Penetrance of Fra(X) gene: Influence of grandparental origin of the gene, mental status of the carrier mother, and presence of a normal transmitting male

Smits, A.P.T.; Oost, B.A. van; Haan, A.F.J. de; Hamel, B.C.J.; Dreesen, Jos; Smeets, Dominique

doi:10.1002/ajmg.1320430157

Cited by 6 publications

(4 citation statements)

References 8 publications

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“…On the other hand, an allele expanded to a lesser degree might be transmitted normally, and in this case the paternal-age effect would prevail. This assertion is supported by the report that alleles that are inherited from grandfathers possess a higher penetrance in males than those inherited from grandmothers (21). It should also be noted that many females who carry an expanded allele might be protected from manifestation of the disorder by X chromosome inactivation; many such females (some of whom have learning disabilities) maintain active reproduction, thereby enhancing the bias toward maternal transmission.…”

Section: Fragile X Syndromesupporting

confidence: 64%

Allelic instability in mitosis: a unified model for dominant disorders.

Zheng

Byers²,

Moolgavkar³

1993

Proc. Natl. Acad. Sci. U.S.A.

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Recent findings indicate that tandemly repeated triplet sequences in certain disease-causing human genes may render these genes highly unstable not only in meiosis but also in mitosis. Typically, a dominant mutation arises upon expansion in the number of these repeated elements. We have considered how mitotic instability of this sort might affect both phenotypic expression and allele transmission. A model based on these considerations leads to the following predictions: (i) Phenotypic severity among individuals who inherit an unstable allele should be highly variable due to stochastic variation in the stage of its earliest mutagenic expansion. (ii) Strikingly increased severity or decreased age of onset in some offspring should arise because of parental germ-line mosaicism for an expanded or mutant allele. (iit) The magnitude of genetic anticipation should be more strongly correlated with paternal than with maternal age at the time of conception. (iv) Given a child born with a severe phenotype, the recurrence risk for a second severely affected child should be significantly elevated. (v) The severity of phenotype in a child should be positively correlated with that in a parent. Available data on fragile X syndrome, Huntington disease, and myotonic dystrophy are shown to be consistent with the model, and implications for an understanding of achondroplasia and other dominant disorders are discussed.

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Section: Fragile X Syndromesupporting

confidence: 64%

Allelic instability in mitosis: a unified model for dominant disorders.

Zheng

Byers²,

Moolgavkar³

1993

Proc. Natl. Acad. Sci. U.S.A.

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“…If these figures for specificity and sensitivity are to be presented as positive and negative predictive values the frequency of mental retardation in the target population (fra(X) carriers) must be specified. We used the previously derived penetrance value of 85% and 64% (a) for males and females, respectively (Smits et al, 1992b), and applied the rule of Bayes. The positive predictive value in males was 100% and in females only 82% (b).…”

Section: Predictive Value Of the Cgg Repeat Length Determinationmentioning

confidence: 99%

Prediction of mental status in carriers of the fragile X mutation using CGG repeat length

et al. 1994

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For genetic counseling in fragile X (fra(X)) families, it is important to know the diagnostic impact of the CGG repeat length in carriers of the fragile X mutation. We have analyzed the CGG repeat length in 106 males and 73 females who had inherited the maternal fra(X) mutation. The sensitivity, specificity, and predictive value of the CGG repeat analyses, as measured on Southern blots of PstI/EcoRI digests, were calculated. In males the sensitivity, specificity and negative predictive value were 99%, 100% and 94%; respectively. In females the specificity (60%) and, consequently, the positive predictive value (82%) was reduced. Therefore, it remains impossible to predict accurately whether a female fetus demonstrating a full mutation will be affected. On the other hand, the negative predictive value of the CGG test in females was 100%. We have no evidence, as yet, that for female carriers with the full mutation, cytogenetic analysis is of additional value to predict the mental status. However, we have observed one mentally retarded fra(X) case with extreme mosaicism in which a typical premutation fragment was the predominant DNA species. Therefore, until more data and better DNA tests are available, we would like to advocate additional cytogenetic investigation if in a fetus a CGG repeat length in the premutation range is found.

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“…In the ideal situation that in this scenario everyone agrees to be tested, only 15% of all couples who will have a child with fragile X syndrome are detected. Generations tested Detected carriers (%) 15 10 0 5…”

Section: Discussionmentioning

confidence: 99%

“…[5][6][7][8][9][10][11][12] One of these testing strategies identifies (index) cases from a high-risk population-for example, special schools or institutions for mentally handicapped people-and oVers fragile X carrier testing to their relatives. [13][14][15][16][17][18] Some authors use the term "screening" for this strategy, but we prefer to call this cascade testing, as screening is generally thought to be oVered to a more general target population. 19 20 The term cascade testing was first proposed by Super et al 21 to describe a procedure for testing the extended members of families where the proband had cystic fibrosis.…”

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confidence: 99%