHANG Liu-tao1,FENG Hai-lan1,LIU Yang1,Δ(),HAN Dong1,Δ()   

  1. 1. Department of Prosthodontics, Peking University School and Hospital of Stomatology & National Clinical Research Center for Oral Disease & National Engineering Laboratory for Digital Material Technology of Stomatology & Beijing Key Laboratory of Digital Stomatology, Beijing 100081, China
    2. Department of Dental Implantology & Prosthetic Dentistry, Shen-zhen Stomatology Hospital, Shenzhen 518001, Guangdong, China
    3. Department of Stomatology, Beijing Hospital;National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing 100010, China
  • Received:2020-10-10 Online:2021-02-18 Published:2021-02-07
  • Contact: Yang LIU,Dong HAN E-mail:pkussliuyang@bjmu.edu.cn;donghan@bjmu.edu.cn
  • Supported by:
    National Natural Science Foundation of China(81970902);National Natural Science Foundation of China(81600846)

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Abstract:

Objective: To detect the ectodysplasin A (EDA) gene mutation in patients with hypohidro-tic ectodermal dysplasia (HED), and to analyze the distribution pattern of missing permanent teeth and the systemic manifestation of HED patients with EDA gene mutation.Methods: Twelve HED families were enrolled from clinic for genetic history collection, systemic physical examination and oral examination. Peripheral blood or saliva samples were collected from the probands and the family members to extract genomic DNA. PCR amplification and Sanger sequencing were utilized to detect the EDA gene variations, which were compared with the normal sequence (NM_001399.5). The functional impact of EDA gene variants was then evaluated by functional prediction of mutation, conservation analysis and protein structure prediction. The pathogenicity of each EDA gene variation was assessed according to the stan-dards and guidelines of the American College of Medical Genetics and Genomics (ACMG). The systemic phenotype and missing permanent tooth sites of HED patients with EDA gene mutations were summarized, and the missing rate of each tooth position was analyzed and compared.Results: Eight out of twelve HED families were identified to carry EDA gene mutations, including: c.164T>C(p.Leu55Pro); c.457C>T(p.Arg153Cys); c.466C>T(p.Arg156Cys); c. 584G>A(p.Gly195Glu); c.619delG(p.Gly207Profs*73); c.673C>T(p.Pro225Ser); c.676C>T(p.Gln226*) and c.905T>G(p.Phe302Cys). Among them, c.164T>C(p.Leu55Pro); c.619delG(p.Gly207Profs*73); c.673C>T(p.Pro225Ser); c.676C>T(p.Gln226*) and c.905T>G(p.Phe302Cys) were novel mutations. The HED patients with EDA gene mutations in this study were all male. Our results showed that the average number of missing permanent teeth was 13.86±4.49, the average number of missing permanent teeth in the upper jaw was 13.14±5.76, the missing rate was 73.02%. And in the lower jaw, the average number of missing permanent teeth was 14.57±3.05, the missing rate was 80.95%. There was no significant difference in the number of missing teeth between the left and right sides of the permanent dentition (P>0.05). Specifi-cally, the maxillary lateral incisors, the maxillary second premolars and the mandibular lateral incisors were more likely to be missing, while the maxillary central incisors, the maxillary and mandibular first molars had higher possibility of persistence.Conclusion: This study detected novel EDA gene pathogenic variants and summarized the distribution pattern of missing permanent teeth of HED patients, thus enriched the variation and phenotype spectrum of EDA gene, and provided new clinical evidence for genetic diagnosis and prenatal consultation.

Key words: Hypohidrotic ectodermal dysplasia, Tooth agenesis, EDA gene, Gene mutation

CLC Number: 

  • R394.1

Figure 1

Pedigree and EDA gene sequencing chromatograms of family members A-H, pedigree and EDA gene sequencing chromatograms, semicircle shade indicates female carrier with hypodontia and hypotrichosis, quarter-circle shades indicate female carriers with hypodontia."

Table 1

Summary of EDA mutations in this study"

Proband
number		 Age/
years		 Gender Mutational analysis Mutation
type		 Polyphen-2
(score)		 Mutation
taster		 Provean
(score)		 Reference ID
(source)		 ACMG classification
(evidence of pathogenicity)
#632 16 Male c.457C>T
p.Arg153Cys		 Missense Probably damage
(0.85)		 Disease
causing		 Neutral
(-2.48)		 rs397516662
(dbSNP)		 Likely pathogenic
(PS3+PP1+PP4+PP5)
#688 6 Male c.457C>T
p.Arg153Cys		 Missense Probably damage
(0.85)		 Disease
causing		 Neutral
(-2.48)		 rs397516662
(dbSNP)		 Likely pathogenic
(PS3+PP1+PP4+PP5)
#742 3 Male c.584G>A
p.Gly195Glu		 Missense Probably damage
(1.00)		 Disease
causing		 Deleterious
(-4.81)		 CM080229
(HGMD)		 Likely pathogenic
(PS2+PP3+PP4+PP5)
#652 6 Male c.164T>C
p.Leu55Pro		 Missense Probably damage
(1.00)		 Disease
causing		 Neutral
(-0.9)		 Likely pathogenic
(PM2+PM5+PP1+PP4)
#362 6 Male c.673C>T
p.Pro225Ser
c.676C>T
p.Gln226*		 Missense

Nonsense		 Probably damage
(1.00)		 Disease
causing
Disease
causing		 Neutral
(-2.04)
Deleterious
(-5.17)		 Likely pathogenic
(PM1+PM2+PP1+PP4)
Pathogenic
(PVS1+PM1+PM2+PP1+PP4)
#729 8 Male c.619delG
p.Gly207Profs*73		 Frameshift Disease
causing		 Pathogenic
(PVS1+PM2+PP1+ PP4)
#593 6 Male c.905T>G
p.Phe302Cys		 Missense Probably damage
(1.00)		 Disease
causing		 Deleterious
(-3.12)		 Likely pathogenic
(PM1+PM2+PM5+PP1+PP3+PP4)
#685 7 Male c.466C>T
p.Arg156Cys		 Missense Possibly damaging
(0.48)		 Disease
causing		 Deleterious
(-2.65)		 rs132630313
(dbSNP)		 Likely pathogenic
(PS3+PP1+PP3+PP4+PP5)

Figure 2

Clinical appearance and panoramic radiograph of subjects A, the face photograph of #632 proband; B-C, the intraoral photographs of #632 proband; D-E, the detailed photographs show sparse eyebrows of #632 proband and his mother; F-G, the panoramic radiographs of #632 proband and his mother; H, the face photograph of #688 proband; I-J, the intraoral photographs of #688 proband; K, the photograph shows absent nipple and areola of #688 proband; L-M, the panoramic radiographs of #688 proband and #742 proband; N, the intraoral photograph of #652 proband; O, the face photograph of #652 proband; P-Q, the panoramic radiographs of #652 proband and his cousin; R, the cephalometric radiograph of #362 proband; S, the intraoral photograph of #729 proband; T-V, the panoramic radiographs of #729 proband, #593 proband and #685 proband. The black block represents the missing tooth, the red arrow refers to the tapered tooth. MAX, maxillary dental arch; MAND, mandibular dental arch."

Figure 3

Location and conservation analysis of EDA mutations A, location of EDA mutations identified in this study, reported mutations are in black, novel mutations are in red; B, schematic diagram of the EDA gene; C, conservation analysis of affected amino acids in the EDA protein among 8 different species. TM, transmembrane domain; TNF, tumor necrosis factor."

Figure 4

The structure prediction of EDA mutant proteins A-B, the tertiary structure of wild-type EDA-A1; C-D, the tertiary structure of the p.Phe302Cys mutant; E, the secondary structure of wild-type EDA protein; F-K, the secondary structure of the p.Leu55Pro, p.Arg153Cys, p.Arg156Cys, p.Gly195Glu, p.[pro225ser; Gln226*] and p.Gly207Profs*73 mutants."

Table 2

Numbers and distribution of the missing teeth in the HED patients with EDA mutation"

Quadrant Teeth position Total missing
number
CI LI Ca PM1 PM2 M1 M2
Max R 1/9 9/9 8/9 8/9 9/9 5/9 6/9 46/63
11.11% 100.00% 88.89% 88.89% 100.00% 55.56% 66.67% 73.02%
Max L 1/9 9/9 8/9 8/9 9/9 5/9 6/9 46/63
11.11% 100.00% 88.89% 88.89% 100.00% 55.56% 66.67% 73.02%
Mand R 8/9 9/9 7/9 8/9 8/9 5/9 6/9 51/63
88.89% 100.00% 77.78% 88.89% 88.89% 55.56% 66.67% 80.95%
Mand L 9/9 9/9 7/9 8/9 8/9 5/9 5/9 51/63
100.00% 100.00% 77.78% 88.89% 88.89% 55.56% 55.56% 80.95%
Max 2/18 18/18 16/18 16/18 18/18 10/18 12/18 92/126
11.11% 100.00% 88.89% 88.89% 100.00% 55.56% 66.67% 73.02%
Mand 17/18 18/18 14/18 16/18 16/18 10/18 11/18 102/126
94.44% 100.00% 77.78% 88.89% 88.89% 55.56% 61.11% 80.95%
R 9/18 18/18 15/18 16/18 17/18 10/18 12/18 97/126
50.00% 100.00% 83.33% 88.89% 94.44% 55.56% 66.67% 76.98%
L 10/18 18/18 15/18 16/18 17/18 10/18 11/18 97/126
55.56% 100.00% 83.33% 88.89% 94.44% 55.56% 61.11% 76.98%

Figure 5

Distribution and percentage of missing permanent teeth in HED patients with EDA mutations A and B, percentage of missing tooth positions at each maxillary and mandibular dentition in HED patients with EDA mutations. Max, maxillary; Mand, mandibular; CI, central incisor; LI, lateral incisor; Ca, canine; PM1, first premolar; PM2, second premolar; M1, first molar; M2, second molar. Statistical significant P-value is marked with *P< 0.05, △P < 0.01, ◇P < 0.001, and ※P < 0.000 1; HED, hypohidrotic ectodermal dysplasia."

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