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Maternal age specific rates for all major chromosome aberrations have been determined in 52 965 pregnancies in mothers 35 years of age and over at the time of amniocentesis. Rates increase exponentially with advancing maternal age for trisomies 21, 18 and 13, and for the XXX and XXY syndromes, but in the autosomal trisomies this rise appears to be followed by a levelling off at the upper end of the age range. A significant inverse relationship with maternal age is found for 45,X cases. It is postulated that these various patterns are the result of the interaction of three principal factors: a maternal age effect acting particularly on first meiotic nondisjunction: a higher spontaneous abortion rate with advancing maternal age for aneuploid as compared to euploid conceptions; and an increased probability of spontaneous abortion before the time of amniocentesis for conceptions with more extensive chromosome imbalance. A stepwise logistic regression analysis of 13 299 pregnancies in which both parental ages are known shows that the father's age does not influence these maternal age specific rates, with the possible exception of the 47,XXY syndrome.

Paternal age distribution for 1279 cases of Down's syndrome born in 1952--1968 was compared with the corresponding distribution for the general population, corrected for the maternal age as well as for the year of birth of the patients. Although there was no difference in the mean paternal age, the two distributions differed significantly, largely due to the excess of fathers aged 55 years and over and to the deficit of those aged 40--44 years in the patients born to mothers aged 30 years and over. The overall pattern of the relative incidence of Down's syndrome with advancing paternal age, with maternal age controlled, seems consistent with the hypothesis proposed by Stene et al. (1977). It increased from 0.8 for fathers aged 20--24 years slowly up to 1.2 for those aged 45--49 years, though with an intermediate drop to 0.8 at the age of 40--44 years, and then sharply to 2.4 for those aged 55 years and over. This rising pattern of the relative incidence with paternal age was essentially the same for the patients born in 1952--1960 and for those born in 1961--1968, although the slope was less steep in the latter than in the former group.

The discovery that in 20% to 30% of Down's syndrome cases the extra chromosome is of paternal origin, and the recent independent report of two groups that maternal age-specific rates are two-fold greater for livebirths to couples in which the father is aged 55 years and over prompted this investigation. Analyses were of coded birth certificate reports of Down's syndrome in Upstate New York residents in the years 1963-1974. The expected numbers of cases, on the assumption of no paternal age effect, were determined at each paternal age interval (and at each paternal age minus maternal age interval) adjusting for an effect of maternal age; these were compared with observed values. There was a slightly lower number of observed than expected cases for fathers aged 55 years and over (ratio = 0.76), and the results exclude with 95% confidence an increase of 1.5-fold or greater in rates in this group after correction for maternal age. There was, moreover, no overall evidence for any trend to increasing rates with paternal age. Regression analyses in which the data were first fit to functions of maternal age and subsequently terms involving paternal age were introduced also revealed no evidence that paternal age made a significant independent contribution to the observed rates in contrast to the conclusion of earlier positive reports.

A statistical method is developed for detecting a moderate effect on the incidence of a disorder caused by advancing age of one parent when it is known that advancing age of the other parent is of great aetiological importance. The method is a conditional test procedure given the parental ages, therefore no assumptions about the parental age distributions have to be made. The method is applied on Danish material on Down's syndrome, for which a paternal age effect is demonstrated. Methods used in some well-known previous investigations have been discussed. Several of them, e.g. the classical one of Penrose (1933), could hardly detect any paternal age effect in Down's syndrome on the available data, because these methods are heavily affected by certain fertility patterns not recognized previously.

There are certain de novo germline mutations associated with genetic disorders whose mutation rates per generation are orders of magnitude higher than the genome average. Moreover, these mutations occur exclusively in the male germ line and older men have a higher probability of having an affected child than younger ones, known as the paternal age effect (PAE). The classic example of a genetic disorder exhibiting a PAE is achondroplasia, caused predominantly by a single-nucleotide substitution (c.1138G>A) in FGFR3. To elucidate what mechanisms might be driving the high frequency of this mutation in the male germline, we examined the spatial distribution of the c.1138G>A substitution in a testis from an 80-year-old unaffected man. Using a technology based on bead-emulsion amplification, we were able to measure mutation frequencies in 192 individual pieces of the dissected testis with a false-positive rate lower than 2.7 × 10(-6). We observed that most mutations are clustered in a few pieces with 95% of all mutations occurring in 27% of the total testis. Using computational simulations, we rejected the model proposing an elevated mutation rate per cell division at this nucleotide site. Instead, we determined that the observed mutation distribution fits a germline selection model, where mutant spermatogonial stem cells have a proliferative advantage over unmutated cells. Combined with data on several other PAE mutations, our results support the idea that the PAE, associated with a number of Mendelian disorders, may be explained primarily by a selective mechanism.

Analysis by the method of Smith (1972) of birth order and parental age data collected from 38 of 42 patients with fibrodysplasia ossificans progressive shows a significant paternal age effect. This finding among the sporadically occurring cases would support the proposition that this condition usually arises as a new dominant mutation.

Background: Advanced paternal age is robustly associated with several human neuropsychiatric disorders, particularly autism. The precise mechanism(s) mediating the paternal age effect are not known, but they are thought to involve the accumulation of de novo (epi)genomic alterations. In this study we investigate differences in the frontal cortex transcriptome in a mouse model of advanced paternal age. Findings: Transcriptomic profiling was undertaken for medial prefrontal cortex tissue dissected from the male offspring of young fathers (2 month old, 4 sires, n= 16 offspring) and old fathers (10 month old, 6 sires, n =1 6 offspring) in a mouse model of advancing paternal age. We found a number of differentially expressed genes in the offspring of older fathers, many previously implicated in the aetiology of autism. Pathway analysis highlighted significant enrichment for changes in functional networks involved in inflammation and inflammatory disease, which are also implicated in autism. Conclusions: We observed widespread alterations to the transcriptome associated with advanced paternal age with an enrichment of genes associated with inflammation, an interesting observation given previous evidence linking the immune system to several neuropsychiatric disorders including autism.