Chapter 063. Chromosome Disorders (Part 8)

Maternal Age and TrisomyThe association between increasing maternal age and trisomy is the most important etiologic factor in congenital chromosomal disorders. Among women under the age of 25, ~2% of all clinically recognized pregnancies are trisomic; by the age of 36, however, this figure increases to 10% and by the age of 42, to 33% (Fig. 63-5). This association between maternal age and trisomy is exerted without respect to race, geography, or socioeconomic factors and likely affects segregation of all chromosomes.Figure 63-5Estimated maternal age–adjusted rates of trisomy among all clinically recognized pregnancies (e.g., spontaneous abortions, stillbirths, and livebirths). ...
Nội dung trích xuất từ tài liệu:
Chapter 063. Chromosome Disorders (Part 8) Chapter 063. Chromosome Disorders (Part 8) Maternal Age and Trisomy The association between increasing maternal age and trisomy is the mostimportant etiologic factor in congenital chromosomal disorders. Among womenunder the age of 25, ~2% of all clinically recognized pregnancies are trisomic; bythe age of 36, however, this figure increases to 10% and by the age of 42, to >33%(Fig. 63-5). This association between maternal age and trisomy is exerted withoutrespect to race, geography, or socioeconomic factors and likely affects segregationof all chromosomes. Figure 63-5 Estimated maternal age–adjusted rates of trisomy among all clinicallyrecognized pregnancies (e.g., spontaneous abortions, stillbirths, and livebirths).Among women in their forties, over 25% of all pregnancies are estimated toinvolve a trisomic conception; the vast majority of these spontaneously abort, withonly trisomies 13, 18, and 21 and sex chromosome trisomies surviving to termwith any appreciable frequency. Despite the importance of increasing age, little is known about themechanism by which aging leads to abnormal chromosomal segregation. As notedabove, it is thought to originate in maternal meiosis I owing to the protracted timeto completion (often ≥40 years) in females, and recent studies suggest that it maybe associated with alterations in meiotic crossing-over. In trisomy 21, for example,crossover patterns appear to be similarly abnormal in younger and older mothersof trisomic conceptions. Thus, it has been suggested that two distinct steps, orhits, may be involved in maternal age–related nondisjunction. The first hit,which is age independent, involves the establishment of a vulnerable crossoverconfiguration in the fetal oocyte; the second hit, which is age dependent, involvesabnormal processing of the vulnerable bivalent structure at metaphase I. If thismodel is correct, it suggests that the nondisjunctional process is the same inyounger and older women, but it occurs more frequently with aging, possiblybecause of age-dependent degradation of meiotic proteins. Structural Chromosome Abnormalities Structural rearrangements involve breakage and reunion of chromosomes.Although less common than numerical abnormalities, they present additionalchallenges from a genetic counseling standpoint. This is because structuralabnormalities, unlike numerical abnormalities, can be present in balanced formin clinically normal individuals but transmitted in unbalanced form to progeny,thereby resulting in a hereditary form of chromosome abnormality. Rearrangements may involve exchanges of material between differentchromosomes (translocations) or loss, gain, or rearrangements of individualchromosomes (e.g., deletions, duplications, inversions, rings, or isochromosomes).Of particular clinical importance are translocations, which involve two basictypes: Robertsonian and reciprocal. Robertsonian rearrangements are a specialclass of translocation, in which the long arms of two acrocentric chromosomes(chromosomes 13, 14, 15, 21, and 22) join together, generating a fusionchromosome that contains virtually all of the genetic material of the original twochromosomes. If the Robertsonian translocation is present in unbalanced form, amonosomic or trisomic conception ensues. For example, ~3% of Down syndromecases are attributable to unbalanced Robertsonian translocations, most ofteninvolving chromosomes 14 and 21. In this instance, the affected individual has 46chromosomes, including one structurally normal chromosome 14, two structurallynormal chromosomes 21, and one fusion 14/21 chromosome. This effect leads to anormal diploid dosage for chromosome 14 and to a triplication of chromosome 21,thus resulting in Down syndrome. Similarly, a small proportion of individuals withtrisomy 13 syndrome are clinically affected because of an unbalancedRobertsonian translocation. Reciprocal translocations involve mutual exchanges between any twochromosomes. In this circumstance, the phenotypic consequences associated withunbalanced translocations depend on the location of the breakpoints, which dictatethe amount of material that has been exchanged between the two chromosomes.Because most reciprocal translocations involve unique sets of breakpoints, it isdifficult to predict the phenotypic consequences in any one situation. In general,severity is determined by the amount of excess or missing chromosome material inindividuals with unbalanced translocations. In addition to rearrangements between chromosomes, there are severalexamples of intrachromosome structural abnormalities. The most common anddeleterious of these involve loss of chromosome material due to delet ...