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
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
Affiliations
Alfred Klausegger
EB House Austria, Department of Dermatology and Allergology, University Hospital of the Paracelsus Medical University, 5020 Salzburg, Austria
Niklas Jeschko
EB House Austria, Department of Dermatology and Allergology, University Hospital of the Paracelsus Medical University, 5020 Salzburg, Austria
Markus Grammer
EB House Austria, Department of Dermatology and Allergology, University Hospital of the Paracelsus Medical University, 5020 Salzburg, Austria
Jan Cemper-Kiesslich
Department of Legal Medicine, University of Salzburg, 5020 Salzburg, Austria
Franz Neuhuber
Department of Legal Medicine, University of Salzburg, 5020 Salzburg, Austria
Anja Diem
EB House Austria, Department of Dermatology and Allergology, University Hospital of the Paracelsus Medical University, 5020 Salzburg, Austria
Hannelore Breitenbach-Koller
Department of Biosciences, University of Salzburg, 5020 Salzburg, Austria
Gabriele Sander
Institute of Human Genetics, Department of Pediatrics, University Hospital of the Paracelsus Medical University Salzburg, 5020 Salzburg, Austria
Dieter Kotzot
Institute of Human Genetics, Department of Pediatrics, University Hospital of the Paracelsus Medical University Salzburg, 5020 Salzburg, Austria
Johann Wolfgang Bauer
EB House Austria, Department of Dermatology and Allergology, University Hospital of the Paracelsus Medical University, 5020 Salzburg, Austria
Martin Laimer
EB House Austria, Department of Dermatology and Allergology, University Hospital of the Paracelsus Medical University, 5020 Salzburg, Austria
Background: Dystrophic Epidermolysis bullosa (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 COL7A1 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 PFKFB4 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.
