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Prenatal Diagnosis for Recessive Dystrophic Epidermolysis Bullosa in 10 Families by Mutation and Haplotype Analysis in the Type VII Collagen Gene (COL7A1)

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Abstract

Background

Epidermolysis bullosa (EB) is a group of heritable diseases that manifest as blistering and erosions of the skin and mucous membranes. In the dystrophic forms of EB (DEB), the diagnostic hallmark is abnormalities in the anchoring fibrils, attachment structures beneath the cutaneous basement membrane zone. The major component of anchoring fibrils is type VII collagen, and DEB has been linked to the type VII collagen gene (C0L7A1) at 3p21, with no evidence for locus heterogeneity. Due to life-threatening complications and significant long-term morbidity associated with the severe, mutilating form of recessive dystrophic EB (RDEB), there has been a demand for prenatal diagnosis from families with affected offspring.

Materials and Methods

Intragenic polymorphisms in C0L7A1 and flanking microsatellite markers on chromosome 3p21, as well as detection of pathogenetic mutations in families, were used to perform PCR-based prenatal diagnosis from DNA obtained by chorionic villus sampling at 10–15 weeks or amniocentesis at 12–15 weeks gestation in 10 families at risk for recurrence of RDEB.

Results

In nine cases, the fetus was predicted to be normal or a clinically unaffected carrier of a mutation in one allele. These predictions have been validated in nine cases by the birth of a healthy child. In one case, an affected fetus was predicted, and the diagnosis was confirmed by fetal skin biopsy.

Conclusions

DNA-based prenatal diagnosis of RDEB offers an early, expedient method of testing which will largely replace the previously available invasive fetal skin biopsy at 18–20 weeks gestation.

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Acknowledgments

We sincerely appreciate the willingness of RDEB patients and their families to participate in this study. We would like to thank the following physicians and genetic counselors: Family A: Lori Finn, M.S., and Eugene Pergament, M.D., Northwestern Memorial Hospital, Chicago, IL; Family B: Annette Yen-Batey, M.S., and David R. Witt, M.D., Kaiser Permanente Medical Group, San Jose, CA, and Sheila Gibbons, L.V.N, and Lexie Nall, Ph.D., of the National EB Registry, Stanford University School of Medicine, Stanford, CA; Family C: Gregory Ryan, M.D., and David Chitayat, M.D., University of Toronto Hospital, Ontario; Family D: Cindy Quinn, M.S., and Sterling McColgin, M.D., University of Colorado Health Sciences Center, Denver, CO; Family E: Shearon Roberts, M.S., and Karen Holbrook, Ph.D., University of Florida, Gainesville, FL; Family F: Valerie Hani, M.S., Dartmouth Hitchcock Medical Center, Lebanon, NH, Andrew N. Lin, M.D., Mary D. Brust, R.N., and the late D. Martin

Carter, M.D., Ph.D., National EB Registry, Rockefeller University, New York, NY; Family G: Ishwar C. Verma, M.D., F.R.C.P., All India Institute of Medical Sciences, New Delhi, India; Family H: Shearon Roberts, M.S., University of Florida, Gainesville, FL, and Jo-David Fine, M.D., M.P.H., National EB Registry, University of North Carolina, Chapel Hill, NC; Family I: Takeji Nishikawa, M.D., Ph.D., Keio University School of Medicine, Tokyo, Japan, and Kaoru Suzumuri, M.D., Ph.D., Nagoya City University Medical School, Nagoya, Japan; Family J: Laura Turlington, M.S., Washington University School of Medicine, St. Louis, MO. We gratefully acknowledge the assistance of National EB Registry for evaluation of the patients. Electron microscopic and immunohisto-chemical analyses were performed by Wedad Hanna, M.D., Women’s College Hospital, Toronto, Ontario (Family C); Byron P. Croker, M.D., Ph.D., University of Florida, Gainesville, FL, and Robert A. Briggaman, M.D., University of North Carolina, Chapel Hill, NC (Family E); Jo-David Fine, M.D., M.P.H., National EB Registry, University of North Carolina, Chapel Hill, NC, and Lynne T. Smith, Ph.D., National EB Registry, University of Washington, Seattle, WA (Family F); Jo-David Fine, M.D., M.P.H., The National EB Registry, University of North Carolina, Chapel Hill, NC (Family H). We thank Xin Zhang and Yili Xu for technical help, and Tamara Alexander and Beth Attig for secretarial assistance. The Automated DNA Sequencing Core of the Jefferson Cancer Institute, directed by Dr. Hansjürg Alder, performed direct PCR sequence analysis.

This work was supported by grants from USPHS, National Institutes of Health (PO1-AR38923, P01-AR41045, and N01-AR2-2204), the March of Dimes Birth Defects Foundation, and the Dystrophic Epidermolysis Bullosa Research Association of America. AMC was supported by the Society for Investigative Dermatology Research Career Development Award from the Dermatology Foundation.

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Authors and Affiliations

  1. Departments of Dermatology and Cutaneous Biology, and Biochemistry and Molecular Biology, Jefferson Medical College, and Section of Molecular Dermatology, Jefferson Institute of Molecular Medicine, Thomas Jefferson University, 233 South 10th Street, Suite 450, Philadelphia, Pennsylvania, 19107, USA

    Angela M. Christiano, Sal LaForgia & Jouni Uitto

  2. Children’s Memorial Hospital, Northwestern University School of Medicine, Chicago, Illinois, USA

    Amy S. Paller

  3. Department of Dermatology, Stanford University Medical Center, Palo Alto, California, USA

    Joseph McGuire

  4. Department of Dermatology, Keio University School of Medicine, Tokyo, Japan

    Hiroshi Shimizu

Authors
  1. Angela M. Christiano
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  2. Sal LaForgia
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  3. Amy S. Paller
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  4. Joseph McGuire
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  5. Hiroshi Shimizu
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  6. Jouni Uitto
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Contributed by D. J. Prockop on September 11, 1995.

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Christiano, A.M., LaForgia, S., Paller, A.S. et al. Prenatal Diagnosis for Recessive Dystrophic Epidermolysis Bullosa in 10 Families by Mutation and Haplotype Analysis in the Type VII Collagen Gene (COL7A1). Mol Med 2, 59–76 (1996). https://doi.org/10.1007/BF03402203

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