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The Frequency of Aneuploidy in Cultured Lymphocytes Is Correlated with Age and Gender but Not with Reproductive History

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The Frequency of Aneuploidy in Cultured Lymphocytes Is Correlated with Age and Gender but Not with Reproductive History Am. J. Hum. Genet. 46:1101-11, 1990 The Frequency of Aneuploidy in Cultured Lymphocytes Is Correlated with Age and Gender but Not with Reproductive History Gregory R Nowinski,$* Daniel L. Van Dyke, * Barbara C. Tilley, * Gordon Jacobsen,* V. Ramesh Babu,* Maria J. Worsham,* Golder N. Wilsont and Lester Weiss* * Medical Genetics and Birth Defects Center, and Division of Biostatistics and Research Epidemiology, Henry Ford Hospital, Detroit; and tDepartment of Pediatrics, University of Texas Southwestern Medical Center, Dallas Summary The clinical significance of low numbers of aneuploid cells in routine cytogenetic studies of cultured lym- phocytes is not always clear. We compared the frequencies of chromosome loss and gain among five groups of subjects whose karyotypes were otherwise normal; these groups were (1) subjects studied because of multiple miscarriages, (2) parents of live borns with autosomal trisomy, (3) subjects studied because they had a relative with Down syndrome, (4) an age-matched control group of phenotypically normal adults studied for other reasons (e.g., parent of a dysmorphic child or member of a translocation family), and (5) other mostly younger and phenotypically abnormal subjects who could not be assigned to the first four groups (e.g., individuals with multiple congenital anomalies or mental retardation). No significant age, sex, or group effects were observed for autosomal loss (hypodiploidy) or gain (hyperdiploidy). Au- tosomal loss was inversely correlated with relative chromosome length, but autosomal gain was not. Sex- chromosome gain was significantly more frequent in females than in males, but sex-chromosome loss was not significantly different between the sexes. Significant age effects were observed for both gain and loss of sex chromosomes. When age and sex were accounted for, the frequencies of sex-chromosome loss and gain were not significantly different among the five clinical groups. In general, low numbers of aneuploid cells are not clinically important when observed in blood chromosome preparations of subjects studied because of multiple miscarriages or a family history of autosomal trisomy. Introduction ing the course of the cytogenetic analysis of these sub- Karyotype studies are done on a large number ofpheno- jects to be of no clinical significance (e.g., see Sandberg typically normal adults. These are often couples who et al. 1967; Wenger et al. 1984; Horsman et al. 1987; have experienced more than one miscarriage or who Castle and Bernstein 1988; Hassold et al. 1988). But are relatives of subjects with autosomal trisomy. The others have described a higher frequency ofhyperdiploid expectation is that some will have a balanced chromo- cells or "sex chromosome mosaicism" in parents of some rearrangement. Some workers have considered the aneuploids and in individuals with multiple miscar- single hypodiploid or hyperdiploid cell observed dur- riages (e.g., see Stallard et al. 1981; Staessen et al. 1983; Ford 1984; Hecht et al. 1984; Holzgreve et al. 1984; Juberg et al. 1985; Sachs et al. 1985). Larger-scale in- Received May 30, 1989; final revision received February 1, 1990. vestigations with age-matched controls were recom- Address for correspondence and reprints: Daniel L. Van Dyke, mended to assess the significance of these aneuploid Ph.D., Henry Ford Hospital, Detroit, MI 48202. cells (Michels et al. 1982). Here we report our findings 1. Present address: Department of Orthopedics, William Beau- mont Hospital, Royal Oak, MI. from a retrospective study to examine the pattern of X 1990 by The American Society of Human Genetics. All rights reserved. aneuploidy against a normal karyotypic background, 0002-9297/90/4606-0011$02.00 particularly in adults within their reproductive years. 1101 1102 Nowinski et al. Material and Methods The karyotype data sheets were reviewed to identify hypodiploid or hyperdiploid cells. Next we confirmed, All peripheral blood karyotypes processed over the microscopically or from photographs, which chromo- 5-year period 1979-83 at Henry Ford Hospital and the somes were lost or gained. A cell was defined as hyper- University of Michigan were included in a retrospec- diploid if it had more than 46 structurally normal tive study. Each karyotype record typically included data chromosomes and if the extra chromosome(s) was on analysis of 15-30 G-banded mitotic spreads of pe- recognizable and structurally normal. Cells were ex- ripheral leukocytes cultured using standard techniques. cluded which were found to be "hyperdiploid" because Each karyotype record was placed in one of the five of gain of a chromosome which differed greatly in the following groups: (1) multiple miscarriages, including degree of condensation compared with that in the re- 698 individuals who had had-or whose spouses had maining chromosomes in the metaphase spread, since had-two or more spontaneous abortions, (2) parents such a chromosome usually represents a "floater" from of trisomics, including 62 parents of offspring with a broken metaphase cell (i.e., a technical artifact). Ex- trisomy 21, nine parents of offspring with trisomy 13, tra X chromosomes with "premature centromere divi- and seven parents ofoffspring with trisomy 18, (3) other sion" were not excluded (Fitzgerald et al. 1975). If a relatives of Down syndrome subjects whose exact karyo- subject had a cell with sex-chromosome aneuploidy, type was unknown to the relatives, including 161 chro- our routine laboratory procedures dictated counting mosomally normal first- and second-degree relatives of 35-50 additional cells whenever possible. For statisti- unkaryotyped Down syndrome subjects, (4) control cal analysis reasons these additional cells were not in- adults, constituting an age-matched comparison group cluded in the study. and including 332 phenotypically and karyotypically Statistical tests were performed on individuals rather normal adults (e.g., members of translocation families than on cells. Since a varying number ofcells were stud- and parents of a karyotypically normal dysmorphic ied per individual (range 3-99, mean 20, median 16 child), and (5) all others, including 1,139 mostly youn- cells/person), Mantel-Haenszel X2 tests were used to ger individuals who could not be assigned to one of compare the presence or absence of hypo- and hyper- the preceding groups (e.g., chromosomally normal sub- diploid cells among groups, separately for each sex af- jects with multiple congenital anomalies or with men- ter subjects.were stratified by number of cells scored. tal retardation). None of the multiple miscarriage sub- Strata used were <10, 11-15, 16-20, 21-25, and >26 jects had a trisomic live-born offspring. The karyotypes cells scored. Mantel-Haenszel tests were also used to of their miscarriages were unknown. About 5% of the compare males and females for sex-chromosome hypo- couples in the parents of trisomics group had had two and hyperdiploidy, again with adjustment for the num- miscarriages, but these subjects were all referred ber of cells scored. A weighted regression analysis was for chromosome analysis because of their trisomic also used to test for a group effect on hyper- or offspring. hypodiploidy, after adjustment for age, age squared, Subjects with abnormal karyotypes and those inter- and sex. For all regression analyses the proportion of preted as having chromosomal mosaicism were excluded cells with the finding ofinterest was computed for each from the study. The mosaics included an infant with person, and this proportion was used as the dependent ambiguous genitalia and X/XY mosaicism; two measure being studied. An arcsin transformation (Neter Klinefelter patients with XY/XXY mosaicism; six Down and Wasserman 1974) ofthe proportions was used. By syndrome patients with trisomy 21 mosaicism; one using a proportion for each subject and using a weighted each with malformations and mosaicism for r(5), +8, regression analysis, it was possible to adjust for the +18, r(21), +22, or + small ring chromosome; one differing number of cells studied per person. Age man with 46,XY (three cells)/47,XYY (14 cells) whose squared was included because plots suggested some wife had had multiple miscarriages; two blood speci- findings were not linearly related to age. The five clini- mens to confirm prenatally diagnosed mosaicism: cal groups were represented in the regression model by 46,XX/47,XXX and 45,XYt(13;13) (pll;pll)/46,XY; four dummy variables. The dummy variables were for- and 25 females with features consistent with Turner mulated such that the group "all others" would be rep- syndrome who had X numerical mosaicism, X/XY resented by a negative response to membership in any mosaicism, X isochromosomes, rings, deletions, trans- of the other four groups. Where no group effect was locations, and a familial small supernumerary ring chro- detected, a stepwise regression analysis was run with mosome. age, age squared, and sex as the independent variables Frequency of Aneuploidy in Cultured Lymphocytes 1103 to assess the effects of these variables. Because of the somes (R = .04; fig. 1). No significant differences were many analyses, a P-value of .01 was used as the criterion found among the groups in the distributions of au- for significance of a group effect in the regression anal- tosomal hyperdiploidy in either males or females (P > yses and for entry in the stepwise analysis. The regres- .19 and P> .43, respectively). No significant group (P> sion analysis statistics are summarized in the Appendix. .18) and no age or sex effects were detected when regres- sion analysis was used. Only two of the parents of tri- somics an extra autosome. Subject B79- Results had cells with 267, the 22-year-old father of an individual with trisomy In all, 47,361 cells were analyzed from 2,408 sub- 21, had one cell among 14 with 47,XY,+19. This was jects (tables 1 and 2). At least one cell with autosomal his first child. Subject B79-71, a 26-year-old mother hypodiploidy was found in 39.7% of the karyotype of a trisomy 21, had one cell among 20 with 48,XX, studies, and 2.8% of all female cells and 3.0% of all +10,+11.
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