Chromosomal Syndromes and Genetic Disease

Chromosomal Syndromes and Genetic Disease Frederick W Luthardt, Swedish Hospital Medical Center, Seattle, Washington, USA Elisabeth Keitges, Dynacare ...
Author: Godfrey Pierce
3 downloads 0 Views 349KB Size
Chromosomal Syndromes and Genetic Disease Frederick W Luthardt, Swedish Hospital Medical Center, Seattle, Washington, USA Elisabeth Keitges, Dynacare Northwest, Seattle, Washington, USA

Introductory article Article Contents . Introduction . Chromosome Abnormalities . Outline of Chromosome Syndromes . Maternal Age Effects

The normal human chromosome complement consists of 46 chromosomes comprising 22 morphologically different pairs of autosomes and one pair of sex chromosomes. Variation in either chromosome number or structure frequently results in significant mental and/or clinical abnormalities. Chromosomal syndromes are associated with specific chromosomal abnormalities.

Introduction With the discovery in 1956 that the correct chromosome number in humans is 46, the new era of clinical cytogenetics began its rapid growth. During the next few years, several major chromosomal syndromes with altered numbers of chromosomes were reported, i.e. Down syndrome (trisomy 21), Turner syndrome (45,X) and Klinefelter syndrome (47,XXY). Since then it has been well established that chromosome abnormalities contribute significantly to genetic disease resulting in reproductive loss, infertility, stillbirths, congenital anomalies, abnormal sexual development, mental retardation and pathogenesis of malignancy. Specific chromosome abnormalities have been associated with over 60 identifiable syndromes. They are present in at least 50% of spontaneous abortions, 6% of stillbirths, about 5% of couples with two or more miscarriages and approximately 0.5% of newborns. In women aged 35 or over, chromosome abnormalities are detected in about 2% of all pregnancies. Some of the abnormalities and their clinical consequences will be discussed in the following sections.

. Recurrence Risks . Summary

Figure 1 (Down syndrome karyotype with trisomy 21), or to the absence of a single chromosome, or monosomy, as seen in Figure 2 (Turner syndrome karyotype with 45,X). The most common clinically significant chromosome abnormalities involving aneuploidy are frequently detected in newborns (Table 1). Although autosomal and sex chromosome trisomies result in clinical abnormalities they are more viable than monosomies, with the exception of monosomy X (45,X Turner syndrome). However, fewer than 5% of 45,X conceptions actually survive to birth. Aneuploidy is frequently associated with maternal age and constitutes a significant portion of chromosome abnormalities observed in spontaneous abortions (Table 2) and detected prenatally in fetuses (Table 3). Polyploidy resulting from triploidy (69 chromosomes) or tetraploidy (92 chromosomes) are lethal conditions most frequently seen in spontaneous abortions and very

Chromosome Abnormalities Numerical abnormalities Chromosome abnormalities are classified as either numerical or structural and may involve more than one chromosome. In discussing numerical abnormalities, certain terms need to be clarified. The normal human chromosome complement consists of 46 chromosomes (diploid) which is double the euploid (haploid) or gamete complement of 23. Exact multiples of euploid chromosome sets are either diploid or polyploid, i.e. triploid or tetraploid consisting of three or four euploid sets, respectively. Aneuploidy refers to the presence of an extra copy of a specific chromosome, or trisomy, as seen in

Figure 1 47,XX, 1 21 female Down syndrome karyotype demonstrating trisomy 21. (Karyotype prepared by Dave McDonald.)

ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group /


Chromosomal Syndromes and Genetic Disease

Table 1 Incidence of chromosomal abnormalities in newborns Type of abnormality Approximate incidence Sex chromosome abnormalities in males 47,XXY 1/1080 male births 47,XYY 1/1080 Other 1/1350 Total 1/385 Sex chromosome abnormalities in females 45,X 1/9600 female births 47,XXX 1/960 Other 1/2740 Total 1/660 Autosomal numerical abnormalities in infants Trisomy 21 1/800 live births Trisomy 18 1/8140 Trisomy 13 1/19 000 Triploidy 1/57 000 Total 1/695 Figure 2 45,X Turner syndrome karyotype demonstrating monosomy X. (Karyotype prepared by Dave McDonald.)

rarely in newborns with a short survival time. Triploidy is more common and is related to abnormal events prior to or during fertilization: most often triploidy results from two haploid sperm fertilizing a single haploid egg. Aneuploid and normal diploid cells can occasionally exist simultaneously in an individual. This condition is known as mosaicism and involves two or more distinct cell populations derived from a single zygote or fertilized egg. Mosaicism can involve either autosomal or sex chromosomes but most frequently involves sex chromosomes. Mosaicism is seen in approximately 0.2% of fetuses prenatally, 1% of Down syndrome patients, 10% of Klinefelter syndrome patients and over 30% of patients with Turner syndrome. The clinical significance of mosaicism depends upon the proportion and tissue distribution of the aneuploid cells. Chimaerism, in contrast, is distinguished from mosaicism in that the different cell lines are derived from more than one zygote.

Structural abnormalities Structural rearrangements frequently alter chromosome morphology. Chromosome morphology is based upon location of the centromere or primary constriction that divides a chromosome into a short arm ‘p’ and a long arm ‘q’ (Figure 3a). Chromosomes are metacentric when the centromere is in the middle with short and long arms of roughly equal length (Figure 3i), submetacentric when the centromere is closer to one end with short and long arms of unequal length (Figure 3a), and acrocentric when the centromere is near one end with very small short arms (Figure 3l). The centromere is essential for correct segregation of chromosomes during cell division. DNA replication prior to cell division ensures that each chromosome 2

Structural abnormalities in infants (autosomes and sex chromosomes) Balanced rearrangements Robertsonian 1/1120 live births Other 1/965 Unbalanced rearrangements 1/1675 Total 1/395 1/160 live births All chromosome abnormalities (autosomes and sex chromosomes) Modified from Thompson et al. (1991) Genetics in Medicine, 5th edn. WB Saunders.

Table 2 Relative frequencies of different abnormalities in chromosomally abnormal spontaneous abortions Abnormality


Trisomies 45,X Triploidy Translocations

52 18 17 2–4

Modified from Harper (1988) Practical Genetic Counselling, 3rd edn. Wright.

consists of two identical sister chromatids joined at the centromere. Chromosomes normally have one centromere. A dicentric chromosome has two centromeres (Figure 3l) and an acentric chromosome has none. At metaphase, when chromosomes are typically examined, sister chromatids appear fused as a result of the staining method necessary to produce the banding patterns essential for chromosome identification (Figures 1 and 2). Each band and subband has an assigned designation that identifies the chromosome arm, region and specific number as published

ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group /

Chromosomal Syndromes and Genetic Disease

Figure 3 Chromosome structural rearrangements, described in the text. (a) Chromosome arm and numerical banding designations according to ISCN (1995). (b) Terminal deletion and (c) interstitial deletion, each with loss of acentric fragment. (d) Pericentric inversion and (e) paracentric inversion, each with rotation of segment between breaks. (f) Direct duplication and (g) inverted duplication. (h) Isochromosome generation for short and long arms. (i) Ring chromosome with two acentric fragments. (j) Insertion of segment from one chromosome into a nonhomologous chromosome. (k) Reciprocal translocation with exchange of segments between nonhomologous chromosomes. (l) Robertsonian translocation between two acrocentric chromosomes. (Illustration prepared by Dave McDonald.)

by the 1995 International System for Human Cytogenetic Nomenclature (Figure 3a). Banding patterns are necessary to identify specific structural rearrangements within or between different chromosomes. Structural rearrangements involve chromosome breakage and reunion within a single chromosome or between two or more different chromosomes resulting in either balanced or unbalanced karyotypes. Rearrangements are balanced if there is no net change in chromosome material

or unbalanced if there is either a gain (partial trisomy) or loss (partial monosomy) of chromosome material. The frequency of structural abnormalities varies considerably in different populations. The highest frequency is in spontaneous abortions and the lowest in newborns (Table 4). This reduction can, in part, be explained by fetal losses prior to birth, particularly in those cases with significant unbalanced rearrangements.

ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group /


Chromosomal Syndromes and Genetic Disease

Table 3 Maternal age related frequency of aneuploid fetuses detected prenatally Aneuploid rate per 1000 Maternal age range (years)

Total number of fetuses

Trisomy 21

Trisomy 18

Trisomy 13





19 672







Modified from Schreinemachers et al. (1982) Human Genetics 61: 318–324.

Table 4 Frequency of structural chromosome abnormalities in various populations Structural rearrangement Balanced Unbalanced

Spontaneous abortions (%)


Prenatal diagnosis (%)

Newborn (%)





Data from various sources.

Unbalanced rearrangements Unbalanced rearrangements usually result in significant clinical abnormalities due to loss, duplication or both (in some cases) of genetic material. Some examples of unbalanced rearrangements are deletions, duplications, rings and isochromosomes (Figure 3). Deletions result in loss of chromosome material from a single chromosome. Terminal deletions result from a single break within one chromosome arm with loss of material distal to the break (Figure 3b). Interstitial deletions involve two breaks within the same chromosome arm with loss of the material between the breaks (Figure 3c). Ring chromosomes are formed by breaks occurring in each chromosome arm with loss of material distal to the breaks and with subsequent rejoining of the broken ends (Figure 3i). Ring chromosomes vary in size depending upon how much material has been lost. They are often unstable during cell division and can, very rarely, be transmitted from parent to offspring. Duplication of a chromosome segment usually occurs by unequal crossing over between homologous chromosomes or sister chromatids (Figure 3f). Duplications can also result from abnormal meiotic segregation in a translocation (Figure 3k,l) or meiotic crossing over in an inversion (Figure 3d,e) carrier. In general, duplications are less harmful than deletions but they inevitably are associated with some clinical abnormalities. The degree of clinical severity is correlated with size of the duplicated segment. An isochromosome is a chromosome consisting of two identical copies of one arm and none of the other (Figure 3h). In a person with 46 chromosomes, an isochromosome results in partial monosomy and partial trisomy. Isochromosomes most likely result from exchange between homologues during meiosis, or from breakage and reunion of sister chromatids near the centromere. Centromere misdivision during meiosis II is also considered to be a


possible, though less likely, mechanism. The most common isochromosome involves the long arm of the X-chromosome which is frequently seen in individuals with Turner syndrome. Most X-isochromosomes are actually dicentric. Inactivation of one centromere makes this abnormal chromosome more stable during cell division. Autosomal isochromosomes also occur and most frequently involve acrocentric chromosomes with loss of their short arms. Unbalanced isochromosomes are always associated with clinical abnormalities owing to their inherent genetic imbalance. Balanced rearrangements Carriers of balanced chromosomal rearrangements are usually clinically normal if no essential chromosome material is lost and no genes are damaged by the breakage and reunion process. However, they can produce unbalanced gametes and have an increased risk for chromosomally abnormal offspring. Balanced rearrangements include inversions, insertions, reciprocal translocations and Robertsonian translocations (Figure 3). Inversions are rearrangements within a single chromosome resulting from two breaks with the intervening segment being rotated 1808 prior to reconstitution. Inversions are classified as either pericentric, which have a single break in each arm (Figure 3d) or paracentric, which have two breaks in one arm (Figure 3e). Pericentric inversions frequently produce a change in the relative arm lengths; paracentric inversions do not but can be identified by changes in the banding pattern of the chromosome arm affected. Inversion carriers are usually clinically normal but may have an increased risk for offspring with partial trisomy and monosomy. This is because when chromosomes pair during meiosis an inversion loop is formed when the inverted segment pairs with its normal homologue and if an odd number of crossovers occur, unbalanced recombinant chromosomes

ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group /

Chromosomal Syndromes and Genetic Disease

are produced. Pericentric inversions can produce recombinants with duplication and deficiency of chromosome segments. The viability of these recombinant products is dependent upon the size of the unbalanced segments. Recombinant chromosomes derived from paracentric inversions are typically acentric or dicentric and usually result in nonviable offspring since these chromosomes are unstable during cell division. Translocations result from the exchange of chromosome segments between two or more nonhomologous chromosomes. There are three types of translocations: reciprocal, Robertsonian and insertional. Reciprocal translocations are produced by the exchange of broken-off segments between two different chromosomes (Figure 3k). Carriers of balanced reciprocal translocations are usually normal but they have an increased risk for unbalanced offspring. The actual risk is associated with segregation of the translocation components, position of breakpoints and centromere location. In general, viability is correlated with size of the unbalanced segment. Robertsonian translocations involve two acrocentric chromosomes that join near their centromeres, to form a single chromosome (Figure 3l). Frequently, this single chromosome has two centromeres, resulting in a dicentric chromosome. Balanced Robertsonian translocation carriers have only 45 chromosomes including the dicentric chromosome. Carriers of balanced Robertsonian translocations are usually clinically normal but have an increased risk of unbalanced offspring. This risk is higher for female carriers since males frequently have infertility problems. An insertional translocation is the result of three breaks such that a nonreciprocal change occurs when the segment from one chromosome is inserted into another chromosome (Figure 3j). Insertions are relatively rare since they involve three breaks. Insertion carriers are clinically normal but have an increased risk for offspring with partial monosomy or partial trisomy for the inserted segment.

Outline of Chromosome Syndromes Common autosomal trisomies Trisomy 21 (Down syndrome) is one of the best-recognized and most common chromosome disorders. It is the single most common genetic cause for mental retardation. The incidence of Down syndrome is approximately 1/800 newborns. The risk for having a child with trisomy 21 Down syndrome increases with maternal age. Clinical features include mental and growth retardation, characteristic facies and other abnormalities described in Table 5. Approximately 94% of Down syndrome patients have trisomy 21 (Figure 1) resulting from meiotic nondisjunction, the failure of homologous chromosomes or sister chromatids to separate during cell division. In about 95% of cases the extra chromosome 21 is of maternal origin, and of these

cases approximately 80% are due to an error during meiosis I. About 4% of Down syndrome patients have an unbalanced Robertsonian translocation involving chromosome 21. Approximately 60% of these translocations involve the long arm of chromosome 13, 14, or 15 (most frequently chromosome 14). About half of these translocations are de novo and half are inherited from a balanced carrier parent (usually the mother). Nearly 40% of unbalanced Robertsonian translocations involve only chromosomes 21 and 22. Most of these (  90%) involve 21/21 long-arm fusions or isochromosomes and nearly all are de novo. The rare parent who is a balanced 21/21 isochromosome carrier has a 100% risk for having a viable offspring with Down syndrome. Female carriers of balanced 14/21 or 21/22 Robertsonian translocations have a 10–15% risk for an unbalanced Down syndrome child. Male carriers have a risk of less than 5%. Mosaicism involving a mixture of normal diploid cells and trisomy 21 cells is present in about 2% of Down syndrome patients. Trisomy 18 (Edwards syndrome) is the second most common autosomal trisomy syndrome. It has a frequency of about 1 in 8000 live births. Clinical features include failure to thrive, cardiac and kidney problems and other congenital abnormalities (Table 5). Postnatal survival is poor and more than 90% die within the first 6 months. About 80% are female. The incidence of trisomy 18 increases with maternal age. Very few cases of trisomy 18 mosaicism have been reported. Many features characteristic of trisomy 18 have also been reported in patients with unbalanced translocations involving all or most of chromosome 18 long arm. Based upon limited data, the recurrence risk for trisomy 18 is approximately 1%. Trisomy 13 (Patau syndrome) is the least common of the major autosomal trisomies with an estimated incidence of 1 in 20 000 live births. Owing to severe clinical abnormalities including central nervous system malformations, heart defects, growth retardation and numerous other congenital anomalies (Table 5), trisomy 13 patients rarely survive the newborn period. Trisomy 13 is associated with advanced maternal age. The extra 13 usually results from a maternal meiotic nondisjunctional error. About 20% of cases have an unbalanced Robertsonian translocation involving chromosome 13. Balanced 13/14 Robertsonian translocation carriers have less than 2% risk of having an unbalanced trisomy 13 offspring. Trisomy 13 mosaicism is rare and may be associated with less severe clinical anomalies.

Common sex chromosome abnormalities Sex chromosome abnormalities have less severe clinical anomalies than those associated with comparable autosomal imbalances. This difference can be attributed to genetic inactivation of all but one X-chromosome in those cases where multiple copies are present, and the relatively

ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group /


Chromosomal Syndromes and Genetic Disease

Table 5 Clinical features of patients with common autosomal or sex chromosome aneuploidy Syndrome


Main clinical features


Trisomy 21


Trisomy 18


Trisomy 13





Triple X




Short, broad hands with single palmar crease, decreased muscle tone, mental retardation, broad head with characteristic features, open mouth with large tongue, up-slanting eyes Multiple congenital malformations of many organs, low-set malformed ears, receding mandible, small eyes, mouth and nose with general elfin appearance, severe mental deficiency, congenital heart defects, horseshoe or double kidney, short sternum, posterior heel prominence Severe mental deficiency, small eyes, cleft lip and/or palate, extra fingers and toes, cardiac anomalies, midline brain anomalies, genitourinary abnormalities Female with retarded sexual development, usually sterile, short stature, webbing of skin in neck region, cardiovascular abnormalities, hearing impairment, normal intelligence Male, infertile with small testes, may have some breast development, tall, mild mental deficiency, long limbs, at risk for educational problems Female with normal genitalia and fertility, at risk for educational and emotional problems, early menopause Tall male with normal physical/sexual development, normal intelligence, increased tendency for behavioural and psychological problems

Data from various sources.

low gene content of the Y-chromosome. Sex chromosome aneuploidy is relatively common, with overall frequency of about 1 in 500 live births (Table 1). Some (XXX, XXY, XYY) are relatively frequent in newborns but rare in spontaneous abortions. Monosomy X (Turner syndrome), in contrast, is one of the most common chromosome abnormalities seen in spontaneous abortions but relatively rare in newborns.

Turner syndrome (45,X) The frequency of Turner syndrome is about 1 in 8000 newborn females. Clinical features in newborns often include webbed neck, low hairline, puffy hands and feet, wide spaced nipples and cardiovascular problems. Later in life, these girls are typically short, sexually immature and infertile (Table 5). Slightly more than 50% of Turner syndrome patients have a 45,X karyotype (Figure 2). The remaining Turner patients have other sex chromosome abnormalities of the X-chromosome involving isochromosomes, short-arm deletions and rings. About 30% of Turner patients are mosaics consisting of 45,X cells plus other cells with two or more normal X-chromosomes, structurally abnormal X-chromosomes or a Y-chromosome. Approximately 95–99% of 45,X conceptions fail to survive to term and account for about 18% of chromosomally abnormal spontaneous abortions. The incidence of 45,X is not associated with maternal age. The paternal Xchromosome is missing in about 75% of 45,X patients. 6

Klinefelter syndrome (47,XXY) Klinefelter syndrome has a frequency of about 1 in 1000 newborn males (Table 1). Unlike Turner syndrome, males with Klinefelter syndrome are not usually detected in the newborn period. These individuals are generally normal in appearance before puberty. After puberty they are frequently ascertained in infertility clinics or identified by their small testes, breast enlargement and tall stature (Table 5). Significant mental retardation is not part of this syndrome but patients have a higher incidence of educational and emotional problems. Most Klinefelter patients have a 47,XXY karyotype. At least 10% have mosaicism involving normal 46,XY cells plus another population of cells with two or more X chromosomes. Mosaic patients have more variable clinical features and occasionally may have relatively normal testicular development. Cytogenetic and molecular data have indicated that 47,XXY is equally likely to result from a maternal or paternal meiotic nondisjunctional error. Maternally derived cases are associated with maternal age. Variants of Klinefelter syndrome include those patients with more than two X-chromosomes, multiple X-chromosome mosaicism and multiple Y-chromosomes. The presence of additional X-chromosomes (more than two) is associated with increasing severity of clinical abnormalities including mental retardation, sexual development and skeletal anomalies. 47,XYY syndrome Approximately 1 in 1000 newborn males have a 47,XYY karyotype (Table 1). XYY males have no discernible clinical

ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group /

Chromosomal Syndromes and Genetic Disease

features at birth or in infancy. Their mental and physical development is normal and they are fertile (Table 5). Although most 47,XYY patients are clinically normal, they tend to be taller than normal and have an increased tendency for behavioural and learning problems as children and young adults. Y-chromosome aneuploidy results from paternal meiotic nondisjunction and is not associated with maternal age. Trisomy X syndrome (47,XXX) The frequency of 47,XXX in newborn females is about 1 in 1000 (Table 1) and is associated with maternal age. Most XXX females are clinically normal with normal gonadal function and fertility. However, there is an increased risk for learning disabilities, reduction in performance IQ, menstrual problems and early menopause (Table 5). Females with more than three X-chromosomes (XXXX and XXXXX) have been reported but, in comparison to 47,XXX, are quite rare. These tetra-X and penta-X females are all mentally retarded and have more severe clinical problems.

Autosomal deletion and duplication syndromes Identification of common autosomal deletions requires precise chromosomal localization of the missing segment. Chromosome banding patterns make this localization possible if the deletion is cytogenetically visible. Detection of common deletions and also very small deletions not visible by routine cytogenetic analysis (microdeletions) has been made possible by fluorescence in situ hybridization (FISH) technology. This technique involves hybridizing specific fluorescently tagged DNA probes to metaphase chromosomes, which are detectable by UV excitation. Absence of a locus-specific fluorescent probe from one homologue is indicative of a microdeletion. Several common autosomal deletion syndromes are described in Table 6. The critical region for Wolf–Hirschhorn syndrome has been assigned to 4p16.3. In 90% of cases the deletion is de novo and in 10% it is inherited as an unbalanced translocation. The deletion is usually visible

cytogenetically, but occasionally it is too small and can only be identified molecularly with specific DNA probes utilizing FISH methods. Cri du chat syndrome is one of the earliest deletion syndromes to be described. It has an incidence of about 1 in 50 000 births. The critical region has been mapped to 5p15.2. About 90% of deletions are de novo and 10% are derived from an unbalanced familial translocation. Langer–Giedion syndrome is a rare condition with microcephaly and mental retardation. The critical region has been assigned to 8q24.11-q24.13. A cytogenetically visible deletion is seen in about 50% of cases. More recently, a group of autosomal microdeletions or contiguous gene syndromes have been identified that have a consistent but complex phenotype associated with a very small (usually 5 5 Mb) chromosomal deletion. Although some microdeletions are cytogenetically visible, the current method is to identify these syndromes by FISH utilizing fluorescently labelled DNA probes specific for the deleted segments. Some of the more common microdeletion syndromes are described in Table 7. In Williams syndrome about 96% of patients have a deletion for the elastin gene, which produces a protein necessary for elasticity of large blood vessels, skin and other organs. The de novo deletion is of maternal origin in 61% of cases and paternal in 39%. Genomic imprinting, the differential expression of alleles depending on the parent of origin, has been reported for the maternal deletion group of Williams patients since they had significantly more severe growth retardation and microcephaly than the paternal deletion group. Some genes mapped to the WAGR critical region have also revealed genomic imprinting. The incidence for Prader– Willi syndrome and Angelman syndrome is approximately 1 in 10 000 births, respectively. About 60% of Prader–Willi and Angelman syndrome patients have a cytogenetically visible deletion in the same region of chromosome 15. FISH analysis identifies a microdeletion in about 70% of cases of both syndromes. DNA polymorphism demonstrated that in Prader–Willi syndrome the deleted 15 was of paternal origin and was of maternal origin in Angelman syndrome patients. These observations suggested that the difference in clinical features for patients with identical

Table 6 Common autosomal deletions Syndrome

Chromosome region deleted

Main clinical features



Cri du chat




Severe growth retardation, midline facial defects, mental retardation, small head, prominent frontal bone between eyebrows, cleft lip/ palate, cardiac defects, wide-spaced eyes, broad nasal bridge High-pitched cry, wide-spaced eyes, small chin, small head, round face, severe psychomotor and mental retardation Small head, mental retardation, sparse hair, bulbous nose, short stature, multiple cartilaginous growths on bone surfaces

Data from various sources. ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group /


Chromosomal Syndromes and Genetic Disease

deletions implies differential expression depending upon parental origin (genomic imprinting). About 30% of Prader–Willi patients have two copies of maternal chromosome 15 and no paternal copy, a condition called uniparental disomy (UPD). Fewer than 5% of Angelman patients have paternal UPD for chromosome 15. A small proportion (1% Prader–Willi and 4% Angelman) have neither deletions nor UPD but have abnormal methylation patterns (differential expression of imprinted genes) at loci in 15q11-q13 due to imprinting mutations. At least 20% of nondeletion, non-UPD 15, normally methylated and cytogenetically normal Angelman patients have other genetic mutations. A visible cytogenetic deletion is seen in about 50% of Miller–Dieker syndrome patients. FISH analysis identifies a microdeletion in 90% of all Miller– Dieker patients. Hemizygosity for an interstitial deletion of chromosome 22q11.2 is associated with variable but overlapping syndromes known as Catch 22, DiGeorge syndrome and velocardiofacial syndrome. As a group, these syndromes have an incidence of about 1 in 5000 births and may account for 5% of all congenital heart defects. Cytogenetic deletions are seen in about 30% of these patients. FISH analysis is much more sensitive and identifies 85–90% of patients with microdeletions. Autosomal duplication syndromes are much less common than autosomal deletion syndromes. Several autosomal duplication syndromes are described in Table 8. Beckwith–Wiedeman syndrome has an incidence of 1 in 13 700 births. Approximately 85% are de novo and 20– 28% of these cases are due to paternal UPD for region

11p15.5. Fifteen per cent of cases are familial, due to maternal carriers with translocations or inversions with a breakpoint on 11p. These female carriers are clinically normal but their offspring may have clinical effects suggesting a role for genomic imprinting. Cytogenetic abnormalities are present in 2–3% of Beckwith–Wiedeman patients. The most frequent abnormality is duplication of 11p13!p15 resulting from the unbalanced segregation of a paternal translocation or inversion. De novo 11p15.5 duplications of paternal origin have also been reported in some patients with Beckwith–Wiedeman syndrome. Patients with duplication or trisomy for 11p15.5 have a higher incidence of clinical abnormalities than those with normal chromosomes. Charcot–Marie– Tooth disease type 1A (CMT1A) is the most common inherited peripheral neuropathy in humans and has a prevalence rate of 1 in 2500. In most cases CMT1A patients have normal chromosomes with duplication of DNA markers within 17p11.2!p12. A number of CMT1A patients have been reported with cytogenetically visible duplication of 17p11.2p12, demonstrating that this syndrome is correlated with a gene dosage effect for this chromosome region. Misalignment of homologous chromosomes resulting in unequal crossing over between nonsister chromatids during meiosis is the most likely mechanism for this type of de novo chromosome duplication. Cat-eye syndrome results from duplication of the proximal portion of the chromosome 22 long arm. The most common form of this duplication is a supernumerary (extra) dicentric bisatellited chromosome 22 designated as

Table 7 Autosomal microdeletion syndromes Syndrome

Chromosome region


Main clinical features



1/20 000

WAGR Prader–Willi

11p13 15q11.2

1/10 000



1/10 000

Miller–Dieker Smith–Magenis

17p13.3 17p11.2

1/25 000



Catch 22




Cardiac anomalies, mental retardation, characteristic facies, growth retardation, gregarious disposition, connective-tissue problems Kidney tumour, absence of iris, genital abnormalities, growth retardation Developmental delay, mental retardation, decreased muscle tone, obesity, small genitals, excessive appetite, hypopigmentation Developmental delay, mental retardation, unstable gait, absence of speech, hyperactivity, spontaneous laughter, hypopigmentation Smooth brain, small head, small chin, growth failure, cardiac abnormalities Flat midface, wide head, broad nasal bridge, short fingers and toes, mental retardation, hyperactivity, short stature, characteristic behavioural problems Chronic bile flow suppression, dysmorphic facies, ring-like corneal opacity, vertebral arch defects, narrowing of heart opening Cardiac defects, abnormal facies, underdeveloped thymus, cleft palate, decreased calcium in blood Underdeveloped thymus and parathyroid glands, facial abnormalities, cardiac defects Cleft palate, abnormal nose, developmental delay, cardiac abnormalities

Velocardiofacial 22q11.2


Data from various sources.


ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group /

Chromosomal Syndromes and Genetic Disease

Table 8 Autosomal duplication syndromes Syndrome Beckwith–Wiedemann Charcot–Marie–Tooth disease type 1A Cat-eye

Chromosome region duplicated 11p15.5 17p11.2-p12 22pter-q11.2

Main clinical features Large tongue, tissue and organ overgrowth, mild mental retardation Decreased reflexes, progressive distal muscular wasting, decreased muscle tone, sensory neuropathy Eye defects, absence of anal opening, skin tags in front of ears, characteristic facies, renal, skeletal and genital anomalies, mental retardation

Data from various sources.

inv dup(22)(q11.2). This inverted duplication process requires breakage at 22q11.2 in each of two sister or nonsister chromatids and produces a chromosome containing two copies of the cat-eye syndrome critical region (CESCR) or a total of four copies for the patient. These patients typically have 47 chromosomes owing to the presence of the supernumerary inv dup(22)(q11.2).

Chromosome instability syndromes There are several rare inherited syndromes characterized by increased rates of spontaneous or induced chromosomal breakage and predisposition to leukaemia and solid cancers. The most extensively studied of these syndromes, each caused by a different autosomal recessive gene, are Bloom syndrome, Fanconi anaemia, ataxia telangiectasia and xeroderma pigmentosum. These syndromes have distinctive chromosome aberrations. Bloom syndrome is characterized by quadriradial formations, which is the exchange of chromatid segments between two chromosomes, and a high rate of sister chromatid exchange (SCE) or exchanges between homologous chromosome segments. Fanconi anaemia patients exhibit a high frequency of chromosome breakage and nonhomologous chromosome interchange following exposure to alkylating agents or ultraviolet radiation. Their SCE rate is normal. Individuals with ataxia telangiectasia show an increased level of chromosome breaks and rearrangements and may have abnormalities involving chromosome 14. These patients have a normal SCE level. Patients with xeroderma pigmentosum do not exhibit spontaneous chromosome breakage; however, rearrangement, breaks, and increased SCE rate are observed after exposure to ultraviolet radiation.

Maternal Age Effects Prenatal and live birth risks for trisomy 21 Down syndrome are well established and are clearly associated with maternal age (Table 9). In addition to trisomy 21, other viable autosomal and sex chromosome aneuploidies, i.e.

trisomy 13, trisomy 18, XXX and XXY are also associated with maternal age (Table 10). Over 50% of chromosomally abnormal spontaneous abortions are trisomic for various chromosomes and, as a group, are more frequently associated with maternal age when compared to polyploid and nontrisomic abortions. Other chromosomally abnormal spontaneous abortions with sex chromosome monosomy (45,X), triploidy, tetraploidy and various other structural abnormalities are not associated with maternal age. The risk for aneuploidy increases with maternal age primarily owing to meiotic nondisjunction errors associated with reduced recombination or crossing over prior to the first meiotic division. This relationship has been demonstrated in Down syndrome patients with trisomy 21. Using DNA polymorphisms, the extra chromosome 21 was identified to be of maternal origin in over 90% of cases and in approximately 80% of these cases nondisjunction occurred during the first meiotic division. A similar relationship implicating a higher frequency of maternal nondisjunction errors has also been reported for trisomy 13, 16, 18, XXX and XXY. In addition to being associated with various aneuploid syndromes, the maternal age effect has also been observed in cases involving structural rearrangements associated with nondisjunction and segregation errors. Data from some balanced translocation carriers indicate that the risk for unbalanced offspring due to 3:1 disjunction increases with maternal age similarly to the risk pattern for trisomy 21. A maternal age effect has also been reported for some de novo structural rearrangements, particularly those involving bisatellited supernumerary marker chromosomes. In contrast to maternal age-related risk for aneuploidy, younger women (less than 30 years of age) have an increased recurrence risk for another trisomy 21 pregnancy above what is normally expected for their age. In women aged 30 or older, the recurrence risk for trisomy 21 is similar to their age-related risk. The reason for the higher recurrence risk in younger women is not known. In cases of familial Robertsonian translocations involving chromosome 21, the risk for an unbalanced Robertsonian translocation Down syndrome is higher for women less

ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group /


Chromosomal Syndromes and Genetic Disease

Table 9 Maternal age incidence of Down syndrome in fetuses and liveborns Incidence Maternal age (years) 15–19 20–24 25–29 30 33 34 35 36 37 38 39 40 45 and over

At birth 1/1250 1/1400 1/1100 1/900 1/625 1/500 1/350 1/275 1/225 1/175 1/140 1/100 1/25

At amniocentesis (16 weeks) – – – – 1/420 1/325 1/250 1/200 1/150 1/120 1/100 1/75 1/20

Modified from Thompson et al. (1991) Genetics in Medicine, 5th edn. WB Saunders.

than 30 years of age than for those over 30. In this situation, lack of a maternal age effect can be attributed to knowledge of being a translocation carrier and the impact of this knowledge upon the decision to have more children.

Recurrence Risks Recurrence risks for chromosomal abnormalities depend upon the type of abnormality, i.e. numerical or structural,

its origin (de novo or familial) and the sex of the carrier patient. The empirical recurrence risk for trisomy 21 for parents with normal chromosomes is approximately 1% and increases to 2% if the mother is aged 40 or over. This indicates that in younger women the recurrence risk is increased over what is expected for their age, while in women 35 years or older the risk is age-related. With the exception of trisomy 21, the recurrence risk for other specific aneuploidy or polyploid conditions is rare. Recurrence risk for unbalanced offspring of carriers with various structural rearrangements has been derived empirically (Table 11). Relatively specific risk estimates are known for more common types of Robertsonian translocations. The recurrence risk for an unbalanced Robertsonian translocation Down syndrome child is dependent upon which parent is the 14/21 or 21/22 carrier. However, if a person is a 21/21 carrier, the recurrence risk is 100% regardless of which parent is the carrier. For carriers of 13/14 Robertsonian translocation, the risk for an unbalanced trisomy 13 offspring is 1–2%. Carriers of balanced rearrangements are usually clinically normal but have an increased risk for producing unbalanced offspring. Risk for unbalanced gametes or segregation products depends upon location of chromosome breakpoints relative to the centromere and crossover frequency. Since it is difficult theoretically to predict the rate of unbalanced offspring to be expected for any particular structural rearrangement, risk estimates are based upon pooling of pregnancy outcome data from all translocation or inversion carriers (Table 11). More precise risk figures are available, however, for carriers of t(11;22) translocations since this is probably the most frequent reciprocal translocation found in humans. This translocation is often familial, with reduced fertility in males. Unbalanced probands are nearly always born to carrier females. The recurrence risk for the unbalanced

Table 10 Maternal age and chromosome abnormalities detected at amniocentesis Rate per 1000 Age

Trisomy 21

Trisomy 18

Trisomy 13



All chromosome anomalies

35 36 37 38 39 40 41 42 45

3.9 5.0 6.4 8.1 10.4 13.3 16.9 21.6 44.2

0.5 0.7 1.0 1.4 2.0 2.8 3.9 5.5 –

0.2 0.3 0.4 0.5 0.8 1.1 1.5 2.1 –

0.6 0.7 0.7 0.8 1.2 1.5 1.8 2.4 18.0

0.5 0.6 0.8 1.1 1.4 1.8 2.4 3.1 7.0

8.7 10.1 12.2 14.8 18.4 23.0 29.0 29.0 62.0

Modified from Harper (1988) Practical Genetic Counselling, 3rd edn. Wright.


ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group /

Chromosomal Syndromes and Genetic Disease

Table 11 Risks of unbalanced offspring for rearrangement carriers

rearrangement, the recurrence risk is generally considered to be negligible.

Type of rearrangement

Percentage of unbalanced offspring

Robertsonian translocations 14/21, female 14/21, male 13/14, both sexes 21/22, female 21/22, male 21/21 both sexes

10–15 2–5 1–2 10–15 1–2 100

Chromosome abnormalities contribute significantly to genetic disease. This impact is seen in various human populations in the effect on the fetus or individual directly or in the ability to produce healthy offspring. Autosomal abnormalities are generally more detrimental than sex chromosome abnormalities. Abnormalities involving entire chromosomes or subtle microdeletions can result in clinically abnormal syndromes.

6–12 20 50

Further Reading

Reciprocal translocations Pooled, both sexes Ascertained by unbalanced child Ascertained by unbalanced child with small unbalanced segment Other ascertainment t(11;22)(q23;q11.2) Recurrence risk unbalanced t(11;22) Pericentric inversions Ascertained by unbalanced child Other ascertainment

2–5 5–7 2 5–10 2

Modified from Nora and Fraser (1993) Medical Genetics: Principles and Practices, 4th edn. Lea and Febiger.

translocation is approximately 2%. It should also be emphasized that the recurrence risk is substantially higher if the parental rearrangement was originally ascertained through a liveborn child with an unbalanced chromosome rearrangement, since this identifies unbalanced chromosome complements that are compatible with survival to term. In those cases involving a de novo structural


de Grouchy J and Turleau C (1984) Clinical Atlas of Human Chromosomes, 2nd edn. New York: Wiley. Gelehrter TD, Collins FS and Ginsburg D (1998) Principles of Medical Genetics, 2nd edn. Baltimore, MD: Williams and Wilkins. Harper PS (1988) Practical Genetic Counseling, 3rd edn. Boston, MA: Wright. Hassold TJ (1986) Chromosome abnormalities in human reproductive wastage. Trends in Genetics 2: 105–110. Mitelman F (ed.) (1995) An International System for Human Cytogenetic Nomenclature recommendations of the International Standing Committee on Human Cytogenetic Nomenclature, Memphis, Tennessee, USA, October 9–13, 1994 Basel, Switzerland: Karger. Nora JJ, Clarke Fraser F, Bear J, Greenberg CR, Patterson D and Warburton D (1993) Medical Genetics: Principles and Practices, 4th edn. Philadelphia: Lea and Febiger. Schreinemachers DM, Cross PK and Hook EB (1982) Rates of trisomies 21,18,13 and other chromosome abnormalities in about 20 000 prenatal studies compared with estimated rate in live births. Human Genetics 61: 318–324. Therman E and Sulsman M (1992) Human Chromosomes: Structure, Behavior and Function, 3rd edn. New York: Springer. Thompson MW, McInnis RR and Willard HF (1991) Genetics in Medicine, 5th edn. Philadelphia: WB Saunders.

ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group /


Chromosomal Syndromes and Genetic Disease


ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group /

Suggest Documents