Cj. Zheng et al., ALLELIC INSTABILITY IN MITOSIS - A UNIFIED MODEL FOR DOMINANT DISORDERS, Proceedings of the National Academy of Sciences of the United Statesof America, 90(21), 1993, pp. 10178-10182
Recent findings indicate that tandemly repeated triplet sequences in c
ertain disease-causing human genes may render these genes highly unsta
ble not only in meiosis but also in mitosis. Typically, a dominant mut
ation arises upon expansion in the number of these repeated elements.
We have considered how mitotic instability of this sort might affect b
oth phenotypic expression and allele transmission. A model based on th
ese considerations leads to the following predictions: (i) Phenotypic
severity among individuals who inherit an unstable allele should be hi
ghly 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-l
ine mosaicism for an expanded or mutant allele. (iii) 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 severel
y affected child should be significantly elevated. (v) The severity of
phenotype in a child should be positively correlated with that in a p
arent. Available data on fragile X syndrome, Huntington disease, and m
yotonic dystrophy are shown to be consistent with the model, and impli
cations for an understanding of achondroplasia and other dominant diso
rders are discussed.