Epidemiology of double aneuploidies involving chromosome 21 and the sex chromosomes

Abstract

The chance of two chromosome abnormalities occurring in one conceptus is very small. However, some authors have suggested that double aneuplodies (DAs) might be more common than the product of their individual frequencies. The nonrandomness of such DA events was considered to be evidence that nondisjunction (NDJ) may be genetically determined. Data collected from the National Down syndrome Cytogenetic Register (NDSCR) in England and Wales and from the literature indicate that the frequencies of all nonmosaic DAs, except for 48,XXY,+21, are lower than expected, probably because of strong intrauterine selection against such pregnancies. Collectively, we identified 52 cases of nonmosaic 48,XXY,+21; 28 cases of 48,XYY,+21; and 14 cases of 48,XXX,+21 in liveborns and 13 cases of 48,XXY,+21; four cases of 48,XYY,+21; and two cases of 48,XXX,+21 after prenatal diagnoses. Among these cases, analysis of the published unbiased cytogenetic surveys of liveborn DS revealed 24 cases of 48,XXY,+21; nine cases of 48,XYY,+21; and seven cases of 48,XXX,+21. These figures are different from the expected proportion of 1:1:1 (P < 0.001), with carriers of XXY overrepresented in the group of carriers of DA. Mechanisms put forth to account for the higher occurrence of 48,XXY,+21 may include greater accessibility of disomic ovum to Y-carrying sperm, and promotion of NDJ in ovum by Y-bearing sperm. 48,XXY,+21 DA was found to be age-dependent, as the proportion of mothers over age 35 (x = 33.0) was increased over the general population. This is in contrast to the apparently age-independent 48,XYY,+21 DA, with a mean maternal age of 24.7 (P < 0.001). Paternal ages were also remarkably different between the groups, with a mean age of 37.9 in 48,XXY,+21 cases and a mean age of 27.9 in 48,XYY,+21 cases (P < 0.01). Maternal age-related factors, rather than genetic predisposition, may play a more important role in the etiology of the most common DA, 48,XXY,+21.

Gender Affects Clinical Suspicion of Down Syndrome

“…Several hypotheses have been put forward to explain the skewed sex ratio in Down syndrome. Meiotic disturbance (non-homologous co-orientation in male meiosis) [Kovaleva, 1992;Petersen et al 1993], fertilization event (greater accessibility of Y-bearing sperm to ova disomic for chromosome 21 or promotion of non-disjunction in the ova by Y-bearing sperm) [Ferguson-Smith & Yates, 1984;Kovaleva & Mutton, 2005], and post-fertilization events (intrauterine selection against females) [Huether et al, 1996;Hook et al, 1999] have been discussed. Data from recent studies supports suggestion that male excess among live born with non mosaic trisomy 21 might be due to selection against female fetuses [Oliver et al, 2009;Kovaleva, 2010].…”

Down-Klinefelter syndrome (48,XXY,+21) in a Child with Congenital Heart Disease: Case Report and Literature Review

“…Both these aneuploidies could have the same or different parental origin. The coincidence rate of both DS and KS in the same individual is about 0.098% in newborn (3). Many cases of DT of XXY and trisomy 21 have been published since the first reported by Ford et al (4) However, to our knowledge, only 8 cases of 48, XXY, +21 chromosome pattern with congenital Heart Disease (CHD) were reported previously with limited information (5)(6)(7)(8)(9)(10)(11)(12).…”

Double Aneuploidy: A Case of Trisomy 21 with XYY

“…Classical trisomy 21 results from maternal meiotic nondisjunction. Y chromosome of XYY is always paternal and it occurs by nondisjunction at meiosis II or mitosis after fertilization (3,7,9). Etiological predisposition factor is not known for 48,XYY,+21.…”