Child ; Ectodermal Dysplasia/genetics* ; Ectodermal Dysplasia 1, Anhidrotic/genetics* ; Ectodysplasins/genetics* ; Genetic Testing ; Humans ; Mutation ; Pedigree

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.
Ectodermal Dysplasia ; Ectodermal Dysplasia 1, Anhidrotic/genetics* ; Ectodysplasins/genetics* ; Humans ; Male ; Mutation ; Pedigree ; Phenotype

Objective: To detect gene mutation in patients with hypohidrotic ectodermal dysplasia (HED) by using whole exome sequencing, to analyze the pathogenicity of the mutations, and to provide reference for the genetic diagnosis of HED patients. Methods: Peripheral blood genomic DNA was extracted from each of the HED patients and their family members collected in Peking University School and Hospital of Stomatology from August 2016 to August 2021. Whole exome sequencing and sanger sequencing were performed to detect gene mutations. Functions of the rare variants after the database filtering were analyzed by bioinformatics tools. Results: Three reported mutations of ectodysplasin A (EDA) gene (c.2T>C, c.161A>G, c.467G>A) and a mutation of ectodysplasin A receptor (EDAR) gene (c.871G>A) were detected by whole genome sequencing in four HED patients, and were verified by Sanger sequencing in four HED families. The EDAR gene mutation founded in this research was reported in HED patients for the first time. Bioinformatics tools predicted that the mutations of EDA gene detected in this study were highly species conserved and disease-causing. The combined annotation dependent depletion (CADD) scores of EDA gene mutations c.2T>C, c.161A>G and c.467G>A were 22.5, 26.3 and 25.5 respectively, and the genomic evolutionary rate profiling (GERP) scores were 2.16, 2.26 and 2.18 respectively. The EDAR gene mutation c.871G>A detected in this study was species conserved and possibly disease-causing. The CADD and GERP scores of EDAR gene mutation c.871G>A were 22.0 and 1.93 respectively. Conclusions: Three reported mutations of EDA gene and a previously unreported mutation of EDAR gene were detected in four HED families. Different mutations of EDA gene and EDAR gene could make different influence on the protein function and lead to the occurrence of HED.
Ectodermal Dysplasia/genetics* ; Ectodermal Dysplasia 1, Anhidrotic/genetics* ; Edar Receptor/genetics* ; Humans ; Mutation ; Pedigree ; Whole Exome Sequencing

OBJECTIVE: To investigate the clinical phenotype and genetic characteristics of a patient with hypohidrotic ectodermal dysplasia (HED) due to partial deletion of EDA gene. METHODS: The child has presented with HED complicated with epilepsy. Family trio whole exome sequencing (Trio-WES), copy number variation sequencing (CNV-seq), and karyotype analysis were carried out to explore the underlying genetic etiology. RESULTS: The proband, a 7-year-and-8-month-old boy, presented with thin curly hair, thin and sparse eyebrow, xerosis cutis, susceptibility to hyperthermia from childhood, hypohidrosis, sharp/sparse/absent teeth, saddle nose, prominent forehead, auricle adulation and seizure. He was found to have a normal chromosomal karyotype, and no abnormality was found by Trio-WES. Genome-wide CNV-seq revealed a 341.90 kb deletion at Xq13.1q13.1 (chrX: 68 796 566-69 138 468). As verified by PCR-electrophoresis, the deletion has removed part of the EDA gene. The deletion was derived from his mother with normal hair, mild xerosis cutis, and sparse, decidulated and nail-like teeth. The mother was detected with a heterozygous 242.10 kb deletion at Xq13.1q13.1 (chrX: 68 836 154-69 078 250). CONCLUSION Both the proband and his mother have carried a Xq13.1 microdeletion involving part of the EDA gene. The clinical phenotypes of the mother and the proband were consistent with the clinical characteristics of X-linked recessive HED, for which partial deletion of the EDA gene is probably accountable.
Child ; DNA Copy Number Variations ; Ectodermal Dysplasia ; Ectodermal Dysplasia 1, Anhidrotic/genetics* ; Ectodysplasins/genetics* ; Humans ; Male ; Phenotype

Ectodermal Dysplasia 1, Anhidrotic ; diagnosis ; genetics ; Ectodysplasins ; genetics ; Heterozygote ; Humans ; Infant, Newborn ; Male ; Mutation, Missense

OBJECTIVETo detect mutations in the ED1 gene in two Chinese pedigrees and a sporadic case with X-linked hypohidrotic ectodermal dysplasia (XLHED) and provide evidences with the mutation analysis for genetic counseling, prenatal diagnosis and confirmation of carrier status.

METHODSPeripheral blood samples were obtained from two pedigrees and the sporadic patient, and genomic DNA was extract by salting out method. Polymerase chain reaction (PCR) and direct sequencing were performed to screen mutations in ED1 gene.

RESULTSThree mutations were identified. In one of the pedigrees, a 1045G > A transition was evidenced in exon 9 that resulted in a change of Ala 349 Thr. In the other pedigrees and the sporadic patient, 467G > A and 466C > T transitions were demonstrated in exon 3 that resulted in change of Arg 156 His and Arg 156 Cys. These mutations were not found in 100 normal individuals.

CONCLUSIONSThese mutations were responsible for the disease in the two families and the sporadic patient. All these mutations had been identified previously.

Child ; DNA Mutational Analysis ; Ectodermal Dysplasia 1, Anhidrotic ; genetics ; Ectodysplasins ; genetics ; Humans ; Male ; Mutation, Missense ; Pedigree

OBJECTIVE: To detect variant of EDA gene in a fetus with absence of germ teeth detected by prenatal ultrasonography. METHODS: Clinical data and amniotic fluid and peripheral venous blood samples of the pregnant woman were collected for the analysis. Following extraction of genome DNA, the coding regions of the EDA gene were amplified by PCR and subjected to next-generation sequencing. Candidate variant was verified by Sanger sequencing. RESULTS: The pregnant woman was found to carry a heterozygous c.574G>A variant in the EDA gene, for which the fetus was hemizygous. Bioinformatic analysis suggested the variant to be pathogenic. CONCLUSION Combined ultrasonographic and genetic findings suggested the fetus is affected with X-linked hypohidrotic ectodermal dysplasia due to pathogenic variant of the EDA gene.
Ectodermal Dysplasia 1, Anhidrotic/genetics* ; Ectodysplasins/genetics* ; Female ; Fetus ; Humans ; Mutation ; Pedigree ; Pregnancy ; Prenatal Diagnosis

OBJECTIVE: To carry out genetic testing for a Chinese patient with X-linked hypohidrotic ectodermal dysplasia (XLHED) and explore its genotype-phenotype correlation. METHODS: Clinical data of the patient was collected. Peripheral blood samples were taken from the patient, his parents and 100 unrelated healthy controls. Genetic variants were detected by using next-generation sequencing using a skin-disease panel through targeted capture and next generation sequencing. Candidate variant was verified by Sanger sequencing. All literature related to genetic testing of XLHED patients in China was searched in the database, and the genotypes and phenotypes of patients in the literature and the correlation between them were statistically analyzed. RESULTS: A novel splice site variant c.655_689del was detected in the patient but not among his parents and the 100 unrelated healthy controls. So far 61 variants of the EDA gene have been identified among Chinese patients with XLHED, which suggested certain degree of genotype-phenotype correlation. CONCLUSION A novel c.655_689del variant has been identified in the EDA gene, which has expanded the spectrum of EDA gene variant and facilitated delineation of the genotype-phenotype correlation of XLHED.
Child ; China ; Ectodermal Dysplasia 1, Anhidrotic/genetics* ; Ectodysplasins/genetics* ; Genetic Testing ; Genotype ; Humans ; Phenotype

OBJECTIVE: To explore the clinical and genetic characteristics of a child with X-linked hypohidrotic ectodermal dysplasia (XLHED). METHODS: Clinical data of the child was collected. Peripheral blood samples were taken from the child and his parents with informed consent and subjected to copy number variation (CNV) analysis and whole exome sequencing (WES). RESULTS: The male infant manifested sparse hair, anhidrosis, anuresis due to polycystic kidney dysplasia, external genital malformation and anal atresia. WES has revealed a 406 bp hemizygous deletion at Xq13 (68 836 147-68 836 553) in the proband, which encompassed exon 1 of the EDA gene. A heterozygous deletion at the same site was detected in the mother, while no deletion or duplication of the site was detected in the father. CONCLUSION The hemizygous deletion of EDA gene exon 1 probably underlay the ectodermal dysplasia in the proband. Above result has provided a basis for genetic counseling and prenatal diagnosis for the family.
Child ; DNA Copy Number Variations ; Ectodermal Dysplasia/genetics* ; Ectodermal Dysplasia 1, Anhidrotic/genetics* ; Ectodysplasins/genetics* ; Genetic Testing ; Humans ; Infant ; Male ; Pedigree

OBJECTIVETo identify the mutations of ED1 gene in a family with X-linked hypohidrotic ectodermal dysplasia

METHODSEight coding exons of ED1 gene of two patients with clinically confirmed X-linked hypohidrotic ectodermal dysplasia, their parents, and 100 unrelated population-matched control were amplified by polymerase chain reaction. The products were further analyzed by direct sequencing.

RESULTSTwo patients with X-linked hypohidrotic ectodermal dysplasia in this pedigree showed a point mutation at nucleotide 1 045 ( A > G) . Meanwhile, heterozygous double peaks of nucleotide G and A at the same position were found in their mother, but not in their father and 100 unrelated population-matched controls.

CONCLUSIONThe c. 1 045A > G mutation of ED1 gene may be the pathologic cause of this Chinese family with X-linked hypohidrotic ectodermal dysplasia.

Asian Continental Ancestry Group ; Ectodermal Dysplasia 1, Anhidrotic ; genetics ; Ectodysplasins ; genetics ; Genetic Association Studies ; Humans ; Mutation ; Pedigree