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Recessive dystrophic epidermolysis bullosa caused by a de novo interstitial deletion spanning COL 7A1 and a hemizygous splicing mutation in trans
Author(s) -
Lee M.,
Xu G.,
Wang K.,
Wang H.,
Zhang J.,
Tang Z.,
Lin Z.,
Yang Y.
Publication year - 2016
Publication title -
clinical and experimental dermatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.587
H-Index - 78
eISSN - 1365-2230
pISSN - 0307-6938
DOI - 10.1111/ced.12809
Subject(s) - biology , genetics , exon , proband , genotyping , mutation , gene , genotype
Summary Background Recessive dystrophic epidermolysis bullosa ( RDEB ) is a rare heritable blistering skin condition caused by loss‐of‐function mutations in the COL 7A1 gene. Incongruent gene transmission is occasionally reported in recessive diseases, and its underlying mechanism is often uniparental disomy ( UPD ). Aim To understand the genetic basis of incongruent gene transmission in a Chinese family with RDEB , in which a discrepancy of COL 7A1 genotyping was encountered during our mutation analysis. Methods We used a pCAS 2 minigene‐based in vitro splicing assay to confirm the pathogenicity of the splicing variant we identified in the proband. Next, a combination of genetic tools, including whole‐genome SNP array analysis and multiplex ligation‐dependent probe amplification copy number analysis, was used to unravel the cause of the discrepancy in the COL 7A1 genotyping. Results Sanger sequencing identified a novel, single‐peak mutation, c.4980+5G>C, in COL 7A1 in the proband, which was heterozygous in his father and wild type in his mother. In vitro splicing assay showed that c.4980+5G>C was pathogenic and led to skipping of COL 7A1 exon 53. SNP array analysis and multiplex ligation‐dependent probe amplification of the proband's DNA revealed a maternally derived, de novo , interstitial deletion on chromosome 3p21.31, which removed COL 7A1 and 15 flanking genes, excluding the possibility of UPD . Conclusion Our findings favour an exceptionally rare event, namely a de novo COL 7A1 microdeletion in concurrence with an inherited mutation in trans . This study should aid molecular diagnosis and genetic counselling of RDEB and possibly other recessive diseases in which genotyping discrepancy is encountered.