While most chromosomally abnormal conceptions perish in utero, several conditions are compatible with survival to term. The best-characterized of these are numerical abnormalities, involving loss or gain of individual chromosomes, and abnormalities resulting from unbalanced translocations. FISH, array analysis, and other molecular studies have led to the identification of two "new" types of chromosome abnormalities, commonly referred to as microdeletion syndromes and imprinting syndromes.
Virtually all types of numerical abnormalities are eliminated prenatally, so that only those involving small, gene-poor autosomes or the sex chromosomes are identified with any frequency among liveborns. Clinically, the most important of these is trisomy 21, the most frequent cause of Down syndrome. Depending on the maternal age structure of the population and the utilization of prenatal testing, the incidence of trisomy 21 ranges from 1/600 to 1/1000 livebirths, making it the most common chromosome abnormality in live-born individuals. Like most trisomies, the incidence of trisomy 21 is highly correlated with maternal age, increasing from about 1/1500 livebirths for women 20 years of age to 1/30 for women ≥45 years.
In addition to trisomy 21, only two other autosomal trisomies, 13 and 18, occur with any frequency in livebirths. Incidence rates for trisomies 13 and 18 in livebirths are 1/20,000 and 1/10,000, respectively. Unlike trisomy 21 that is associated with near-normal life expectancy, both trisomies 13 and 18 are associated with death in infancy, typically occurring during the first year of life.
Three sex chromosome trisomies—the 47,XXX, 47,XXY (Klinefelter's syndrome), and 47,XYY conditions—are quite common, with each occurring in about 1/2000 newborns. Of all the trisomic conditions, these three have the fewest phenotypic complications. In fact, with the exception of infertility in Klinefelter's syndrome (Chap. 349), it is likely that most individuals with such trisomic conditions would go undetected. The additional Y chromosome in the 47,XYY condition is small and contains only a few genes. Most Y-linked genes are involved in testicular development or spermatogenesis. Thus, dosage imbalance of Y-linked genes has relatively little effect on other developmental processes. The 47,XYY genotype is associated with increased height. Its role in antisocial behavior, postulated initially because of an increased prevalence among some penalized populations, is unclear.
For the 47,XXX and 47,XXY conditions, the situation is different—the X chromosome contains >1000 genes, many of them essential for normal development. How, then, are 47,XXX and 47,XXY individuals spared from the catastrophic consequences of dosage imbalance? The answer lies in the biology of X chromosome gene expression. In normal females, one of the chromosomes undergoes X inactivation in somatic cells. The inactivation of the paternal or maternal X chromosome occurs randomly in each somatic cell and thereby serves as a mechanism of dosage compensation, ensuring that males and females have equal expression of most X-linked genes. The inactivation process occurs at the blastocyst stage of development; prior to this, both X chromosomes are active. In addition, not all X-linked genes are inactivated. Some genes on the X chromosome "escape" the inactivating mechanism and are expressed from both X chromosomes. In disorders such as Klinefelter's syndrome, some genes may be expressed from both X chromosomes, resulting in its phenotypic features.
As a rule, monosomic conditions are incompatible with fetal development and, consequently, autosomal monosomies are only rarely identified in spontaneous abortions and are not found among live-born individuals. In fact, the only monosomy compatible with livebirth is the 45,X condition that causes Turner's syndrome. The 45,X chromosome constitution occurs with surprisingly high frequency, present in at least 1–2% of all pregnancies. More than 99% of all 45,X conceptions are spontaneously aborted. Thus, live-born individuals with a 45,X chromosome constitution represent a rare group of survivors. The 45,X phenotype is mild, presumably because the second copy of many X chromosomal genes is normally inactivated. Nonetheless, Turner's syndrome causes gonadal dysgenesis, resulting in infertility and failure to undergo secondary sexual development, along with a number of other phenotypic features (Chap. 349). Several other structural abnormalities of the X chromosome such as deletions, isochromosome X, or ring chromosomes can cause Turner's syndrome. Mosaicism, including 45,X/46,XX, 45,X/47,XXX, 45,X/46,XY, and others, also occurs (see below) and contributes to the phenotypic spectrum in Turner's syndrome.
Because numerical abnormalities originate in meiosis (Table 62-3), affected individuals have missing or extra chromosomes in all cells. In a small proportion of cases, a mitotic nondisjunctional event occurs at an early stage in an individual with an initially normal chromosome constitution. Alternatively, a "normalizing" mitotic nondisjunctional event may result in a normal chromosome complement in some cells of an embryo. In either case, the embryo is a mosaic, with some cells bearing a normal chromosome constitution and others an aneuploid number of chromosomes. The phenotypic consequences are difficult to predict because they depend on the timing of nondisjunction and the distribution of normal and abnormal cells in different tissues. Nevertheless, mosaicism may lead to clinical abnormalities indistinguishable from those of nonmosaic individuals (e.g., nearly 5% of all cases of Down syndrome involve individuals with mosaic trisomy 21, and about 15% of individuals with Turner's syndrome are mosaic for various sex chromosomal constitutions as described above).
Table 62-3 Studies of the Parent and Meiotic/Mitotic Stage of Origin of Human Trisomies and Sex Chromosome Monosomy |Favorite Table|Download (.pdf)
Table 62-3 Studies of the Parent and Meiotic/Mitotic Stage of Origin of Human Trisomies and Sex Chromosome Monosomy
The Origin and Etiology of Numerical Abnormalities
Over the past decade, a number of studies have used DNA polymorphisms to investigate the origin of different types of chromosome abnormalities (Fig. 62-5). The most thoroughly investigated types have been numerical abnormalities (Table 62-4). Sex chromosome monosomy usually results from loss of the paternal sex chromosome, regardless of whether the conception is liveborn or spontaneously aborted.
Use of DNA technology to determine the origin of chromosome abnormalities. A. Analysis of a chromosome 21–specific DNA polymorphism demonstrates that the trisomic individual received two chromosomes 21 from his mother and one from his father; thus, the extra chromosome 21 resulted from an error in oogenesis. B. Inheritance of a chromosome 15–specific DNA polymorphism in an individual with Prader-Willi syndrome (PWS). The affected individual has received two maternal, but no paternal, chromosomes 15; thus, the individual is said to have maternal uniparental disomy 15, a common cause of PWS.
Table 62-4 Some Commonly Identified MI-Crodeletion and Microduplication Syndromes—FISH Analysis |Favorite Table|Download (.pdf)
Table 62-4 Some Commonly Identified MI-Crodeletion and Microduplication Syndromes—FISH Analysis
|Syndrome||Cytogenetic Location||Principal Features||Imprinting Effects|
|Langer-Giedion syndrome||8q24.1 (del)||Sparse hair, bulbous nose, variable mental retardation||No|
|WAGR complex||11p13 (del)||Wilms' tumor, aniridia, genitourinary disorders, mental retardation||No|
|Beckwith-Wiedemann syndrome||11p15 (dup)||Macrosomia, macroglossia, omphalocele||Yes, occasionally associated with "paternal uniparental disomy" (see text)|
|Retinoblastoma||13q14.11 (del)||Retinoblastoma due to homozygous loss of functional RB allele||No obvious effect, although abnormal RB allele more likely to be paternal|
|Prader-Willi syndrome||15q11-13 (del)||Obesity, hypogonadism, mental retardation||Yes, prototypic imprinting disorder (see text)|
|Angelman syndrome||15q11-13 (del)||Ataxic gait||With Prader-Willi syndrome, prototypic imprinting disorder (see text)|
|α-Thalassemia and mental retardation||16p13.3 (del)||α-Thalassemia and mental retardation, due to deletion of distal 16p, including α-globin locus||No|
|Smith-Magenis syndrome||17p11.2 (del)||Brachycephaly, midface hypoplasia, mental retarda-tion||No|
|Miller-Dieker syndrome||17p13 (del)||Dysmorphic facies, lissencephaly||No|
|Charcot-Marie-Tooth syndrome type 1A||17p11.2 (dup)||Progressive neuropathy due to microduplication||No|
|DiGeorge syndrome/velocardiofacial syndrome||22q11 (del)||Abnormalities of third and fourth branchial arches||No|
Trisomies show remarkable variation in parental origin. For example, paternal nondisjunction is responsible for nearly 50% of 47,XXY but only 5–10% of cases of trisomies 13, 14, 15, 21, and 22; it is rarely, if ever, the source of the additional chromosome in trisomy 16. Similarly, there is considerable variability in the meiotic stage of origin. For example, all cases of trisomy 16 may be due to meiosis I errors, whereas for trisomy 21, one-third of cases are associated with meiosis II errors, and for trisomy 18, the majority of cases are apparently due to meiosis II nondisjunction. In spite of this variation in parental and meiotic origin, nondisjunction at maternal meiosis I appears to be the most common source of trisomy.
The 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. 62-6). This association between maternal age and trisomy is exerted without respect to race, geography, or socioeconomic factors and likely affects segregation of all chromosomes.
Estimated maternal age–adjusted rates of trisomy among all clinically recognized pregnancies (e.g., spontaneous abortions, stillbirths, and livebirths). Among women in their forties, more than 25% of all pregnancies are estimated to involve a trisomic conception; the vast majority of these spontaneously abort, with only trisomies 13, 18, and 21 and sex chromosome trisomies surviving to term with any appreciable frequency.
Despite the importance of increasing age, little is known about the mechanism by which aging leads to abnormal chromosomal segregation. As noted above, it is thought to originate in maternal meiosis I owing to the protracted time to completion (often ≥40 years) in females, and recent studies suggest that it may be associated with alterations in meiotic crossing-over. In trisomy 21, for example, crossover patterns appear to be similarly abnormal in younger and older mothers of trisomic conceptions. Thus, it has been suggested that two distinct steps, or "hits," may be involved in maternal age-related nondisjunction. The first hit, which is age independent, involves the establishment of a "vulnerable" crossover configuration in the fetal oocyte; the second hit, which is age dependent, involves abnormal processing of the vulnerable bivalent structure at metaphase I. If this model is correct, it suggests that the nondisjunctional process is the same in younger and older women, but it occurs more frequently with aging, possibly because 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 additional challenges from a genetic counseling standpoint. This is because structural abnormalities, unlike numerical abnormalities, can be present in "balanced" form in 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 different chromosomes (translocations) or loss, gain, or rearrangements of individual chromosomes (e.g., deletions, duplications, inversions, rings, or isochromosomes). Of particular clinical importance are translocations that involve two basic types: Robertsonian and reciprocal. Robertsonian rearrangements are a special class of translocation, in which the long arms of two acrocentric chromosomes (chromosomes 13, 14, 15, 21, and 22) join together, generating a fusion chromosome that contains virtually all of the genetic material of the original two chromosomes. If the Robertsonian translocation is present in unbalanced form, a monosomic or trisomic conception ensues. For example, ∼3% of Down syndrome cases are attributable to unbalanced Robertsonian translocations, most often involving chromosomes 14 and 21. In this instance, the affected individual has 46 chromosomes, including one structurally normal chromosome 14, two structurally normal chromosomes 21, and one fusion 14/21 chromosome. This effect leads to a normal diploid dosage for chromosome 14 and to a triplication of chromosome 21, thus resulting in Down syndrome. Similarly, a small proportion of individuals with trisomy 13 syndrome are clinically affected because of an unbalanced Robertsonian translocation involving chromosome 13.
Reciprocal translocations involve mutual exchanges between any two chromosomes. In this circumstance, the phenotypic consequences associated with unbalanced translocations depend on the location of the breakpoints that dictate the amount of material that has been "exchanged" between the two chromosomes. Because most reciprocal translocations involve unique sets of breakpoints, it is difficult to predict the phenotypic consequences in any one situation. In general, severity is determined by the amount of excess or missing chromosome material in individuals with unbalanced translocations.
In addition to rearrangements between chromosomes, there are several examples of intrachromosome structural abnormalities. The most common and deleterious of these involve loss of chromosome material due to deletions. The two best-characterized deletion syndromes, Wolf-Hirschhorn syndrome and cri-du-chat syndrome, result from loss of relatively small chromosomal segments on chromosomes 4p and 5p, respectively. Nonetheless, each is associated with multiple congenital anomalies, developmental delays, profound retardation, and reduced lifespan.
The term contiguous gene syndrome refers to genetic disorders that mimic a combination of single-gene disorders. They result from the deletion of a small number of tightly clustered genes. Because some are too small to be detected cytogenetically, they are termed microdeletions. The application of molecular techniques has led to the identification of at least 18 of these microdeletion syndromes (Table 62-4) that have been diagnosed using a directed FISH analysis. Some of the more common ones include the Wilms' tumor–aniridia complex (WAGR), Miller-Dieker syndrome (MDS), and velocardiofacial (VCF) syndrome. WAGR is characterized by mental retardation and involvement of multiple organs, including kidney (Wilms' tumor), eye (aniridia), and the genitourinary system. The cytogenetic abnormality involves a deletion of a part of the short arm of chromosome 11 (11p13), which typically is detectable on well-banded chromosome preparations. In MDS, a disorder characterized by mental retardation, dysmorphic facies, and lissencephaly, the deletion involves chromosome 17 (17p13.3). Using FISH, 17p deletions have been detected in >90% of patients with MDS as well as in 20% of cases of isolated lissencephaly.
Deletions involving the long arm of chromosome 22 (22q11.21) are the most common microdeletions identified to date, present in ∼1/3000 newborns. VCF syndrome, the most commonly associated syndrome, consists of learning disabilities or mild mental retardation, palatal defects, a hypoplastic aloe nasi and long nose, and congenital heart defects (conotruncal defect). Some individuals with 22q11.21 deletion are more severely affected and present with DiGeorge syndrome that involves abnormalities in the development of the third and fourth branchial arches leading to thymic hypoplasia, parathyroid hypoplasia, and conotruncal heart defects. In ∼30% of these cases, a deletion at 22q11.21 can be detected with high-resolution banding; by combing conventional cytogenetics, FISH, and molecular detection techniques (i.e., Southern blotting or polymerase chain reaction analyses), these rates improve to >90%. Additional studies have demonstrated a surprisingly high frequency of 22q11.21 deletions in individuals with nonsyndromic conotruncal defects. Approximately 10% of individuals with a 22q11.21 deletion inherited it from a parent with a similar deletion.
Smith-Magenis syndrome involves a microdeletion localized to the proximal region of the short arm of chromosome 17 (17p11.2). Affected individuals have mental retardation, dysmorphic facial features, delayed speech, peripheral neuropathy, and behavior abnormalities. Most of these deletions can be detected with cytogenetic analysis, although FISH is available to confirm these findings. In contrast, William syndrome, a chromosome 7 (7q11.23) microdeletion, cannot be diagnosed with standard or high-resolution analysis; it is only detectable utilizing FISH or other molecular methods. Williams' syndrome involves a deletion of the elastin gene and is characterized by mental retardation, dysmorphic features, a gregarious personality, premature aging, and congenital heart disease (usually supravalvular aortic stenosis).
In addition to microdeletion syndromes, there are several well-described microduplication syndromes, one of which is Charcot-Marie-Tooth type 1A (CMT1A). This is a nerve conduction disease previously thought to be transmitted as a simple autosomal dominant disorder. Recent molecular studies have demonstrated that affected individuals are heterozygous for duplication of a small region of chromosome 17 (17p12). Although it is not yet clear why increased gene dosage would result in CMT1A, the inheritance pattern is explained by the fact that one-half of the offspring of affected individuals inherit the duplication-carrying chromosome.
Microdeletion Syndromes—Array Analysis
All of the above-mentioned microdeletions and microduplications were initially identified clinically because of specific phenotypic features. After these were mapped to specific cytogenetic regions, FISH probes were developed to confirm the clinical diagnosis. With the advent of array analysis, new microdeletion and microduplication syndromes have been identified, often having less specific diagnostic criteria. These microdeletions and microduplications include changes in 16p11.2, 16p13.1, 15q13.3, 1q21.1, and are often ascertained because of autism. Often, the detected genetic changes are familial and parents do not always demonstrate any phenotypic abnormalities. Many of these are believed to be susceptibility genes that might increase an individual's risk for developing a disorder. Other changes such as a microdeletion involving 17q11.21, was not diagnosed before the advent of array analysis, and involves loss of the MAPT gene and is seen in patients with mental retardation, dysmorphic features, and hypopigmentation (Fig. 62-3).
Two microdeletion syndromes, Prader-Willi syndrome (PWS) and Angelman syndrome (AS), exhibit parent-of-origin, or "imprinting," effects. For many years, it has been known that cytogenetically detectable deletions of chromosome 15 occur in a proportion of patients with PWS, as well as in those with AS. This seemed curious, as the clinical manifestations of the two syndromes are very dissimilar, but the deletions appeared identical. PWS is characterized by obesity, hypogonadism, and mild to moderate mental retardation, whereas AS is associated with microcephaly, ataxic gait, seizures, inappropriate laughter, and severe mental retardation. New insight into the pathogenesis of these disorders has been provided by the recognition that parental origin of the deletion determines which phenotype ensues: If the deletion is paternal, the result is PWS, whereas if the deletion is maternal, the result is AS (Fig. 62-5B).
This scenario is complicated further by the recognition that not all individuals with PWS or AS carry the chromosome 15 deletion. For such individuals, the parental origin of the chromosome 15 region is again the important determinant. In PWS, for example, nondeletion patients invariably have two maternal and no paternal chromosomes 15 [maternal uniparental disomy (UPD)], whereas for some nondeletion AS patients the reverse is true (paternal UPD). This indicates that at least some genes on chromosome 15 are differently expressed, depending on which parent contributed the chromosome. Additionally, this means that normal fetal development requires the presence of one maternal and one paternal copy of chromosome 15.
Approximately 70% of PWS cases are due to paternal deletions of 15q11-q13, whereas 25% are due to maternal UPD, and about 5% are caused by mutations in a chromosome 15 imprinting center. In AS, 75% of cases are due to maternal deletions, and only 2% are due to paternal UPD. The remaining cases are presumably caused by imprinting mutations (5%), or mutations in the UBE3A gene, which is associated with AS. The UPD cases are mostly caused by meiotic nondisjunction resulting in trisomy 15, subsequently followed by a normalizing mitotic nondisjunction event ("trisomy rescue") resulting in two normal chromosomes 15, both from the same parent. UBE3A is the only maternally imprinted gene known in the critical region of chromosome 15. However, several paternally imprinted genes, or expressed-sequence tags (ESTs), have been identified, including ZNF127, IPW, SNRPN, SNURF, PAR1, and PAR5. Recently it has been postulated that a nontranscribed snoRNA (HBII-85), localized to the paternally imprinted region, may be responsible for the PWS phenotype.
Chromosomal regions that behave in the manner observed in PWS and AS are said to be imprinted. This phenomenon is involved in differential expression of certain genes on different chromosomes. Chromosome 11 is one of these with an imprinted region, since it is known that a small proportion of individuals with the Beckwith-Wiedemann overgrowth syndrome have two paternal but no maternal copies of this chromosome.