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Somatic mosaicism in hemophilia A: A fairly common event

Leuer, M.; Lavergne, J.-M.; Fregin, A.; Eigel, A.; Ljung, R. LU and Olek, K. (2001) In American Journal of Human Genetics 69(1). p.75-87
Abstract
Mutations in the large gene of clotting factor VIII (FVIII) are the most common events leading to severe human bleeding disorder. The high proportion of de novo mutations observed in this gene raises the possibility that a significant proportion of such mutations does not derive from a single germ cell but instead should be attributed to a germline or somatic mosaic originating from a mutation during early embryogenesis. The present study explores this hypothesis by using allele-specific PCR to analyze 61 families that included members who had sporadic severe hemophilia A and known FVIII gene defects. The presence of somatic mosaicisms of varying degrees (0.2%-25%) could be shown in 8 (13%) of the 61 families and has been confirmed by a... (More)
Mutations in the large gene of clotting factor VIII (FVIII) are the most common events leading to severe human bleeding disorder. The high proportion of de novo mutations observed in this gene raises the possibility that a significant proportion of such mutations does not derive from a single germ cell but instead should be attributed to a germline or somatic mosaic originating from a mutation during early embryogenesis. The present study explores this hypothesis by using allele-specific PCR to analyze 61 families that included members who had sporadic severe hemophilia A and known FVIII gene defects. The presence of somatic mosaicisms of varying degrees (0.2%-25%) could be shown in 8 (13%) of the 61 families and has been confirmed by a mutation-enrichment procedure. All mosaics were found in families with point mutations (8 [25%] of 32 families). In the subgroup of 8 families with CpG transitions, the percentage with mosaicism increased to 50% (4 of 8 families). In contrast, no mosaics were observed in 13 families with small deletions/insertions or in 16 families with intron 22 inversions. Our data suggest that mosaicism may represent a fairly common event in hemophilia A. As a consequence, risk assessment in genetic counseling should include consideration of the possibility of somatic mosaicism in families with apparently de novo mutations, especially families with the subtype of point mutations. (Less)
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organization
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Contribution to journal
publication status
published
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keywords
blood clotting factor 8, article, blastocyst, bleeding disorder, chromosome inversion, CpG island, embryo development, gene mutation, germ line, hemophilia A, human, human cell, inner cell mass, major clinical study, mosaicism, point mutation, polymerase chain reaction, priority journal, risk assessment, sequence analysis, somatic cell
in
American Journal of Human Genetics
volume
69
issue
1
pages
13 pages
publisher
Cell Press
external identifiers
  • scopus:0034972486
ISSN
0002-9297
DOI
language
English
LU publication?
yes
id
e72dd9bc-2cc4-4d18-8cfb-967d042509db
date added to LUP
2016-12-29 10:42:03
date last changed
2018-06-10 05:14:12
@article{e72dd9bc-2cc4-4d18-8cfb-967d042509db,
  abstract     = {Mutations in the large gene of clotting factor VIII (FVIII) are the most common events leading to severe human bleeding disorder. The high proportion of de novo mutations observed in this gene raises the possibility that a significant proportion of such mutations does not derive from a single germ cell but instead should be attributed to a germline or somatic mosaic originating from a mutation during early embryogenesis. The present study explores this hypothesis by using allele-specific PCR to analyze 61 families that included members who had sporadic severe hemophilia A and known FVIII gene defects. The presence of somatic mosaicisms of varying degrees (0.2%-25%) could be shown in 8 (13%) of the 61 families and has been confirmed by a mutation-enrichment procedure. All mosaics were found in families with point mutations (8 [25%] of 32 families). In the subgroup of 8 families with CpG transitions, the percentage with mosaicism increased to 50% (4 of 8 families). In contrast, no mosaics were observed in 13 families with small deletions/insertions or in 16 families with intron 22 inversions. Our data suggest that mosaicism may represent a fairly common event in hemophilia A. As a consequence, risk assessment in genetic counseling should include consideration of the possibility of somatic mosaicism in families with apparently de novo mutations, especially families with the subtype of point mutations.},
  author       = {Leuer, M. and Lavergne, J.-M. and Fregin, A. and Eigel, A. and Ljung, R. and Olek, K.},
  issn         = {0002-9297},
  keyword      = {blood clotting factor 8,article,blastocyst,bleeding disorder,chromosome inversion,CpG island,embryo development,gene mutation,germ line,hemophilia A,human,human cell,inner cell mass,major clinical study,mosaicism,point mutation,polymerase chain reaction,priority journal,risk assessment,sequence analysis,somatic cell},
  language     = {eng},
  month        = {12},
  number       = {1},
  pages        = {75--87},
  publisher    = {Cell Press},
  series       = {American Journal of Human Genetics},
  title        = {Somatic mosaicism in hemophilia A: A fairly common event},
  url          = {http://dx.doi.org/},
  volume       = {69},
  year         = {2001},
}