Abstract
Epidermolysis-Bullosa (EB), a rare Mendelian disorder, exhibits complex phenotypic and locus-heterogeneity. We identified a nuclear family of clinically unaffected parents with two offsprings manifesting EB-Pyloric-Atresia (EB-PA), with a variable clinical severity. We generated whole exome sequence data on all four individuals to (1) identify the causal mutation behind EB-PA (2) understand the background genetic variation for phenotype variability of the siblings. We assumed an autosomal recessive mode of inheritance and used suites of bioinformatic and computational tools to collate information through global databases to identify the causal genetic variant for the disease. We also investigated variations in key genes that are likely to impact phenotype severity. We identified a novel missense mutation in the ITGB4 gene (p.Ala1227Asp), for which the parents were heterozygous and the children homozygous. The mutation in ITGB4 gene, predicted to reduce the stability of the primary alpha6beta4-plectin complex compared to all previously studied mutations on ITGB4 reported to cause EB.
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Funding
The study was funded by the Department of Biotechnology (DBT), Government of India.
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AD diagnosed and identified the proband. AD and RR also diagnosed the proband’s sibling. SKP and AB conceived and designed the study. SD and NKB did the primary analysis on the DNA sequence data. SKP, SD and CB did the bioinformatics and data analysis. CB, SKP and AB wrote the final manuscript.
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ERR3675796, ERR3675797, ERR3675798, and ERR3675799 are the accession IDs for the BAM files. The data is currently private up until 21st May 2020. However, we can prepone the public sharing of the data upon publication of our manuscript as well as share the raw data files if required during the review process.
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Communicated by Shuhua Xu.
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Supplementary Figure 1.
Read depth analysis of the region spanning the causal variant chr17:73747079C>A
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Paine, S.K., Das, S., Bhattacharyya, C. et al. Autosomal recessive inheritance of a novel missense mutation of ITGB4 for Epidermolysis-Bullosa pyloric-atresia: a case report. Mol Genet Genomics 297, 1581–1586 (2022). https://doi.org/10.1007/s00438-022-01941-y
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DOI: https://doi.org/10.1007/s00438-022-01941-y