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Recessive Dystrophic <i>Epidermolysis bullosa</i> due to Hemizygous 40 kb Deletion of <i>COL7A1</i> and the Proximate <i>PFKFB4</i> Gene Focusing on the Mutation c.425A>G Mimicking Homozygous Status
oleh: Alfred Klausegger, Niklas Jeschko, Markus Grammer, Jan Cemper-Kiesslich, Franz Neuhuber, Anja Diem, Hannelore Breitenbach-Koller, Gabriele Sander, Dieter Kotzot, Johann Wolfgang Bauer, Martin Laimer
Format: | Article |
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Diterbitkan: | MDPI AG 2022-10-01 |
Deskripsi
Background: Dystrophic <i>Epidermolysis bullosa</i> (DEB) is a rare inherited mechanobullous disease characterised by the hyperfragility of the skin and mucous membranes. It is (typically) caused by (loss-of-function) mutations in the <i>COL7A1</i> gene that impair the formation of collagen type VII, which represents the major constituent of anchoring fibrils within the basement membrane zone of epithelialised tissues. In a 4-year-old patient diagnosed with the clinical features of recessive DEB, genotyping via Next-Generation EB Panel Sequencing initially revealed the homozygosity of the maternal c.425A>G mutation, while the paternal heterozygosity in exon 3 was lacking. This genetic profile suggested incongruent gene transmission due to uniparental isodisomy (UPD) or the occurrence of a hemizygous deletion of unknown size. Methods: Thus, the EB panel sequencing of genomic DNA, followed by a paternity test and analysis of microsatellite markers, as well as multiplex ligation-dependent probe amplification (MLPA) copy number analysis using patient and parental DNA, were performed. Results: This approach revealed a paternally derived hemizygous deletion spanning from exon 3 to exon 118. Linear amplification-mediated PCR (LAM-PCR) determined the breaking points within intron 2 of the COL7A1 gene, comprising a 40kb segment within intron 1 of the adjacent <i>PFKFB4</i> gene. Conclusion: This report highlights the relevance of advanced molecular profiling to determine new/exceptional/unusual genotypes and the accurate mode of genetic transmission in DEB.