Epidermolysis Bullosa Simplex: Recurrent and De Novo Mutations in the KRT5 and KRT14 Genes, Phenotype/Genotype Correlations, and Implications for Genetic Counseling and Prenatal Diagnosis

Abstract Background To define the genotype-phenotype correlation of small supernumerary marker chromosomes (sSMCs) and conduct precise genetic counseling, we retrospectively searched and reviewed de novo sSMC cases detected during prenatal diagnosis at The First Affiliated Hospital of Zhengzhou University. Chromosome karyotypes of 20,314 cases of amniotic fluid from pregnant women were performed. For 16 samples with de novo sSMCs, 10 were subjected to single-nucleotide polymorphism (SNP) array or low-coverage massively parallel copy number variation sequencing (CNV-seq) analysis. Results Among the 10 sSMC cases, two sSMCs derived from chromosome 9, and three sSMCs derived from chromosomes 12, 18 and 22. The remaining 5 cases were not identified by SNP array or CNV-seq because they lacked euchromatin or had a low proportion of mosaicism. Four of them with a karyotype of 47,XN,+mar presented normal molecular cytogenetic results (seq[hg19] 46,XN), and the remaining patient with a karyotype of 46,XN,+mar presented with Turner syndrome (seq[hg19] 45,X). Five sSMC samples were mosaics of all 16 cases. Conclusion Considering the variable origins of sSMCs, further genetic testing of sSMCs should be performed by SNP array or CNV-seq. Detailed molecular characterization would allow precise genetic counseling for prenatal diagnosis.

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A family of severe epidermolysis bullosa simplex caused by a de novo mutation in the KRT5 gene

Chinese Journal of Dermatology ◽

10.35541/cjd.20200315 ◽

2020 ◽

Keyword(s):

Epidermolysis Bullosa ◽

De Novo ◽

De Novo Mutation ◽

Epidermolysis Bullosa Simplex

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Severe Generalized Epidermolysis Bullosa Simplex in Two Hong Kong Children due to De Novo Variants in KRT14 and KRT5

Case Reports in Pediatrics ◽

10.1155/2020/4206348 ◽

2020 ◽

Vol 2020 ◽

pp. 1-5 ◽

Cited By ~ 1

Author(s):

Shuk Ching Chong ◽

Kam Lun Hon ◽

Fernando Scaglia ◽

Chung Mo Chow ◽

Yu Ming Fu ◽

...

Keyword(s):

Hong Kong ◽

Epidermolysis Bullosa ◽

De Novo ◽

Genetic Diagnosis ◽

Recurrence Risk ◽

Severe Form ◽

Epidermolysis Bullosa Simplex ◽

First Case ◽

Heterozygous Variant ◽

History Of

We report two Hong Kong children with severe generalized epidermolysis bullosa simplex (EBS), the most severe form of EBS, without a family history of EBS. EBS is a rare genodermatosis usually inherited in an autosomal dominant fashion although rare autosomal recessive cases have been reported. Genetic studies in these patients showed that the first case was due to a novel de novo heterozygous variant, c.377T>G (NM_000526.5 (c.377T>G, p.Leu126Arg)) in the KRT14 gene and the second case was due to a rare de novo heterozygous variant c.527A>G (NM_000424.4, c.527A>G, p.Asn176Ser) in the KRT5 gene. To our knowledge, the c.377T>G variant in the KRT14 gene has not been previously reported, and the c.527A>G variant in the KRT5 gene is a rare cause of severe generalized EBS. In severe generalized EBS, infants exhibit severe symptoms at the onset; however, they tend to improve with time. A precise genetic diagnosis in these two cases aided in counseling the families concerning the prognosis in their affected children and the recurrence risk for future pregnancies.

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Identification of a de novo mutation in KRT5 gene underlying epidermolysis bullosa simplex by whole exome sequencing in a Vietnamese patient

Vietnam Journal of Biotechnology ◽

10.15625/1811-4989/16111 ◽

2021 ◽

Vol 19 (2) ◽

pp. 223-228

Author(s):

Ma Thi Huyen Thuong ◽

Dang Tien Truong ◽

Nguyen Hai Ha ◽

Nguyen Dang Ton

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Epidermolysis Bullosa ◽

De Novo ◽

Recurrence Risk ◽

Pathogenic Mutation ◽

De Novo Mutation ◽

Causative Mutation ◽

Epidermolysis Bullosa Simplex ◽

Whole Exome

Epidermolysis bullosa simplex (EBS) is a group of epidermolysis bullosa (EB) and accounts for 75-85% EB cases. Most EBS patients are caused by mutations in KRT5 or KRT14, encoding for keratin 5 and keratin 14, respectively, which impair the structural entirety of paired intermediate filaments expressed in the fracture of basal keratinocytes and subsequent blistering of the epithelium. This study aimed to identify the causative mutation in a Vietnamese EB case. Whole exome sequencing (WES) was performed in the affected individual and revealed a de novo heterozygous pathogenic mutation in exon 7 of KRT5 gene, resulting in an amino acid change at position 477, with glutamic acid to lysine substitution (p.E477K). The KRT5 p.E477K was strong associated with the very severe or lethal of generalized severe EBS (GS-EBS), characterized by the severe symptoms at birth, improving with age and evolution to palmoplantar keratoderma and nail dysplasia. Our finding will aid the molecular diagnosis, prognosis prediction of the patient with GS-EBS due to p.E477K and significant genetic counselling the family concerning the recurrence risk for future pregnancies.

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Noninvasive prenatal diagnosis of duchenne muscular dystrophy in five Chinese families based on relative mutation dosage approach

BMC Medical Genomics ◽

10.1186/s12920-021-01128-1 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Ganye Zhao ◽

Xiaofeng Wang ◽

Lina Liu ◽

Peng Dai ◽

Xiangdong Kong

Keyword(s):

Prenatal Diagnosis ◽

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Single Molecule ◽

De Novo ◽

Dna Barcode ◽

De Novo Mutations ◽

Molecular Alteration ◽

Noninvasive Prenatal Diagnosis ◽

Exon Deletion

Abstract Background Relative haplotype dosage (RHDO) approach has been applied in noninvasive prenatal diagnosis (NIPD) of Duchenne muscular dystrophy (DMD). However, the RHDO procedure is relatively complicated and the parental haplotypes need to be constructed. Furthermore, it is not suitable for the diagnosis of de novo mutations or mosaicism in germ cells. Here, we investigated NIPD of DMD using a relative mutation dosage (RMD)-based approach—cell-free DNA Barcode-Enabled Single-Molecule Test (cfBEST), which has not previously been applied in the diagnosis of exon deletion. Methods Five DMD families caused by DMD gene point mutations or exon deletion were recruited for this study. After the breakpoints of exon deletion were precisely mapped with multiple PCR, the genotypes of the fetuses from the five DMD families were inferred using cfBEST, and were further validated by invasive prenatal diagnosis. Results The cfBEST results of the five families indicated that one fetus was female and did not carry the familial molecular alteration, three fetuses were carriers and one was male without the familial mutation. The invasive prenatal diagnosis results were consistent with those of the cfBEST procedure. Conclusion This is the first report of NIPD of DMD using the RMD-based approach. We extended the application of cfBEST from point mutation to exon deletion mutation. The results showed that cfBEST would be suitable for NIPD of DMD caused by different kinds of mutation types.

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