Original Article
Parental Origin of the Extra Chromosome in Trisomy 21 as Indicated by Analysis of DNA Polymorphisms
N Engl J Med 1991; 324:872-876March 28, 1991
- Abstract
- Abstract
Background.
Over the past 20 years, the parental origin of the extra chromosome in children with trisomy 21 has been investigated with cytogenetic methods of identifying morphologic variations in chromosome 21. These studies have concluded that the origin of the extra chromosome 21 was maternal in approximately 80 percent of cases and paternal in about 20 percent.
Methods.
We studied 200 families, each with a single child with trisomy 21, using DNA polymorphisms as markers to determine the parental origin of the nondisjunction causing the extra chromosome 21. These polymorphisms spanned a region of about 120 centimorgans on the long arm of chromosome 21, from the D21S13 locus (the most centromeric) to the COL6A1 gene (the most telomeric).
Results.
The parental origin of nondisjunction could be determined for all but 7 of the 200 children. It was maternal in 184 children (proportion [±SE], 95.3±1.5 percent) and paternal in 9 (4.7±1.5 percent). In a subgroup of 31 families, we compared the results of DNA analysis with those of traditional cytogenetic analysis. According to the cytogenetic analyses, nondisjunction originated in the mother in 26 cases (84 percent) and in the father in 5 (16 percent). DNA analysis demonstrated the origin as maternal in 29 (94 percent) and paternal in 2 (6 percent). With the cytogenetic analyses, there were three false determinations of paternal origin.
Conclusions.
In trisomy 21 the extra chromosome 21 is maternal in origin in about 95 percent of the cases, and paternal in only about 5 percent — considerably less than has been reported with cytogenetic methods. DNA polymorphic analysis is now the method of choice for establishing the parental origin of nondisjunction. (N Engl J Med 1991; 324:872–6.)
Article Activity
- Article
TRISOMY 21 is the most common chromosomal abnormality among children and the most common genetic cause of mental retardation. Since the early 1970s, inherited morphologic variations of the short arms of chromosomes seen in karyotypes (i.e., chromosomal heteromorphisms) have been used in families that have a child with trisomy 21 to determine the parental origin of the extra chromosome.1 , 2 The results of the major published studies have been summarized by Hassold and Jacobs.3 Of a total of 647 families studied, the parental origin of the extra chromosome was determined in 391. The studies of chromosomal heteromorphisms suggested that the origin was paternal in 76 cases (19.4 percent) and maternal in 315 (80.6 percent). The use of chromosomal heteromorphisms in these studies presented two major disadvantages. First, the parental origin of the error in chromosomal segregation (i.e., nondisjunction) could not be determined in 256 of the 647 families (40 percent) because the heteromorphisms were not informative. Second, the scoring of cytogenetic heteromorphisms can be subjective.
The introduction of analytic techniques involving DNA polymorphisms has greatly improved the study of the parental origin of nondisjunction in trisomy 21.4 , 5 The chief advantages of DNA polymorphisms are that they are highly informative, and therefore in most cases the parental origin can be determined; the polymorphic alleles can be scored objectively; and several markers can be used, for greater informative-ness. Furthermore, there is an abundance of DNA polymorphic markers on chromosome 21, most of which have been mapped on both physical and genetic linkage maps.6 , 7 Finally, the introduction of the technique of amplification by the polymerase chain reaction (PCR)8 has enabled investigators to discover novel types of polymorphisms in the DNA sequence and has facilitated the genotyping techniques in such a way that results can now be obtained in a single day.
We therefore attempted to reevaluate the parental origin of nondisjunction using DNA polymorphisms. We examined 200 families that had a child with trisomy 21 with 20 DNA polymorphic markers that map on the long arm of chromosome 21, comparing the results with those obtained from a traditional analysis of chromosomal heteromorphisms.
Methods
Families
A total of 200 families were studied, each with a child with chromosomally diagnosed trisomy 21. For each family, both parents, the proband, and unaffected siblings (if available) were analyzed with DNA polymorphic markers. A subgroup of these families was also studied with use of chromosomal heteromorphisms as described below under Cytogenetic Analysis. The 200 families were referred from the following clinical genetics centers: the Institute of Medical Genetics, University of Zurich, Zurich, Switzerland; the Institut de Progenèse, Hôpital Necker, Paris; the John F. Kennedy Institute, Glostrup, Denmark; the Division of Human Genetics, University of Maryland, Baltimore; Mansoura University, Mansoura, Egypt; the Genetics Center, Texas Children's Hospital, Houston; the Division of Medical Genetics, Alberta Children's Hospital, Calgary, Alberta; the Cytogenetics Laboratories, Athens University School of Medicine, Athens, Greece (these Greek families had participated previously in a study of recombination and nondisjunction9); and the Center for Medical Genetics, Johns Hopkins University School of Medicine, Baltimore. In 186 families, the proband was a child with free trisomy 21 (without translocation); in 14 the proband was a fetus with trisomy 21 diagnosed after prenatal testing. No family had more than one offspring with trisomy 21. The only bias in selection resulted from the willingness of the families to participate in the study. Informed consent was obtained at the laboratory or clinic of origin. Table 1Table 1
Families Studied in Which There Was a Patient with Trisomy 21.* shows the number of families studied at each center and the mean ages of the parents at the birth of the child with trisomy 21.DNA Polymorphic Markers
High-molecular-weight DNA was isolated from peripheral-blood leukocytes, as described elsewhere.10 The majority of the DNA polymorphisms were scored with use of standard Southern blot analysis, which included restriction-endonuclease digestion of genomic DNA, agarose-gel electrophoresis and transfer of the DNA fragments to nitrocellulose or nylon filters, hybridization with radioactive probes, washing, and autoradiography.9 , 11 A number of DNA polymorphisms were scored after PCR amplification8 and the detection of polymorphic alleles in polyacrylamide gels.12 , 13 All the DNA polymorphisms that were scored map on the long arm of human chromosome 21.
The probe—enzyme combinations used in the Southern blot analysis (from the most centromeric to the most telomeric) were D21K9—TaqI of the D21S13 locus; p21–4U—MspI of the D21S110 locus; pPW228C—BamHI of the D21S1 locus; pPW236B—EcoRI of the D21S11 locus; pPW245D—HindIII of the D21S8 locus; B2.3—NcoI/BglII of the amyloid precursor protein gene (APP); pCW21pcq—SstI of the D21S111 locus; SOD-1—MspI of the superoxide dismutase gene; Fr8–77 of the D21S82 locus, which detects a polymorphism with a variable number of tandem repeats (VNTR) and at least three different alleles; H33ets–2—MspI of the ETS-2 oncogene; pPW231C—HindIII and pPW231C—TaqI of the D21S3 locus; p78/2–8b—PstI of the MX1 gene; pMCT15 of the D21S113 locus, which detects a VNTR polymorphic system; pGPFKL3.3—KpnI of the liver type of the phosphofructokinase gene (PFKL); CRI-L427 of the D21S112 locus, which detects a highly informative VNTR polymorphic marker; and ML18 of the COL6A1 gene, which also detects a very informative VNTR polymorphism (see Petersen et al.7 and Warren et al.9 for description of the probes). The DNA polymorphic markers detected after amplification by PCR were a (GT)n dinucleotide repeat at the fourth intervening sequence (IVS4) of the high-molecular-group 14 (HMG14) gene, a (GT)n repeat at IVS5 of the HMG14 gene, a polymorphism at the poly(A) tract of an Alu repetitive element at IVS5 of the HMG14 gene, and a (GT)n repeat of the D21S156 locus. The oligonucleotide primers used in the PCR amplification have been described elsewhere, as have detailed laboratory protocols for the labeling of specific primers and for the PCR programs, polyacrylamide-gel electrophoresis of the PCR products, and autoradiography.13 14 15 The order of the loci described above on the long arm of human chromosome 21 has been determined by linkage analysis with the large reference pedigrees of the Centre d'Etude du Polymorphisme Humain (CEPH)7 and by pulsed-field gel electrophoresis and mapping with appropriate somatic-cell hybrids.6
The parental origin of the supernumerary chromosome 21, and therefore the parental origin of nondisjunction, was determined after scoring of the polymorphic alleles in the parents, the proband, and siblings if available. The use of the DNA polymorphisms to determine the parental origin of nondisjunction has been described previously.4 , 5 , 9 , 15 16 17 18 No attempt was made to establish the meiotic stage of the nondisjunction (first vs. second meiotic division), since none of the DNA polymorphisms used mark the centromere of chromosome 21.
Cytogenetic Analysis
Cytogenetic analyses to determine the origin of nondisjunction were performed in three laboratories in a subgroup of families. Chromosomes were prepared from peripheral-blood cultures of patients with Down's syndrome and from their parents with use of standard techniques.19 Heteromorphisms on the short arm of chromosome 21 were scored after standard staining of the slides with quinacrine (or silver-staining nucleolar organizing regions).20 About 20 spreads at metaphase were examined per sample. Only results that were considered to indicate a specific parental origin unequivocally were compared with the results of the DNA analysis. Laboratory A examined cytogenetic heteromorphisms in 24 families and determined the parental origin of nondisjunction in 10. Laboratory B examined 17 families and determined the parental origin in 11. Laboratory C examined 15 families and determined the parental origin in 10. The families studied by Laboratory C were identified from consecutive series of newborns comprising all cases of Down's syndrome in a certain area. The families studied by Laboratories A and B were identified by Down's syndrome clinics that had agreed to participate in the study.
Results
Analysis of DNA polymorphisms was performed in all members of the nuclear families containing one affected person with trisomy 21. The parental origin of nondisjunction was assigned after the polymorphic alleles in a given family were scored. Several examples are shown in Figure 1Figure 1
Representative Autoradiographs of DNA Polymorphic Markers in the Members of Families with a Proband with Trisomy 21.. For some DNA markers, the person with trisomy 21 had three different alleles, and the origin of nondisjunction was easily determined. For other markers the person had two alleles, one appearing in two copies and one in a single copy, as was apparent from the intensity of the signal on the autoradiograph. These alleles were scored either by visual inspection of the autoradiograph or by densitometric analysis. No discrepancies in results were noted between the two methods. Table 2Table 2
Informativeness of the DNA Markers Studied in 200 Families with a Proband with Trisomy 21.* shows the number of pedigrees for which the parental origin of nondisjunction was determined, how many markers were informative, and how the determination was made (e.g., three vs. two alleles, or the intensity of the signal). When two or more independent DNA markers indicated the origin of nondisjunction, there were no discrepancies in the assignment of parental origin.The parental origin of nondisjunction was determined in 193 families, as shown in Table 3Table 3
Parental Origin of Nondisjunction in Trisomy 21, According to Analysis of DNA Polymorphisms.. In these families, the origin was paternal in only 9 cases (4.7 percent) and maternal in 184 (95.3 percent). In seven cases, the origin was not determined, because the DNA markers were not informative, not enough DNA was isolated from the blood samples and the analysis of markers was incomplete, or evidence of nonpaternity was detected. Stewart et al.18 have suggested that more than 50 DNA markers would be needed to assess parental origin in 98 percent or more of the cases analyzed. Clearly, the judicious choice of a few highly polymorphic markers may be just as efficient.21 The distribution of maternal and paternal ages in the families with nondisjunction of maternal, paternal, or unknown origin is shown in Table 4Table 4
Maternal and Paternal Age at the Birth of a Child with Trisomy 21.*. As expected, the mean age of the mother was higher in the maternally derived cases of trisomy 21 than in the paternally derived cases.To test for potential errors in the cytogenetic analyses, we compared the results of the DNA analysis with those of the cytogenetic analysis, with respect to the origin of nondisjunction in a subgroup of 31 families with a child with trisomy 21. Three highly experienced cytogenetic laboratories participated in this comparative exercise (see Methods). Laboratory A provided results for 10 families, Laboratory B for 11, and Laboratory C for another 10. These results, assumed to be definitive, were derived without knowledge of the results of the DNA analysis. There were discrepancies between the results of the DNA analysis and those of the cytogenetic analysis at all three laboratories, as shown in Table 5. The cytogenetic analysis showed paternal origin in 5 of 31 cases (16 percent), whereas the DNA analysis established only 2 cases as paternal in origin (6 percent). All the predictions of maternal origin in the cytogenetic analysis were verified by the DNA analysis, but three of the five predictions of paternal origin made in the cytogenetic analysis were shown to be false by the DNA analysis.
Discussion
The analysis described here using DNA markers on the long arm of human chromosome 21 showed that the origin of nondisjunction was maternal in about 95 percent of the cases of free trisomy 21 and paternal only in about 5 percent. These results contrast with those obtained over the past 20 years in studies using cytogenetic heteromorphisms.3 These cytogenetic studies concluded that the extra chromosome 21 was paternal in origin in about 19.4 percent of persons with trisomy 21 and maternal in 80.6 percent. The data obtained by analysis of cytogenetic heteromorphisms were collected over a period of 14 years, from 1970 through 1984. The pooled data include 391 cases for which the origin was determined, of 647 cases examined.3 The difference between the results of the cytogenetic studies and those of the present study is statistically significant (chi-square = 34.6, P<0.0001, 1 df). There are several possible explanations for this discrepancy. First, it might be said that the population sample for the DNA analysis was different from the samples used in the cytogenetic analysis. This is an unlikely explanation, however, since both studies used unselected children with trisomy 21. The distribution of maternal and paternal ages in our study did not differ from that in earlier studies of trisomy 21 or in the studies in which the origin of nondisjunction was determined by cytogenetic analysis. Some of the cytogenetic studies, however, were surveys of whole populations,20 whereas our data were collected from several centers. Second, it might be said that our sample was small. This is also an unlikely explanation, since the total sample for all cytogenetic studies combined comprised 391 cases, and our sample included 193 cases. Third, the cytogenetic heteromorphisms involve markers of the short arm of chromosome 21, whereas the DNA polymorphisms used represent markers on the long arm, so potential recombination events among the short arms of acrocentric chromosomes may explain some of the differences. Fourth, the cytogenetic determination of the origin of nondisjunction can be difficult, and errors in this determination could have been made. Carothers has suggested that the frequency of misclassification when cytogenetic heteromorphisms are used may be 8 percent or more.22 The experiment summarized in Table 5Table 5
Comparison of Cytogenetic and DNA Polymorphic Markers in Determinations of the Parental Origin of Nondisjunction in Down's Syndrome. provides evidence of this possibility. We conclude that the analysis of DNA polymorphisms is more accurate in determining the parental origin of nondisjunction in trisomy 21, because the DNA polymorphisms are more abundant and highly informative, and the scoring of polymorphic alleles objective.It is surprising that the paternal contribution to the origin of nondisjunction in trisomy 21 in our study was only about 5 percent. The persons with paternally derived trisomy 21 were not apparently different in clinical presentation from those with maternally derived trisomy 21. The small number of cases of paternally derived trisomy 21 does not allow complete evaluation of the potential differences between the two phenotypes, however. Families with two affected persons were not included in the study.
We made no attempt to establish the meiotic stage of the origin of nondisjunction, since none of the DNA markers used mark the centromere and there is currently no estimation of the genetic distance between the centromere and the DNA markers that are the most proximal in the linkage map of the long arm of human chromosome 21 (D21S16 and D21S13).
The results of this study will not alter the current forms of prenatal counseling and diagnosis provided to women of advanced childbearing age. These results can only emphasize the fact that trisomy 21 is mostly due to meiotic errors in the maternal chromosomes. It is possible that the risk of trisomy 21 associated with maternal age has to be recalculated in the light of the present data and conclusions. It would also be of interest to determine the origin of nondisjunction in cases of spontaneous abortion of fetuses with trisomy 21, since it is theoretically possible that maternal origin of the extra chromosome may provide an advantage for intrauterine survival. Finally, the results of this study provide strong evidence that the chief research effort to elucidate the pathogenesis of trisomy 21 should be directed toward study of the meiotic divisions of oocytes.
In summary, our analyses of DNA polymorphisms in families with trisomy 21 suggest that only in about 5 percent of the cases is the nondisjunction paternal in origin. Future research may elucidate the cause of nondisjunction in some pregnancies and the meiotic stage at which nondisjunction occurs in both maternally and paternally derived cases of trisomy 21.
Address reprint requests to Dr. Antonarakis at the Department of Pediatrics, Center for Medical Genetics, Johns Hopkins Hospital, CMSC 1003, Baltimore, MD 21205.
Supported by grants (R01HD19591 and PO1HD24605) to Dr. Antonarakis from the National Institutes of Health. Dr. Chakravarti was supported by a Research Career Development Award (HD00774) from the National Institutes of Health; Dr. Schinzel by the Julius Klaus Stiftung, Zurich; Dr. Petersen by the Danish Research Council and Academy, Else og Mogens Wedell-Wedellsborg Foundation, and a Fulbright Fellowship; Dr. Warren by the Alzheimer's Association; and Dr. Rudd by the Medical Research Council of Canada and Alberta Children's Hospital Foundation.
We are indebted to the families of the patients for participation in the study; to Parents of Children with Down Syndrome, Inc., in Houston; to S. Perez and C. Corbet for specimen collection; to Lisa Taylor for expert assistance in the preparation of the manuscript; and to L. Feisee and J. Kang for technical assistance.
Source Information
* The members of the Down Syndrome Collaborative Group were as follows: Dr. Antonarakis, John G. Lewis, B.S., Patricia A. Adelsberger, B.S., and Michael B. Petersen, M.D., Center for Medical Genetics, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore; Albert A. Schinzel, M.D., Franz Binkert, Ph.D., and Werner Schmid, M.D., Institute of Medical Genetics, University of Zurich, Zurich, Switzerland; Constantine Pangalos, M.D., and Odile Raoul, M.D., Institut de Progenèse, Hôpital Necker, Paris; Aravinda Chakravarti, Ph.D., Department of Human Genetics, University of Pittsburgh, Pittsburgh; Mohamed Hafez, M.D., Mansoura University, Mansoura, Egypt; Maimon M. Cohen, Ph.D., Diane Roulston, Ph.D., and Stuart Schwartz, Ph.D., Division of Human Genetics, Departments of Obstetrics and Gynecology and Pediatrics, University of Maryland, Baltimore; Margareta Mikkelsen, M.D., and Lisbeth Tranebjaerg, Ph.D., the John F. Kennedy Institute, Glostrup, Denmark; Frank Greenberg, M.D., Institute for Molecular Genetics and Department of Pediatrics, Baylor College of Medicine, Houston; David I. Hoar, Ph.D., and Noreen L. Rudd, M.D., Department of Pediatrics and Medical Biochemistry, Alberta Children's Hospital, Calgary, Alta., Canada; Andrew C. Warren, M.D., Ph.D., Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore; Caterina Metaxotou, M.D., Cytogenetics Laboratory, First Department of Pediatrics, Athens University School of Medicine, Agia Sophia Children's Hospital, Goudi, Athens, Greece; and Christos Bartsocas, M.D., Department of Pediatrics, P. and A. Kyriakou Children's Hospital, Athens, Greece.
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