American Journal of Medical Genetics 5: 145-1 5 1 (1980)

Genetic Counseling Dilemmas: Down Syndrome, Paternal Age, and Recurrence Risk after Remarriage Ernest B. Hook

Birth Defects Institute, Division of Laboratories and Research, New York State Depart. ment of Health, Albany, and Department of Pediatrics, Albany Medical College

The recent demonstration that about 20&30%of cases of Down syndrome are of paternal origin has again raised interest in the question of the possible contribu- tion of paternal age independent of matcrnal age to a couple’s risk of a Down syndrome live birth. In this paper the nature of the available evidence is critically reviewed, interpretations reconciling differences between studies that reached opposite conclusions are presented, and an approach t o genetic counseling in the face of such apparent differences in the literature is discussed. It is not like- ly that data from ad hoc studies of parental origin of the extra chromosome will be sufficient t o judge the existence or magnitude of patcrnal age-specific risk, and reliance must be made on statistical studies that searched for paternal age effects while controlling for maternal age. The literature is consistent with an apparent doubling of risk for paternal age 5 5 and ovcr, but n o effect at younger paternal ages. With regard to remarriage, it is suggested that if mem- bers of a couple with a 47, +21 child remarry it be assumed that the excess risk “travels” t o that new couple which includes the parent in whom non- disjunction occurred in the previous marriage. If parental origin is not known, it is suggested that the risk be calculated on the assumption of a 20-30% like- lihood that it was of paternal origin and a 70-807& likelihood that it was of maternal origin, and that the excess ernpiric risks be apportioned accordingly in the new marriages.

Key words: Down syndrome, nondisjunction, maternal age, paternal age, genetic counseling

Received for publication March 29, 1979; revision received May 20, 1979.

Address rcprint rcquests to Frncst 6. Hook, NYS Birth Defects Institute, Division of Laboratories and Research, New York State Department of Health, Albany Medical College, Albany, NY 12237.

0148-7299/80/0502-0145$01.70 0 1980 Alan R. Liss, Inc.

146 Hook

INTRODUCTION

The recent discovery that the extra chromosome in a significant fraction of individuals with 47,+21 Down syndrome (DS) is of paternal origin has revived interest in the question of whether there is a paternal age effect independent of maternal age in DS. Paternal age has, of course, been documented as positively associated with an increased frequency of dominant mendelian mutations, but the absolute aggregate frequencies of such conditions remain small even at advanced age, and of course the possibility of prenatal diagnosis for most of these dominant conditions is remote at present. In contrast, an independent pa- ternal age effect for chromosomal abnormalities, in particular DS, might be of greater significance for prenatal genetic counseling. In this regard an interesting controversy has arisen from conflicting reports. Some observers have suggested a paternal age effect, par- ticularly at ages 55 and over [ I , 21 ~ while others have reported no evidence of such an effect at any age [ 3 ] .

The existence of such reports reaching opposite conclusions, and the fact that at least one paper implying the probable significance of paternal age has received national publicity within the United States [4] , leave genetic counselors in a quandary as to what course to take in adjusting for paternal age effects either quantitatively or qualitatively in counseling individuals concerning risk of DS at birth.

Tn this paper tlie nature of the available evidence on this question is critically re- viewed, the limitations of the data are discussed, possible interpretat,ions reconciling ap- parent diffcrcnces between studies are presented, and a suggested approach to genetic coun- seling in tlie face of such differences in the literature is presented.

The possibility of a paternal age effect in DS has long been of interest. Penrosc, among others, was able to show that if there was a paternal age effect it was considerably weaker than a maternal age effect [5] . Subsequently in many of his writings (see, for example, Penrose and Smith [ 6 ] ) , he appeared t o assume that paternal age was not of significance arid that - except for fathers with 47,+21 mosaicisrn or a balanced translocation - instances of DS were of maternal origin exclusively. Such analyses have been criticized, however, by Mantel and Stark [7] and Lilienfeld [8 J , among others, as lacking power t o exclude a weak or even moderate paternal age effect in tlie face of a strong maternal age effect. It should be noted that different types of paternal age effects are possible, and that a “weak” effect in one sense might be “strong” in another. As one example, paternal age- specific risks (adjusted for maternal age) might be greater than maternal age-specific risks (adjusted for paternal age) at some age categories and lower at others. Thus it is conceivable that a t the extremes of parental age, the absolute association with DS is greater with paternal than maternal age, and this eff-ect is obscured by the vast bulk of cases oc- curring at othcr agcs, at which a paternal age effect is trivial if it exists at all.

I t is also einphasired that it is not necessarily true that because the extra chromo- some in a significant fraction of47,+21 DS is of paternal origin that therefore there must he a paternal age effect, as implied by at least one report [4] . The situation regarding the 47,XYY genotype illustrates this. The extra chromosome in the latter condition is of course of paternal origin, but there is no evidence of an increasc of the risk of X W genotype with paternal age; indeed if anything thcrc is a suggestion of a slight decrease with advancing age 191.

PERTINENCE OF CYTOGENETIC DATA ON PARENTAL ORIGIN

Theoretically it would appear likely that data on parental age in studies which assign parental origin of the extra chromosome would allow inferences a:s to the existence and magnitude of paternal age effects. Unfortunately, the only inference that is likely t o be

Genetic Counseling Dilemmas 147

TABLE I. Parental Ages and Origin of Extra Chromosome in 47, Trisomy 21 in Four Studies

Study

Maternal Paternal Midparental age age age

Paternal No. of origin cases Mean SD Mcan SD Mean SD

~~ ~

Hansson and Mikkelscn [ 101

Magenis et a1 [ 11 ]

Wagenbichler et a1 1121

Uchida (personal communication)

Paternal

Maternal

Paternal

Maternal

Paternal

Maternal

Paternal

19 28.6 6.3 31.6 7.6 30.1 6.8

7 28.3 6.0 29.3 5 . 5 28.8 5.7

24 30.5 7.6 33.1 8.8 31.8 8.0

7 28.4 8.8 29.7 5.9 29.1 7.1

10 37.1 7.0 38.8 6.0 38.0 6.3

8 28.8 7.9 33.9 10.2 31.3 8.8

19 34.3 7.8 35.5 7.9 34.9 7.7

7 27.0 5.3 31.3 4.7 29.1 4.9

available from such studies, at least in the near future, is that a paternal age effect, if it exists, is wzaker than the maternal age effect, a fact already known from the statistical studies. The grounds for this are illustrated by considering an analysis of results from four studies on parental ages and parental origin* (see Table I).

ternal origin are older than those of paternal origin. But for cases of paternal origin the question remains as to what data from the general population are appropriale for compari- son in seeking evidence of a paternal age effect. (Presumably, maternal age is significant in cases of maternal origin and it is only in cases of paternal origin that evidence for a paternal age effect, if it exists, should be expected.) Unfortunately, because of geographic and tem- poral variation, control data cannot be derived from any single vital statistics report. Various biases attributable to demographic changes, and possible selective factors affecting inclusion of cases for study of parental origin make use of statistics from vital records in any jurisdic- tion for any single year inappropriate for this purpose. The reasons for this are that there has been nut only a recent marked drop in fertility in many countries but also a steady decline in the proportion of older wonien among those having live births. This has resulted in a secular decline in mean parental age of individuals with Down syndrome, a decline which antedates the introduction of amniocentesis but which has been accelerated because of the latter factor as well. Therefore the contemporary ages of affected cases will markedly in- fluence the parental ages in any series. If, for example, institutionalized cases are studied, they will tend to have been born some years ago and their parental ages will be on the average much higher than cases born recently. (Indeed such factors may explain the dif- ferences in ages between those in the study of Wagenbichler et a1 [ 121 and the others summarized in Table I.)

tion on the relative strengths of maternal and paternal etiologic categories, may not pro- vide appropriate data on the existence or magnitude of any putative paternal age effect,

A comparison by parent of origin reveals that in each study the parents of cases of ma-

Thus data derived from cytogenetic studies, while they may usefully provide informa-

"Data on the parental origin of the extra chromosome in individuals with DS does not o f course neces- sarily reflect the relative likelihood of parental meiotic nondisjunction for the 21st chromosome be- cause prezygotic or in utero events might selectively influence the relative proportion surviving for study.

148 Hook

without further extensive and detailed studies. (These would involve analyses comparing observed paternal ages with those expected in randomly selected individuals born in the same years and in the same jurisdiction as the DS cases. To expedite such analysis, it is suggested that those publishing their data in the future also include the age at which indi- viduals were studied, and whether they were born in the geographic jurisdiction of the laboratory.) Data of the type and extent necessary may not be available until some years in the future. Until they are available, however, genetic counselors must rely upon results of large-scale statistical studies.

RESULTS OF STATISTICAL STUDIES

Stene e t a1 [ 1) were the first t o report a paternal age effect independent of a mater- nal age effect. In data on 224 cases they reported evidence of a paternal age effect for fathers aged 55 years and over, an approximate doubling in rate, but reported n o direct evidence for an effect in fathers under 55.

A subsequent study by Matsunaga et a1 [2] of births in Japan also found a significant effecl for men 55 and over of about a twofold magnitude. Thcre was no paternal age effect detected, however, for younger men; in fact, there was a deficit of expected cases for those aged 40-44. Matsunaga et a1 also calculated a regression equation of the increase in the relative incidence (defined as ratio of observed t o expected cases) with paternal age (correct- ed for maternal age), and they found the coefficient t o be 0.003 * 0.008 per year, slightly positive but not significantly difrerent from a horizontal line which would be consistent with no change with age. Taking the magnitude of the coefficient at face value, one would predict that a couple in which the man is 10 years older than his wife has a risk only 1.03 times greater, ie, 3% higher, than that of a couple in which both husband and wife are the same age. But even this approach might overestimate the increased risk for fathers under 55 because the bulk, if not all, of the effect came only from fathers 55 and and over. for whom the risk is increased by a factor of 2 . If this is thc case, then the adjustment required is trivial for paternal age under 55 irrespective of maternal age and only significant for fathers 55 and over.

States, Erickson [3] could find no evidence whatever of a paternal effect at any age. Stene and Stene [ 13J , in a detailed review of Erickson’s study, noted that there was an apparent dearth of cases in his series involving some parental age combinations. Specifically, there were fewer cases born to mothers under 35 wed to older f-athers than would be expect- ed. The direct pertinence of this t o Erickson‘s conclusion was not noted by these authors, but the implication is that Erickson’s sample of DS cases, which was based on vital certificate reports, was a biased, not a representative, sample from the general population and thus conclusions drawn from it must be suspect. This would only be the case, however, if the bias in Erickson’s study is relevant t o missing a paternal age effect. Ekcause in Erickson’s series there were a large number of cases born t o older fathers wed to women 35 and over but no evidence of a paternal age effect in this group, the unusual nature of the sample can explain the discrepancy between his report and those of others only if a putative pater- nal age effect of significant magnitude is operative only for older fathers - those 55 and over - married t o women under 35. This is equivalent to there being a complex interaction between maternal and paternal factors with regard t o risk. There is at present, however,

Nevertheless, in a study involving a much larger number of live births in the United

Genetic Counseling Dilemmas 149

no direct evidence in support of such a hypothesis, for which incidentally there appears no precedent with regard to any congenital defect (of multifactorial etiology) of which I am aware.

Data from case-control studies provide additional evidence of the general lack of significance of paternal age over most of the age spectrum. For example, in a study some years ago by Sigler et al [141 for 215 cases of DS matched very closely on maternal age with controls there was no difference in paternal ages [14]. Subsequently, the same group reported a further study of another 128 affected individuals and again found no significant paternal age effect; indeed the trend was to the fathers of DS patients being younger than controls [ lS] . These considerations do not exclude the possibility of an increased risk for veiy elevated paternal ages, eg, 55 and over, but suggest that the overall contribution of paternal age effect to the occurrence of DS in the general population is likely to be of small significance.

IMPLICATIONS FOR GENETIC COUNSELING

Despite the apparent lack of impact of paternal age on the population prevalence of DS in live births, genetic counselors must frequently confront the issue of the possible significance of paternal age as a predisposing factor, particularly among couples sensitized to this issue by the wide publicity given to this factor that resulted from a recent article in the United States [4].

The available evidence to date, reviewed above, suggests that a risk associated with paternal age is present only for nien 55 and over, and even this inference must remain ten- tative because it was found in only 2 of 3 studies that had power to detect an effect, Cer- tainly there is no evidence reported in any of these studies, nor in any other studies in the literature, of an effect of any significant magnitude for men under 55.

On the basis of currently available information, the best estimate of risk for a man 55 or over is obtained by doubling the risk to any couple that would be derived on the basis of age alone.* Thus for a 30-year-old woman married to a 55-year-old man, the es- timated risk would be about 2 per 1,000, about twice that if she were married to a younger man, assuming there are no known factors pertinent to risk in this couple aside from paren- tal age.

It might be suggested in view of Erickson’s data that the cited risk should be pertinent only for cases in which the very old father is married to women under 35, but it would appear best to await further data on this point before introducing this additional adjust- ment into counseling.

possible paternal origin of the extra chromosome in DS. This occurs if the members of a couple who have had a 47, trisomy 21 child (at young maternal age) subsequently marry other individuals. If the mother in the first couple is under 35, sparse data from the litera-

*It is difficult to postulate a biologic mechanism associated with a doubling of maternal age-specific risk associated with a particular paternal age without also invoking an interaction between paternal and maternal factors that would influence the occurrence of af iwted individuals. There is to my knowledge no independent evidence of such a relation. It is possible that the published observations arc also compatible with a simpler quasiadditive model for paternal and maternal age effects which do not depend on such an interaction. For counseling purposes, however, one can use only the analyses of data as published.

There is one other issue that arises in genetic counseling because of concern with

150 Hook

ture [ 161 suggest the recurrence risk of the original couple is about 1-2%. It will be assumed here - in the absence of evidence to the contrary - that this exccss risk pertains irrespec- tive of which parent the extra chromosome is derived from, but is attributable only to the remarried parent, so that the excess risk “travels” with the parent of origin to the new mar- riage*. Thus, if the father were the origin of the extra chromosome and he remarried, his new marriage would have the excess risk, and that risk for his former wife’s new marriage would be purely that associated with parental age.

risks of the new couples may be estimated on the basis of the knowledge that about 20-30% of47,+21 instances are of paternal origin and 75- 80% are of maternal origin. Therefore, for the father of a case (born to a mother under 35) who remarries the risk of this couple because of this factor may be estimated as in thc rangc (0.20) (0.01) to (0.30) (0.02) or 0.2%-0.6%. This is of the order of magnitude associated with maternal age 20 to 34, which ranges from 0.06% to 0.22%. It is suggested that the einpiric risk of the couple therefore be calculated by adding the risk 0.2%-0.6%, attributable to possible paternal origin to that associated with maternal age of the new wifef. For a DS patient’s mother who is under 35 and remarries, the excess risk because of this factor may be calculated analogously as about 0.7%-1.6%, which may also be added to the risk associated with her age.

tion is somewhat more complicated. Sparse data in the literature suggest, but do not es- tablish, that in this instance the increased recurrence risk because of a previous affected case is not important and is outweighed by maternal age-specific risks. But even if this is correct for cases of maternal origin, it may not apply for those of paternal origin. The simplest approach is the more conservative one, to treat risks additively as in the situation discussed above.

The above discussion of remarriage assumes the husband is under 55 in each case. If he is over 55, it would appear appropriatc, in view of earlier discussion, to double the risk associated with maternal age used in all calculations.

It is emphasized that these suggestions concerning risk estimates are based on extra- polations from the available data, are dependent on the assumptions cited, and are subject to a measure of uncertainty whose boundaries cannot be gauged adequately. On the other hand, it appears better to have estimates, however, imperfect, for couples seeking genetic advice that are based on deductions from what is known rather than to have no estimates at all.

In most instances, however, the source of the extra chromosome is unknown. ‘Ihe

If the mother of the first couple is 35 or over at birth of the child with DS, the ques-

ADKNOWLEDGMENTS

I thank Susan Albright and Linda Culotty for the calculation in Table I, and Dr. Irene Uchida for permission to use her data.

*See comments following this paper if this assumption does not hold.

t.4 more appropriate mathematical formulation if factors from both parents contribute to higher empiric risk is as follows: If the risk associated with paternal factors is p and that with maternal factors (such as age) is x, the risk of the couple for a 1)s live birth, assuming no interaction. is approxirnatclp l-[(l-s) (I-y)] = x+y-xy. In almost all counseling situations concerning DS. because xy is so small, this value is very close to (x+y). (Instances of tetrasorny [4R, +21, +211, whose frequency is xy in llik formulation, are likely lo be lethal in embryonic life and not pertinent to tlie risk of affected livebirths. After ad- justing for this in estimating tlie risk in live births, thc value is about [x+y-2xyl / [ I - s y ] , also very close to [x+y] ).

Genet ic Counseling Di lemmas 151

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3. Erickson DJ: Down’s syndrome, paternal age, maternal age and birth order. Ann Hum Genet 41:289- 298,1978.

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Edited by Laurence E. Karp