Women with a reduced ovarian complement may have an increased risk for a child with Down syndrome.

Advanced maternal age is the only well-established risk factor for trisomy 21 Down syndrome (DS), but the basis of the maternal-age effect is not known. In a population-based, case-control study of DS, women who reported surgical removal of all or part of an ovary or congenital absence of one ovary were significantly more likely to have delivered a child with DS than were women who did not report a reduced ovarian complement (odds ratio 9.61; 95% confidence interval 1.18-446.3). Because others have observed that women who have had an ovary removed exhibit elevated levels of FSH and similar hallmarks of advanced maternal age, our finding suggests that the physiological status of the ovary is key to the maternal-age effect. In addition, it suggests that women with a reduced ovarian complement should be offered prenatal diagnosis.

Risk factors for trisomy 21: maternal cigarette smoking and oral contraceptive use in a population-based case-control study.

PURPOSE: We examined maternal smoking and oral contraceptive use as possible risk factors in the genesis of cases of trisomy 21 of maternal origin. This is the first epidemiological study to categorize cases of trisomy 21 by parent of origin and timing of the meiotic error before assessing possible risk factors. METHODS: We used chromosome 21-specific DNA markers to assign origin to each case. Structured interviews were employed to determine maternal smoking and oral contraceptive use around conception. RESULTS: The odds ratio (OR) for maternal smoking was significantly increased among younger mothers (OR = 2.98; 95% CI = 1.01-8.87), but only in a particular subset of meiotically-derived cases. The combined use of cigarettes and oral contraceptives increased the risk further (OR = 7.62; 95% CI = 1.63-35.6); however, oral contraceptive use alone was not a significant risk factor. CONCLUSION: Our results indicate that categorizing cases of trisomy 21 by parent and timing of the meiotic error allows more precision in identifying risk factors and may shed light on mechanisms of meiotic nondisjunction.

Population-based study of congenital heart defects in Down syndrome.

Mental retardation and hypotonia are found in virtually all Down syndrome (DS) individuals, whereas congenital heart defects (CHDs) are only present in a subset of cases. Although there have been numerous reports of the frequency of CHDs in DS, few of the studies have had complete ascertainment of DS in a defined geographic area. The Atlanta Down Syndrome Project, a population-based study of infants born with trisomy 21, provides such a resource. In the first 6.5 years of the study, 243 trisomy 21 livebirths were identified in the five-county Atlanta area (birth prevalence: 9.6/10,000). Cardiac diagnoses were available on 227 (93%) of the cases and 89% of these evaluations were made by echocardiography, cardiac catheterization, surgery, or autopsy. Of the 227 DS infants, 44% had CHDs including 45% atrioventricular septal defect (with or without other CHDs), 35% ventricular septal defect (with or without other CHDs), 8% isolated secundum atrial septal defect, 7%, isolated persistent patent ductus arteriosus, 4% isolated tetralogy of Fallot, and 1% other. This report is unique in that it contains the largest number of trisomy 21 infants ascertained in a population-based study where modern techniques for diagnosing cardiac abnormalities predominate.

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.

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.