Down syndrome (DS) is the most commonly identified genetic form of mental retardation and the leading cause of specific birth defects and medical conditions. Traditional epidemiological studies to determine the prevalence, cause, and clinical significance of the syndrome have been conducted over the last 100 years. DS has been estimated to occur in � 1 in 732 infants in the United States, although there is some evidence that variability in prevalence of estimates exist among racial/ethnic groups. Progress has been made in characterizing the specific types of chromosome errors that lead to DS and in identifying associated factors that increase the risk of chromosome 21 malsegregation, i.e., advanced maternal age and recombination. Studies to examine the variability of the presence of specific DS-associated birth defects and medical conditions provide evidence for genetic and environmental modifiers. Here, we provide a brief survey of studies that address the current state of the field and suggest gaps in research that can soon be filled with new multidisciplinary approaches and technological advances. '2007 Wiley-Liss, Inc. MRDD Research Reviews 2007;13:221–227.

Epidemiology of Down syndrome

Chromosome abnormalities occur with astonishing frequency in humans, being present in an estimated 1030% of all fertilized eggs. Of the different classes of chromosome abnormality, aneuploidy (trisomy and monosomy) is by far the most common and, clinically, the most important. For example, over 25% of all miscarriages are monosomic or trisomic, making aneuploidy the leading known cause of pregnancy loss. Furthermore, among those conceptions that survive to term, aneuploidy is the leading genetic cause of mental retardation. Over the past 25 years, a considerable body of information has accrued on the incidence of aneuploidy in human gametes, fetuses, and newborns. More recently, the application of molecular biological techniques to the study of aneuploidy has begun to uncover some of the underlying causes of human aneuploidy. In this review, we first summarize the cytogenetic data on the incidence of aneuploidy in humans, and then discuss recent molecular data on the mechanism of origin of different aneuploid conditions, the basis of the maternal age effect on aneuploidy, and the importance of aberrant genetic recombination to the genesis of aneuploidy.

http://materiais.dbio.uevora.pt/BD/Intro/Human_Aneuploidy.pdf

Human aneuploidy: Incidence, origin, and etiology

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.

/pdf/origin-and-mechanisms-of-non-disjunction-in-human-autosomal-3w8lctq4s9.pdf

Origin and mechanisms of non-disjunction In human autosomal trisomies

We describe the trajectory of the human sex ratio from conception to birth by analyzing data from (i) 3- to 6-d-old embryos, (ii) induced abortions, (iii) chorionic villus sampling, (iv) amniocentesis, and (v) fetal deaths and live births. Our dataset is the most comprehensive and largest ever assembled to estimate the sex ratio at conception and the sex ratio trajectory and is the first, to our knowledge, to include all of these types of data. Our estimate of the sex ratio at conception is 0.5 (proportion male), which contradicts the common claim that the sex ratio at conception is male-biased. The sex ratio among abnormal embryos is male-biased, and the sex ratio among normal embryos is female-biased. These biases are associated with the abnormal/normal state of the sex chromosomes and of chromosomes 15 and 17. The sex ratio may decrease in the first week or so after conception (due to excess male mortality); it then increases for at least 10–15 wk (due to excess female mortality), levels off after ∼20 wk, and declines slowly from 28 to 35 wk (due to excess male mortality). Total female mortality during pregnancy exceeds total male mortality. The unbiased sex ratio at conception, the increase in the sex ratio during the first trimester, and total mortality during pregnancy being greater for females are fundamental insights into early human development.

/pdf/the-human-sex-ratio-from-conception-to-birth-ca8xjdbegp.pdf

The human sex ratio from conception to birth

Application of fluorescence in situ hybridization (FISH) analysis has opened the way for comprehensive studies on numerical chromosome abnormalities in human sperm. During the last decade, more than five million sperm from approximately 500 normal men were analyzed by a number of laboratories from around the world by this approach. Except for chromosome 19 which has been analyzed in only one study, all other chromosomes have been examined by two or more studies with considerable differences in disomy frequency for an individual chromosome among studies. The mean disomy frequency is 0.15% for each of the autosomes and 0.26% for the sex chromosomes. Most chromosomes analyzed have an equal distribution of disomy with the exception of chromosomes 14, 21, 22 and the sex chromosomes, which display significantly higher disomy frequencies. Slight but significant increases in disomy frequency with advancing paternal age were observed for some chromosomes, in particular for the sex chromosomes. Some lifestyle factors such as smoking, alcohol drinking and caffeine consumption have been investigated and no consistent association between disomy frequency and any type of lifestyle factors has been established. The question of whether different geographic and ethnic groups of men have inherent differences in frequency of disomic sperm has been investigated by two studies with conflicting results.

Aneuploidy in human sperm: a review of the frequency and distribution of aneuploidy, effects of donor age and lifestyle factors.

Paternal nondisjunction accounts for approximately 5% of cases of trisomy 21. We have studied 36 cases of free trisomy 21, in which the supernumerary chromosome was of paternal origin, with DNA markers in the pericentromeric region and along the long arm of chromosome 21. Fifteen of the paternal cases were consistent with meiosis II errors, 8 with mitotic errors and only 7 with meiosis I nondisjunction. This contrasts markedly with maternally derived trisomy 21, in which meiosis I errors predominate. An excess of males was observed in the meiotic cases (21 males:6 females), highly significantly different from a 1.06 ratio. A significant difference in mean maternal age was found between cases of paternal origin (28.1 years) and those of maternal origin (31.8 years, n = 429). This indicates that the maternal age effect is confined to maternal nondisjunction.

Michael B. Patersen

Papers

Paternal nondisjunction in trisomy 21: excess of male patients