Frequency of Somatic and Germ-Line Mosaicism in Retinoblastoma: Implications for Genetic Counseling
Kimberly C. Sippel,Rebecca E. Fraioli,Gary D. Smith,Mary E. Schalkoff,Joanne Sutherland,Brenda L. Gallie,Thaddeus P. Dryja +6 more
TLDR
Genetic tests of germ-line DNA can provide valuable information that is not available through analysis of somatic (leukocyte) DNA, especially in disorders such as retinoblastoma, in which a high proportion of cases represent new mutations.Abstract:
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 ( approximately 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.read more
Citations
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Mechanisms and consequences of somatic mosaicism in humans
TL;DR: The role of selection in the phenotypic manifestations of mosaicism is emphasized, as well as the molecular genetic mechanisms by which they arise, in this review of somatic mosaicism.
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Sensitive and Efficient Detection of RB1 Gene Mutations Enhances Care for Families with Retinoblastoma
Suzanne Richter,Kirk Vandezande,Ning Chen,Katherine Zhang,Joanne Sutherland,Julie Anderson,Li-Ping Han,Rachel L. Panton,Rachel L. Panton,Patricia Branco,Brenda L. Gallie +10 more
TL;DR: A sensitive and efficient strategy to identify RB1 mutations that combines quantitative multiplex polymerase chain reaction (QM-PCR), double-exon sequencing, and promoter-targeted methylation-sensitive PCR is devised.
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Somatic gene mutation and human disease other than cancer: An update
TL;DR: It seems that the frequency of gene mutation in embryonic cells is not markedly different than that in the germ line, and genomic sequencing, performed on DNA from blood, shows many mutations which are conclusively somatic in origin.
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In vivo reversion to normal of inherited mutations in humans
TL;DR: This review examines examples of somatic mosaicism due to differences in DNA sequence arising from in vivo site specific reversion to normal of inherited mutations in humans.
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RB1 gene mutations in retinoblastoma
TL;DR: Analysis of 368 reported small mutations reveals considerable heterogeneity, and a notable recurrence of transitions is observed at 13 CpG‐dinucleotides that are part of CGA codons or splice donor sites.
References
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Journal ArticleDOI
A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma
Stephen H. Friend,Stephen H. Friend,René Bernards,Snezna Rogelj,Robert A. Weinberg,Joyce M. Rapaport,Daniel M. Albert,Thaddeus P. Dryja +7 more
TL;DR: The isolation of a complementary DNA segment that detects a chromosomal segment having the properties of the gene at this locus is described, which is expressed in many tumour types, but no RNA transcript has been found in retinoblastomas and osteosarcomas.
Journal ArticleDOI
Expression of recessive alleles by chromosomal mechanisms in retinoblastoma
Webster K. Cavenee,Webster K. Cavenee,Thaddeus P. Dryja,Robert A. Phillips,William F Benedict,Roseline Godbout,Brenda L. Gallie,A L Murphree,Louise C Strong,R. L. White +9 more
TL;DR: A comparison of constitutional and tumour genotypes from several cases indicates that tumorigenesis may result from the development of homozygosity for the mutant allele at the Rb-1 locus.
Journal Article
Allele-specific hypermethylation of the retinoblastoma tumor-suppressor gene.
Toshiyuki Sakai,Junya Toguchida,Naoko Ohtani,David W. Yandell,Joyce M. Rapaport,Thaddeus P. Dryja +5 more
TL;DR: It is believed that the hypermethylation of the retinoblastoma gene that is found in these tumors corresponds to the allelic inactivation of the gene, and it is speculated that erroneous hyperethylation without alteration of nucleotide sequence occasionally plays a role in the genesis of this cancer.
Journal ArticleDOI
Genetics of retinoblastoma
TL;DR: The genetic basis of retinoblastoma is reviewed and the alternative possibility is suggested that in the nonhereditary variant a single mutational step—possibly a small chromosome aberration—could be enough to produce a tumor.