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. 2003 Oct;73(4):939-47.
doi: 10.1086/378419. Epub 2003 Jul 31.

The Paternal-Age Effect in Apert Syndrome Is Due, in Part, to the Increased Frequency of Mutations in Sperm

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The Paternal-Age Effect in Apert Syndrome Is Due, in Part, to the Increased Frequency of Mutations in Sperm

Rivka L Glaser et al. Am J Hum Genet. .
Free PMC article


A paternal-age effect and the exclusive paternal origin of mutations have been reported in Apert syndrome (AS). As the incidence of sporadic AS births increases exponentially with paternal age, we hypothesized that the frequency of AS mutations in sperm would also increase. To determine the frequency of two common FGFR2 mutations in AS, we developed allele-specific peptide nucleic acid-PCR assays. Analyzing sperm DNA from 148 men, age 21-80 years, we showed that the number of sperm with mutations increased in the oldest age groups among men who did not have a child with AS. These older men were also more likely to have both mutations in their sperm. However, this age-related increase in mutation frequency was not sufficient to explain the AS-birth frequency. In contrast, the mutation frequency observed in men who were younger and had children with AS was significantly greater. In addition, our data suggest selection for sperm with specific mutations. Therefore, contributing factors to the paternal-age effect may include selection and a higher number of mutant sperm in a subset of men ascertained because they had a child with AS. No age-related increase in the frequency of these mutations was observed in leukocytes. Selection and/or quality-control mechanisms, including DNA repair and apoptosis, may contribute to the cell-type differences in mutation frequency.


Figure  1
Figure 1
Specificity and sensitivity of the allele-specific PNA-PCRs. a, Melt-curve analysis after amplification of DNA from a patient with the 755C→G mutation yielded one specific peak. No cross reactivity with the other 758C→G mutation occurred. Inset shows melt-curve analysis for the 758C→G mutation with no cross reactivity for the 755C→G mutation. b, Amplification of standards and three samples of the 758C→G mutation. Standards used were 45, 15, 5, and 1 mutant copies diluted in human genomic DNA. Duplicates of each standard are shown. Negative controls are water and human genomic DNA. c, Melt-curve analysis after amplification of standards and samples from b. d, Standard curve for the 755C→G mutation with duplicates of each standard.
Figure  2
Figure 2
Mutation frequency with age. The number of sperm with either FGFR2 mutation increases with age. a, Average for a given individual. A single diamond symbol may represent more than one individual with the same age and mutation frequency. b, Average for a given decade. Error bars indicate the 95% CIs. c, Percent of men in each age group with both mutations in sperm increases with age. Above each bar is the number of men with both sperm mutations over the total number of men in each age group. Insets are for each mutation or either mutation, as noted. Circles in panel a indicate those individuals who had both mutations in their sperm.
Figure  3
Figure 3
Comparison between the sperm mutation frequency (data from fig. 2a) and frequency of birth of children with AS (Risch et al. 1987), by use of fold change with respect to the value for age <25 years.
Figure  4
Figure 4
Comparison of the mutation frequencies in men who have and have not fathered a child with AS. The inset shows the comparison between men with a child with AS and all men, whether or not they had fathered a child.
Figure  5
Figure 5
Comparison of the mutation frequencies in sperm and white blood cells from the same individual in a subset of 21 men who did not have a child with AS.

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