Paternal Nondisjunction Research Articles

Uniparental maternal tetrasomy X co-occurrence with paternal nondisjunction: investigation of the origin of 48,XXXX

Tetrasomy X or 48,XXXX is a rare sex chromosome aneuploidy. The parental origin of tetrasomy X in a female patient with developmental delay was analyzed; all four X chromosomes were derived from the mother, and there were no paternally derived sex chromosomes. This finding indicates a rare incidental co-occurrence of maternal and paternal nondisjunction or polysomy rescue. The mechanism of 48,XXYY, which is related to developmental delay in males, was analyzed for comparison.

Multiplex Quantitative Fluorescent Polymerase Chain Reaction for Detection of Aneuploidies

Quantitative fluorescent polymerase chain reaction (QF-PCR) is a well-established method in Western countries where commercial kits are being used for rapid prenatal diagnosis of aneuploidies. The limitations of these kits are that these are basically designed for the Caucasian population and are very expensive. Thus there is an urgent need to investigate the informative markers in the Asian population and to develop indigenous informative markers for detection of aneuploidies. This is a cost-effective alternate to the commercial kits and can be easily used in developing countries. We have tested three STR markers (D21S1435, D21S11, and D21S1411) in confirmed cases of Down syndrome and their parents. Origin of nondisjunction was also determined by means of QF-PCR. All the Down syndrome cases were confirmed for trisomy 21 by STR analysis. The results matched 100% with the karyotyping results. Nondisjunction was maternal in 87.5% cases and paternal in 12.5% cases. Nondisjunction during meiosis I was responsible for 87.5% cases of maternal nondisjunction and 100% cases of paternal nondisjunction. The combination of three STR markers is highly informative and can be used for diagnosis of trisomy 21 in India.

Investigation of factors associated with paternal nondisjunction of chromosome 21

Previous studies on relatively small samples of individuals with trisomy 21 caused by paternally derived errors have shown that: (1) advanced paternal age is not a risk factor for chromosome 21 nondisjunction (NDJ), (2) absence of recombination, but not the location of recombination is associated with paternal NDJ and (3) there is an excess of males among live-births with paternally derived trisomy 21. An excess of males is also observed among all individuals with trisomy 21. Using 128 families that had a child with trisomy 21 due to a paternally derived error, we examined: paternal age, recombination and the male/female sex ratio. We genotyped STRs along 21q to identify the origin of the error and the location of recombination on the paternal chromosome. Results showed that 32% of paternal meiotic errors occurred in meiosis I (MI) and 68% in meiosis II (MII). We confirmed the lack of a paternal age association with either type of error (mean paternal age for controls, MI, and MII errors: 31.3 +/- 6.6, 32.2 +/- 6.3, 30.6 +/- 6.5, respectively). However, contrary to previous findings, we did not find altered patterns of recombination among paternal MI or MII errors. We found an increased male/female sex ratio among paternal (1.28, 95% CI: 0.68-1.91) and maternal (1.16, 95% CI: 1.02-1.33) meiotic errors. While the sex ratio among individuals with paternal errors was not statistically significant, these findings suggest that selection against female fetuses with trisomy 21 may contribute to the excess of males observed among all individuals with trisomy 21.

Double paternal nondisjunction in an infant with transient neonatal diabetes mellitus and Klinefelter syndrome

American Journal of Medical Genetics Part AVolume 143A, Issue 8 p. 895-898 Research Letter Double paternal nondisjunction in an infant with transient neonatal diabetes mellitus and Klinefelter syndrome† Têmis M. Félix, Têmis M. Félix Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos, Porto Alegre, RS, BrazilSearch for more papers by this authorMichael J. Tansey, Michael J. Tansey Department of Pediatrics, University of Iowa, Iowa City, IowaSearch for more papers by this authorShivanand R. Patil, Shivanand R. Patil Department of Pediatrics, University of Iowa, Iowa City, IowaSearch for more papers by this authorJeffrey C. Murray, Jeffrey C. Murray Department of Pediatrics, University of Iowa, Iowa City, IowaSearch for more papers by this authorJohn M. Dagle, Corresponding Author John M. Dagle [email protected] Department of Pediatrics, University of Iowa, Iowa City, IowaDepartment of Pediatrics, 200 Hawkins Drive, University of Iowa, Iowa City, IA 52242.Search for more papers by this author Têmis M. Félix, Têmis M. Félix Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos, Porto Alegre, RS, BrazilSearch for more papers by this authorMichael J. Tansey, Michael J. Tansey Department of Pediatrics, University of Iowa, Iowa City, IowaSearch for more papers by this authorShivanand R. Patil, Shivanand R. Patil Department of Pediatrics, University of Iowa, Iowa City, IowaSearch for more papers by this authorJeffrey C. Murray, Jeffrey C. Murray Department of Pediatrics, University of Iowa, Iowa City, IowaSearch for more papers by this authorJohn M. Dagle, Corresponding Author John M. Dagle [email protected] Department of Pediatrics, University of Iowa, Iowa City, IowaDepartment of Pediatrics, 200 Hawkins Drive, University of Iowa, Iowa City, IA 52242.Search for more papers by this author First published: 15 March 2007 https://doi.org/10.1002/ajmg.a.31659Citations: 3 † How to cite this article: Félix TM, Tansey MJ, Patil SR, Murray JC, Dagle JM. 2007. Double paternal nondisjunction in an infant with transient neonatal diabetes mellitus and Klinefelter syndrome. Am J Med Genet Part A 143A:895–898. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Citing Literature Volume143A, Issue815 April 2007Pages 895-898 RelatedInformation

Concurrence of fragile X and Klinefelter syndromes: report of a new case of paternal nondisjunction

The concurrence of fragile X and Klinefelter syndromes would be expected occasionally. Therefore, the analysis of the literature showed that the concurrence of both conditions was found at least 16 times. Among them, only seven cases were analyzed for the parental origin of the extra chromosome X, suggesting that the maternal nondisjunction was preferentially inherited. We present the third patient with the concurrence of fragile X and Klinefelter syndromes, in which the parental origin of the supernumerary chromosome X was paternal. This finding reinforces that the parent-of-origin predisposition of the concurrence of the fragile X and Klinefelter syndromes is a pure coincidence.

Absence of Age Effect on Meiotic Recombination between Human X and Y Chromosomes

Recombination between the X and Y chromosomes is limited to the pseudoautosomal region and is necessary for proper segregation of the sex chromosomes during spermatogenesis. Failure of the sex chromosomes to disjoin properly during meiosis can result in individuals with a 47,XXY constitution, and approximately one-half of these result from paternal nondisjunction at meiosis I. Analysis of individuals with paternally derived 47,XXY has shown that the majority are the result of meiosis in which the X and Y chromosomes have failed to recombine. Our studies of sperm have demonstrated that aneuploid 24,XY sperm have a decreased recombination frequency, compared with that of normal sperm. Some studies have indicated a relationship of increased paternal age with 47,XXY offspring and with the production of XY disomic sperm, whereas others have failed to find such relationships. To determine whether there is a relationship between paternal age and recombination in the pseudoautosomal region, single-sperm genotyping was performed to measure the frequency of recombination between a sex-specific locus, STS/STS pseudogene, and a pseudoautosomal locus, DXYS15, in younger men (age < or =30 years) compared with older men (age > or =50 years). A total of 2,329 sperm cells were typed by single-sperm PCR in 20 men who were heterozygous for the DXYS15 locus (1,014 sperm from 10 younger men and 1,315 sperm from 10 older men). The mean recombination frequency was 39.2% in the younger men and 37.8% in the older men. There was no heterogeneity in the frequency of recombination rates. There was no significant difference between the recombination frequencies among the younger men and those among the older men, when analyzed by the clustered binomial Z test (Z=.69, P=.49). This result suggests that paternal age has no effect on the recombination frequency in the pseudoautosomal region.

Origin of uniparental disomy 15 in patients with Prader-Willi or Angelman syndrome.

Maternal uniparental disomy (UPD) accounts for approximately 25% of Prader-Willi patients (PWS) and paternal UPD for about 2-5% of Angelman syndrome (AS) patients. These findings and the parental origin of deletions are evidence of genomic imprinting in the cause of PWS and AS. The natural occurrence of UPD individuals allows the study of meiotic mechanisms resulting in chromosomal nondisjunction (ND). We selected patients with UPD15 from our sample of 30 PWS and 40 AS patients to study the origin of ND and the recombination along chromosome 15. These patients were analyzed with 10 microsatellites throughout the entire chromosome 15 (D15S541, D15S542, D15S11, D15S113, GABRB3, CYP19, D15S117, D15S131, D15S984, D15S115). The analysis disclosed seven heterodisomic PWS cases originating by meiosis I (MI) ND (four showed recombination and three no recombination), and one isodisomic PWS UPD15 originating by postzygotic duplication. Among the five paternal UPD15, we detected four isodisomies, three of which showed homozigosity for all markers, corresponding to a mitotic error, and one case originating from a paternal MII ND. Our results indicate that besides maternal MI and MII ND, paternal ND occurs when a PWS UPD15 patient originates from mitotic duplication of the maternal chromosome 15. ND events in AS are mainly due to mitotic errors, but paternal MII ND can occur and give origin to an AS UPD15 individual by two different mechanisms: rescue of a trisomic fetus or fertilization of a nullisomic egg with the disomic sperm, and in this case paternal and maternal ND are necessary.

FISH studies of the sperm of fathers of paternally derived cases of trisomy 21: no evidence for an increase in aneuploidy.

Paternal nondisjunction accounts for approximately 5% of cases of trisomy 21. To test the hypothesis that, in some such cases, the fathers might be predisposed to meiotic nondisjunction, we utilized fluorescence in situ hybridization (FISH) to screen for aneuploidy in sperm. We analyzed sperm samples from ten males with a trisomy 21 offspring of paternal origin. Among these individuals, the overall frequency of disomy 21 was 0.15%, comparable to estimates of disomy 21 in the general male population. Furthermore, none of the ten fathers of trisomy 21 individuals had significantly elevated levels of disomic sperm. Thus, our results provide no evidence that the occurrence of a trisomy 21 conceptus of paternal origin imparts an increased risk of trisomy in subsequent pregnancies.

Elucidating the mechanisms of paternal non-disjunction of chromosome 21 in humans.

Paternal non-disjunction of chromosome 21 accounts for 5-10% of Down syndrome cases, therefore, relative to the maternally derived cases, little is known about paternally derived trisomy 21. We present the first analysis of recombination and non-disjunction for a large paternally derived population of free trisomy 21 conceptuses ( n = 67). Unlike maternal cases where the ratio of meiosis I (MI) to meiosis II (MII) errors is 3:1, a near 1:1 ratio exists among paternal cases, with a slight excess of MII errors. We found no paternal age effect for the overall population nor when classifying cases according to stage of non-disjunction error. Among 22 MI cases, only five had an observable recombinant event. This differs significantly from the 11 expected events ( P < 0.02, Fisher's exact), suggesting reduced recombination along the non-disjoined chromosomes 21 involved in paternal MI non-disjunction. No difference in recombination was detected among 27 paternal MII cases as compared with controls. However, cases exhibited a slight increase in the frequency of proximal and medial exchange when compared with controls (0.37 versus 0.28, respectively). Lastly, this study confirmed previous reports of excess male probands among paternally derived trisomy 21 cases. However, we report evidence suggesting an MII stage-specific sex ratio disturbance where 2.5 male probands were found for each female proband. Classification of MII cases based on the position of the exchange event suggested that the proband sex ratio disturbance was restricted to non-telomeric exchange cases. Based on these findings, we propose new models to explain the association between paternally derived trisomy 21 and excessive male probands.

Origin and mechanisms of non-disjunction in human autosomal trisomies.

Chromosomal aneuploidy is one of the major causes of pregnancy wastage. In this review we summarize the knowledge about the origin and mechanisms of non-disjunction in human autosomal trisomies 8, 13, 15, 16, 18, and 21, accumulated during the last decade by using DNA polymorphism analysis. Maternal meiosis I non-disjunction is the most important single class, but chromosome-specific patterns exist. For the acrocentric chromosomes 15 and 21, meiosis I errors predominate among the maternal errors, in contrast to trisomy 18 where meiosis II errors predominate. For trisomy 16, virtually all cases are due to maternal meiosis I non-disjunction. Postzygotic (mitotic) non-disjunction constitutes 5-15% of cases of trisomies 15, 18, and 21, whereas for trisomy 8 and trisomy 8 mosaicism the majority of cases are due to mitotic non-disjunction. For paternal non-disjunction of chromosomes 18 and 21, meiosis II or mitotic errors predominate. There is aberrant meiotic recombination associated with maternal meiotic non-disjunction in all trisomies studied in detail so far. Advanced maternal age remains the only well documented risk factor for maternal meiotic non-disjunction, but there is, however, still a surprising lack of understanding of the basic mechanism(s) behind the maternal age effect.

Paternal Contributions to Birth Defects

The question of the extent of paternal contributions to birth defects and adverse reproductive outcomes gained new urgency with the concerns of Vietnam veterans exposed to Agent Orange. There is well-established evidence for the occurrence of certain autosomal dominant sporadic mutations in the offspring of older fathers. Paternal nondisjunction at meiosis or mitosis accounts for a significant proportion of chromosomal errors such as trisomy 21. Certain chromosomal abnormalities in males also contribute to adverse reproductive outcomes in relation to repetitive spontaneous abortion and infertility. The question of whether or not teratogens can act through the male is complex. While certain suggestive evidence is reviewed here, conclusive data are yet to be found. Yet, we must remember that it was not long ago that the placenta was assumed to be an impenetrable barrier between mother and fetus. This field is ripe for further well-designed and careful investigation.

A trisomic child after in vitro fertilization: result of paternal nondisjunction

A trisomic child after in vitro fertilization: result of paternal nondisjunction

Selection against chromosomally abnormal sperm?Fact or fiction?

Martin-DeLeon and Boice (1982) recently published results from a very interesting study that appears to implicate sperm selection in mice after aging in the male genital tract. In their discussion Martin-DeLeon and Boice cited a number of papers which they construed as support for the idea of prezygotic selection against chromosomally abnormal sperm. They stated that "Rudak et al. (1978) estimated that paternal nondisjunction in man is the order of 40%" and that "Hulten and Pearson (1971) reported that sperm with multiple Y chromosomes occur much more commonly in man than the XYY karyotype is encountered in complete population surveys." Both of these studies are based on indirect evidence, assuming that the fluorescent spot(s) seen in sperm heads always reflect the presence of a Y chromosome(s). In fact, Rudak et al. did not make any estimates of paternal nondisjunction. Their paper was the first report on direct analysis of human sperm chromosomes by fertilization of hamster eggs. Rudak et al. studied one normal male and found a 5% (3/60) frequency of aneuploidy. I assume that MartinDe Leon and Boice are referring to the fluorescent Y body studies of Pawlowitzki and Pearson (1972) cited by Rudak et al. Pawlowitzki and Pearson found that 1.3% of sperm had two fluorescent spots and presumed that these sperm were 24,YY. They extrapolated this frequency of nondisjunction to other chromosomes, and this provided the estimate of nondisjunction approaching 40%. Martin-DeLeon and Boice suggested that since the frequency of aneuploidy is much lower in newborns, "chromosomally unbalanced sperm are less likely to effect

Higher incidence of small Y chromosome in humans with trisomy 21 (Down syndrome).

The length of the Y chromosome was measured in 42 black patients with trisomy 21 (47,XY,+21) and a similar number of normal individuals of American black ancestry. The length of the Y was expressed as a function of Y/F ratio and arbitrarily classified into five groups using subjectively defined criteria as follows: very small, small, average, large, and very large. Thirty-eight % of the trisomy 21 patients had small or very small Ys compared to 2.38% of the controls (P less than 0.01). In both populations the size of the Y was not normally distributed. In the normals it was skewed to the left, whereas in the Downs the distribution was flat (platykurtic). A significantly higher incidence of Y length heteromorphisms was noted in the Down as compared to the normal black population. In the light of our current understanding that about one-third of all trisomy 21 patients are due to paternal nondisjunction, it may be tempting to speculate that males with small Y are at an increased risk for nondisjunction of the 21 chromosome.

Down syndrome, paternal age, maternal age and birth order.

Recent cytogenetic evidence has shown that trisomy 21 can arise, perphaps even in substantial proportion, from paternal nondisjunction. The statistical association between Down syndrome incidence and maternal age, paternal age and birth order has been studied in a sample of over 4000 cases. The size of this sample made it possible to control for the effect of maternal age by single years of age during the search for a paternal age effect and vice versa, and the importance of such stringent control is emphasized. The maternal age association was confirmed with an extremely high degree of statistical significance while no independent effect of paternal age was found; indeed, the rates at paternal ages over 45 years appear to be nearly constant. After adjusting for the effects of parental age, a significant inverse association of birth order with incidence was noted. It also appears that the incidence among very young mothers may be high: for maternal ages 15 years and less the rates seem to be equivalent to those found at 30 or 35 years. In order to help answer the question of whether the maternal age association is the result of increasing rates of nondisjunction or of some other mechanism (for example, an age related defect in a spontaneous abortion screening mechanism), the proportion of cases due to maternal and paternal nondisjunction at different parental ages must be determined.

The incidence of sex-chromosome anomalies following irradiation of mouse spermatogonia with single or fractionated doses of X-rays

Attempts to recover XO offspring resulting from 600 R irradiation of spermatogonia proved negative. X-Rays were administered either in a single dose or in 100+ 500 R fractions separated by 24 h, and controls were strictly comparable in all respects. Altogether 14016 offspring were scored, including a small group derived from irradiated mature spermatozoa. The breeding scheme allowed phenotypic detection of paternal or maternal sex-chromosome loss, paternal nondisjunction, and certain translocations. All phenotypically exceptional mice were examined cytologically and through breeding tests. Similar tests of the mothers of presumed O/X p exceptionals revealed that in 9 of 14 cases there was a pre-existing XO condition, indicating the importance of performing such a test. Two of the 3a X m /O-appearing mice were probably X m /O///X m /X p mosaics, with the integument predominantly XO and the germinal tissue predominantly X/X. The frequency of paternal sex-chromosome loss was 2.4 · 10 −3 in the controls and 2.0 · 10 −3 in the two irradiated groups, where X m /O's must therefore be assumed to be of spontaneous origin. Since translocation experiments provide evidence that chromosome breaks are induced by irradiation of spermatogonia, the failure to recover XO's is explained in one of two possible ways. (1) Breakage in spermatogonia does not lead to recoverable single-chromosome loss, either because no sister-chromatid joining occurs, or, if it does, because this leads to cell-division failure. (2) Alternatively, sex chromosome loss does occur, but resulting X/O and O/Y cell progeny is inviable in the testis—a suggestion supported by evidence from natural and artificial mosaics. The results of the present experiment lend further support to our earlier suggestion that most spontaneously occurring X m /O mice are the result of events occurring after sperm entry into the egg. The spontaneous frequency of paternal sex-chromosome loss has ranged over two orders of magnitude in various reports. On the other hand, the frequencies of spontaneous X m loss (O/X p daughters of X/X females/total daughters) and of paternal nondisjunction (2 · X m /X p /Y frequency)

46. Origin of the X chromosome in patients with XO Turner's syndrome

The frequence of maternal versus paternal origin of the single X chromosome in cases of XO Turner's syndrome has not been decided with certainly. Additional data from informative families are needed for the statistical approach to the problem. In order to obtain the most information regarding maternal or paternal nondisjunction, the simultaneous determination of color blindness, Xg blood group, and G-6-PD deficiency, know to have polymorphic frequency in Greece, have been studied in 10 patients with XO Turner's syndrome and their available parents. Four families were informative. In the first the patient was Xg (a+) and the mother Ng(a−). In the second the patient and the father were G-6-PD deficient, while the mother was normal. Clearly in these two families the single X was of paternal origin. In a third family the patient was color-blind and the mother had normal color vision, and in the fourth the patient was Xg (a−) while her mother was Xg (a+). Unfortunately, in both cases the father was dead and since these two sex-linked characters cannot be detected in the heterozygous state the origin of the single X could not be located. Clearly the inclusion in this type of study of an X-linked trait which can be detected in the heterozygous condition is advantageous, as has been shown in the first family.