TY - JOUR
T1 - Frequency of somatic and germ-line mosaicism in retinoblastoma
T2 - Implications for genetic counseling
AU - Sippel, Kimberly C.
AU - Fraioli, Rebecca E.
AU - Smith, Gary D.
AU - Schalkoff, Mary E.
AU - Sutherland, Joanne
AU - Gallie, Brenda L.
AU - Dryja, Thaddeus P.
N1 - Funding Information:
Initial mutations in families 26, 139, 218, and 266 were identified in 1991, in collaboration with D. W. Yandell's laboratory. We wish to thank Terri L. McGee, Joyce M. Rapaport, Julie Anderson, Liping Han, T.P. Dryja III, and Maricarmen Planas-Silva for their advice and assistance. This research was supported by National Eye Institute grants EY05321 and EY08683, by the Massachusetts Lions Eye Research Fund, Inc., and by gifts to the Taylor R. Smith Laboratory and the Ocular Molecular Genetics Institute. T.P.D. is a Research to Prevent Blindness Senior Scientific Investigator.
PY - 1998/3
Y1 - 1998/3
N2 - Although mosaicism can have important implications for genetic counseling of families with hereditary disorders, information regarding the incidence of mosaicism is available for only a few genetic diseases. Here we describe an evaluation of 156 families with retinoblastoma; the initial oncogenic mutation in the retinoblastoma gene had been identified in these families. In 15 (~10%) families, we were able to document mosaicism for the initial mutation in the retinoblastoma gene, either in the proband or in one of the proband's parents. The true incidence of mosaicism in this group of 156 families is probably higher than our findings indicate; in some additional families beyond the 15 we identified, mosaicism was likely but could not be proven, because somatic or germ-line DNA from key family members was unavailable. Germ-line DNA from two mosaic fathers was analyzed: in one of these, the mutation was detected in both sperm and leukocyte DNA; in the other, the mutation was detected only in sperm DNA. Our data suggest that mosaicism is more common than is generally appreciated, especially in disorders such as retinoblastoma, in which a high proportion of cases represent new mutations. The possibility of mosaicism should always be considered during the genetic counseling of newly identified families with retinoblastoma. As demonstrated here, genetic tests of germ-line DNA can provide valuable information that is not available through analysis of somatic (leukocyte) DNA.
AB - Although mosaicism can have important implications for genetic counseling of families with hereditary disorders, information regarding the incidence of mosaicism is available for only a few genetic diseases. Here we describe an evaluation of 156 families with retinoblastoma; the initial oncogenic mutation in the retinoblastoma gene had been identified in these families. In 15 (~10%) families, we were able to document mosaicism for the initial mutation in the retinoblastoma gene, either in the proband or in one of the proband's parents. The true incidence of mosaicism in this group of 156 families is probably higher than our findings indicate; in some additional families beyond the 15 we identified, mosaicism was likely but could not be proven, because somatic or germ-line DNA from key family members was unavailable. Germ-line DNA from two mosaic fathers was analyzed: in one of these, the mutation was detected in both sperm and leukocyte DNA; in the other, the mutation was detected only in sperm DNA. Our data suggest that mosaicism is more common than is generally appreciated, especially in disorders such as retinoblastoma, in which a high proportion of cases represent new mutations. The possibility of mosaicism should always be considered during the genetic counseling of newly identified families with retinoblastoma. As demonstrated here, genetic tests of germ-line DNA can provide valuable information that is not available through analysis of somatic (leukocyte) DNA.
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U2 - 10.1086/301766
DO - 10.1086/301766
M3 - Article
C2 - 9497263
AN - SCOPUS:0031959590
SN - 0002-9297
VL - 62
SP - 610
EP - 619
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 3
ER -