Numerical aberrations

Numerical aberrations represent a significant proportion of chromosomal changes found in humans. These errors can occur in meiosis or mitosis and therefore be constitutive (present in all cells) or mosaic (present in some cells). They represent a significant cause of pregnancy loss as well as abnormalities found in livebirths.

Meiotic Nondisjunction

Meiosis is the process by which a diploid cell (one with twocopies of all distinct chromosomes) produces a haploid gamete (oocyte or spermatocyte) containing a single copy of each chromosome. The normal product of meiosis in humans is a gamete containing 23 chromosomes: 22 autosomes and a sex chromosome (X or Y). In human females meiosis Iis initiated during fetal development, but is not completed until some 2040 years later when an egg is released from a follicle during ovulation. Meiosis II is not completed unless the egg is fertilized by a sperm. In contrast, spermatogenesis occurs continuously after puberty in males and it takes 9 weeks for a spermatogonium to develop into mature sperm, with meiosis requiring only 24 days to complete. Segregation of chromosomes in human meiosis is remarkably error-prone and roughly 20% of oocytes and a few per cent of spermatocytes are either aneuploid, having a numerically unbalanced chromosome complement, e.g. 22 or 24 chromosomes, or diploid (46 chromosomes). This error rate is at least an order of magnitude higher than seen in any studied experimental organism. There is no explanation for this difference, but it could possibly be related to longer duration of meiosis in humans. Some consequences of these errors to human reproductive health are failure of implantation, early pregnancy loss and birth defects or developmental delay in liveborns. Chromosome nondisjunction is defined as the unbalanced segregation of chromosomes leading to aneuploidy and may occur at meiosis I(when homologous chromosomes segregate to opposite poles) or at meiosis II (when the two sister chromatids separate at the centromere and segregate to opposite poles). Nondisjunction in experimental organisms has been shown to result from a variety of causes, including improper alignment of chromosomes on the spindle, failure of spindle proteins that serve to pull homologous chromosomes to opposite poles, premature resolution of chiasmata (location where homologous chromosomes exchange genetic material), or premature separation of sister chromatids (Hawley et al., 1994). Very little is known about the causes of nondisjunction in humans but some data suggest that premature separation of chromatids may often be involved. The vast majority of aneuploidy in humans is maternal in origin (i.e. due to an error present in the oocyte) and itsincidence increases dramatically with maternal age (Hassold et al., 1996). The exceptions to this rule are 47,XYY (presence of an extra Y-chromosome) and 45,X (a missing sex chromosome), which are predominantly due to paternal or postfertilization events. The cause of the increase of nondisjunction with maternal age is not known but the ovarian environment may become compromised as a woman ages owing to poorer regulation of hormone levels (Freeman et al., 2000). Nondisjunction appears to increase only slightly or not at all with paternal age (Martin and Rademaker, 1992). As yet there is no evidence from population studies for a significantly increased risk of having a second aneuploid pregnancy in couples who have experienced one pregnancy loss due to aneuploidy, once maternal age is accounted for (Warburton et al., 1987). However, increased rates of aneuploidy can be found in some carriers of balanced structural rearrangements (e.g. robertsonian translocations) or mutations in genes affecting found to be mosaic for a trisomy (e.g. trisomy 21 mosaicism). Furthermore, some men experiencing infertility show a disruption of chromosome pairing and meiotic arrest that consequently leads to low (oligospermia) to no (azoospermia) mature sperm. In such men the sperm that are found may have a higher than expected rate of sex chromosome abnormalities and diploidy.

Mitotic Nondisjunction

Mitosis is the process by which somatic cells divide; it involves the replication of chromatids followed by segregation of sister chromatids to opposite poles. Chromosome segregation errors may also occur during mitotic cell divisions and thus lead to mosaicism, with the presence of both aneuploid and normal diploid cells within one individual. Mitotic nondisjunction occurring during the somatic cell divisions preceding meiosis in oogenesis or spermatogenesis may lead to germline mosaicism, and result in an increased rate of eggs or sperm with aneuploidy for a specific chromosome. Mitotic errors occurring during early development may lead to a mixture of abnormal and normal cells in the developing embryo (below). The abnormal cells may be confined to placental tissues or be present in both placenta and fetus. It is also possible for loss of a supernumerary chromosome in a trisomic conceptus to occur, resulting in mosaicism between the progenitor trisomic cell line and a derivative diploid cell. Although balanced in chromosome number, the resulting diploid cell may not be balanced in terms of parental contribution, as it is possible for both chromosomes from the involved pair to be derived from a single parent, a situation termed uniparental disomy (UPD).

Aneuploidy
Aneuploidy is the condition of having less than or more than the normal diploid number of chromosomes, and is the most frequently observed type of cytogenetic abnormality. In other words, it is any deviation from euploidy, although many authors restrict use of this term to conditions in which only a small number of chromosomes are missing or added. Generally, aneuploidy is recognized as a small deviation from euploidy for the simple reason that major deviations are rarely compatible with survival, and such individuals usually die prenatally. The two most commonly observed forms of aneuploidy are monosomy and trisomy:

Monosomy is lack of one of a pair of chromosomes. An individual having only one chromosome 6 is said to have monosomy 6. A common monosomy seen in many species is X chromosome monosomy, also known as Turner's syndrome. Monosomy is most commonly lethal during prenatal development. Trisomy is having three chromosomes of a particular type. A common autosomal trisomy in humans in Down syndrome, or trisomy 21, in which a person has three instead of the normal two chromosome 21s. Trisomy is a specific instance of polysomy, a more general term that indicates having more than two of any given chromosome.

Another type of aneuploidy is triploidy. A triploid individual has three of every chromosome, that is, three haploid sets of chromosomes. A triploid human would have 69 chromosomes (3 haploid sets of 23), a triploid dog 117 chromosomes. Production of triploids seems to be relatively common and can occur by, for example, fertilization by two sperm. However, birth of a live triploid is extraordinarily rare and such individuals are quite abnormal. The rare triploid that survives for more than a few hours after birth is almost certainly a mosaic, having a large proportion of diploid cells. A chromosome deletion occurs when the chromosome breaks and a piece is lost. This of course involves loss of genetic information and results in what could be considered "partial monosomy" for that chromosome. A related abnormality is a chromosome inversion. In this case, a break or breaks occur and that fragment of chromosome is inverted and rejoined rather than being lost. Inversions are thus rearrangements that do not involve loss of genetic material and, unless the breakpoints disrupt an important gene, individuals carrying inversions have a normal phenotype. Birth Formula Nomenclature Frequency 2n+1 Down's Syndrome Edward's Syndrom 2n+1 47,+18 1/7500 47,+21 1/700

Condition

Phenotype Round, broad head;simian palm crease; narrow, high palatte; low IQ

Mental retardation; multiple congenital defects of all organs; death within 6 months Simalr to Edward;s Syndrome; death within 3 months

Patau Syndrome 2n+1

47,+13

1/15,000

Turner's Syndrome Klinefelter's Syndrome

2n-1

45,X

1/2000 females 1/500 Males

Retarded development of feamle >sex organs; sterility

2n+1 2n+2 2n+2 2n+3 2n+4

47,XXY 48,XXXY 48,XXYY ,49,XXXXY 50,XXXXXY

Poor male sex organ development; breast development; subfertility

"Homoeologous Group I. The three nullisomics of this group are reduced in plant height in varying degrees and have spikes that are a little less dense than normal, with slightly stiffer glumes (Fig. 2). All three nullisomics are both female and male fertile. On the basis of vigor and fertility of the nullisomics, chromosome I is the least essential of the three with XIV slightly less essential than XVII. The tetrasomics are all slightly less fertile than the normal, tetraXIV being the least fertile. The monosomics and trisomics are essentially normal under favorable conditions." Effects of Nullisomics

male and female fertile chromosome 1 less essential for fertility

Effects of Tetrasomics

slightly less fertile

Homoeologous Group 2. This is a very distinctive group. All three nullisomics are very dwarfish, with greatly reduced tillering. All are male fertile but male sterile. The spikes have thin, papery glumes and are completely awnless. The three tetrasomics are virtually indistinguishable from each other. All have small culms and narrow leaves, with increased awn length, and with glumes somewhat stiffer than normal. The trisomics are distinguishable from normal by their rather narrower leaves and longer awns. The monosomics tend to be coarser than normal, with slightly shortened awns and reduced fertility except under very favorable conditions. In this series, deficiency for chromosome II seems to cause the greatest abnormality and XX the least." Effects of Nullisomics

dwarf less tillering female fertile male sterile awnless chromosome II has the greatest effect

Effects of Tetrasomics

small culms narrow leaves longer awns

Clinical and biological significance of aneuploidy in human tumours. Aneuploidy is a well recognised feature of human tumours, but the investigation of its biological and clinical significance has been hampered by technological constraints. Quantitative DNA analysis reflects the total chromosomal content of tumour cells and can now be determined rapidly and reliably using flow cytometry; this has resulted in renewed interest in its potential clinical applications. This article reviews the accumulating evidence that tumour ploidy reflects the biological behaviour of a large number of tumour types and that diploid tumours in particular have a relatively good prognosis. The measurement of tumour ploidy is likely to become a valuable adjunct to the clinical and histopathological assessment of cancers.

Polyploidy

A polyploid organism has more than two sets of chromosomes in every somatic cell (Lawrence 2000). Organisms with two sets of chromosomes, like ourselves, are referred to as diploids, those with three sets are called triploids, and organisms having four sets of chromosomes are tetraploids and so on. The condition is called polyploidy and has been studied for over one hundred years (Winge 1917). In the beginning, polyploidy was regarded as a rare condition. However, estimates of the frequency of polyploid occurrence have gradually risen. Today, some authors argue that more than 70% of all angiosperms have undergone polyploidization at some stage in their evolution (Masterson 1994) and that 2 to 4 % of all speciation events in flowering plants are due to polyploidy (Otto & Whitton 2000). Polyploidy also occurs in animals, but to a lesser extent; yet there are some hundred examples, mostly of insects (Otto & Whitton 2000). One of the reasons for the paucity of polyploid animals is that polyploidy interferes with sex determination (Mller 1925, reviewed in Otto & Whitton 2000). The importance of polyploidy has also been the subject of lively debate over the years. In 1970, Wagner proposed that polyploid lineages were comparatively short-lived and without significance for long term evolution. He recognized that polyploids arise repeatedly but argued that they did not contribute to the speciation process. Wagner quoted Mosquin (1966) and stated that the evolutionary capacity of polyploids is lower than for diploids and that polyploidy puts a strong damper on the evolutionary process (Wagner 1970). Nowadays, most researchers believe that polyploidization is a dynamic process that can give rise to new evolutionary lineages. In fact, a number of classical diploid species have been shown, through genome mapping and comparative analysis, to have experienced polyploidy stages earlier in their history. Such examples include Arabidopsis thaliana (Vision et al. 2000), maize (Zea mays) (Gaut & Doebley 1997) and Brassica (Lagercrantz 1998). These diploids are called paleoploids to denote their polyploid history. The paleoploids are thus ancient polyploids that have become functional diploids through a process called diploidization. The process includes DNA loss, genome restructuring and gene silencing. The diploidized genome may again be duplicated and follow another round of diploidization. This cycling makes the terms polyploid and diploid rather static and hard to define (Wendel 2000). Polyploidy can arise naturally in a number of different ways. The somatic doubling of the genome is called endopolyploidy or asexual formation and it may occur in meristematic, zygotic or embryonic cells. It is unknown to what extent endopolyploidy occurs in nature (Ramsey & Schemske, 1998). A second route, the sexual formation, involves unreduced gametes and is considered the more common mechanism of polyploid formation (Harlan & de Wet 1975, Thompson & Lumaret 1992, Ramsey & Schemske 1998). The polyploid is formed either when two unreduced gametes fuse directly or via a triploid phase. Sexual formation of polyploids is thought to happen repeatedly between parental lineages, and consequently, the hybrids (polyploids) have multiple origins (Soltis & Soltis 1993, Leitch & Bennett 1997). When unreduced gametes of sufficiently divergent lineages fuse, an allopolyploid is formed (Stebbins 1947). The genome then consists of two different sets of chromosomes, denoted homoeologous chromosomes, or homoeologs. The homoeologs will exchange little genomic material during meiosis and thus maintain their integrity through generations. When homoeologous chromosomes have different alleles at a given locus the locus is denoted heterozygotic. Due to the maintained integrity, the heterozygosity of the homoeologs will be preserved. This phenomenon is called fixed heterozygosity. Autopolyploids, on the other hand, arise through the fusion of two homologous genomes (Stebbins 1947). They do not have fixed heterozygosity because their chromosomes are able to pair and recombine just like they do in a normal diploid. There are at least two reasons why allopolyploids attract more interest than autopolyploids. First, the allopolyploids are considered more common than autopolyploids in nature (Stebbins 1950). Second, allopolyploidy may lead to the formation of new taxa (Leitch & Bennett 1997, Soltis & Soltis 1999) with character combinations that are unknown among their diploid parents. The formation of the polyploid is followed by a critical period when the establishment of the polyploid is limited by reproductive isolation and competition from the surrounding parents. Additionally, the polyploid genome may suffer from unbalance and large changes. Consequently, the first generations in a polyploids life are of great importance. If a polyploid manages to become established and reproduce, an important question arises on what evolutionary impact the polyploid may have on its surrounding populations. Is it better prepared for environmental change than the diploid parents? Is it less successful under certain circumstances? To be able to answer these kinds of questions we need to know more about the genomic changes that happen after a polyploidization event. Many reviews have been written on the genetic, ecological and evolutionary consequences of polyploidization in plants (Jackson 1976, Thompson & Lumaret 1992, Soltis & Soltis 1993, Leitch & Bennett 1997, Soltis & Soltis 1999, Comai 2000, Otto & Whitton 2000, Wendel 2000, Liu & Wendel 2003, Soltis et al.. 2003). Here, I try to summarize the

genetic effects of polyploidization and discuss different evolutionary aspects of polyploidy, with a special focus on allopolyploidy. Polyploidy in Animals Geneticist Hermann Muller argued that polyploidy is more rare in animals than plants because animals have a more complex development, with more organ systems that are fine-tuned to dosages of genes. Any given gene is represented three times in a triploid. If the amount (dosage) of gene product causes a heart, brain, or other vital organ not to form, the embryo will abort. When these developmental genes produce too much or too little of the products that induce organ formation, as they might if there are too many or too few copies of the genes, events occur too soon or too late to be coordinated. Muller raised the possibility that the sex chromosomes serve as a barrier to polyploidy in most animals. Plants, by contrast, do not usually have sexchromosomes, and thus this sexual reproductive barrier is not a problem for them. Muller noted that most animals use a sex-chromosomemechanism for sex determination. In fruit flies and humans, diploid males have the sex chromosomes XY, whereas diploid females have XX. A triploid fly or human would have three chromosomesalong with three sets of autosomes. In such a triploid, XXX will result in a female. However, a zygote having XXY XYY may not produce a male. Rather, it may result in an intersex organism, with abnormal mixed male and female reproductive organs. While human triploids do not survive, this is not the case for fruit flies. The XXY or XYY is an intersex, sterile form, but the triploid female is fertile. If the 3N female is mated to a 2N XY male, however, only a relatively few offspring will emerge, because many of the eggs will have an incorrect number of chromosomes. This state of excesses or deficits of chromosomes in an otherwise diploid or triploid cell is called aneuploidy. Aneuploid embryos rarelysurvive in humans or other animals, although there are exceptions (such as infants born with Down syndrome).

Turner syndrome
What is Turner syndrome? Turner syndrome is a chromosomal condition that alters development in females. Women with this condition tend to be shorter than average and are usually unable to conceive a child (infertile) because of an absence of ovarian function. Other features of this condition that can vary among women who have Turner syndrome include: extra skin on the neck (webbed neck), puffiness or swelling (lymphedema) of the hands and feet, skeletal abnormalities, heart defects and kidney problems. This condition occurs in about 1 in 2,500 female births worldwide, but is much more common among pregnancies that do not survive to term (miscarriages and stillbirths). Turner syndrome is a chromosomal condition related to the X chromosome. Researchers have not yet determined which genes on the X chromosomeare responsible for most signs and symptoms of Turner syndrome. They have, however, identified one gene called SHOX that is important for bone development and growth. Missing one copy of this gene likely causes short stature and skeletal abnormalities in women with Turner syndrome.

What are the symptoms for Turner syndrome? Girls who have Turner syndrome are shorter than average. They often have normal height for the first three years of life, but then have a slow growth rate. At puberty they do not have the usual growth spurt. Non-functioning ovaries are another symptom of Turner syndrome. Normally a girl's ovaries begin to produce sex hormones (estrogen and progesterone) at puberty. This does not happen in most girls who have Turner syndrome. They do not start their periods or develop breasts without hormone treatment at the age of puberty. Even though many women who have Turner have non-functioning ovaries and are infertile, their vagina and womb are totally normal.

In early childhood, girls who have Turner syndrome may have frequentmiddle ear infections. Recurrent infections can lead to hearing loss in some cases. Girls with Turner Syndrome are usually of normal intelligence with good verbal skills and reading skills. Some girls, however, have problems with math, memory skills and fine-finger movements. Additional symptoms of Turner syndrome include the following:

An especially wide neck (webbed neck) and a low or indistinct hairline. A broad chest and widely spaced nipples. Arms that turn out slightly at the elbow. A heart murmur, sometimes associated with narrowing of the aorta(blood vessel exiting the heart). A tendency to develop high blood pressure (so this should be checked regularly). Minor eye problems that are corrected by glasses. Scoliosis (deformity of the spine) occurs in 10 percent of adolescent girls who have Turner syndrome. The thyroid gland becomes under-active in about 10 percent of women who have Turner syndrome. Regular blood tests are necessary to detect it early and if necessary treat with thyroid replacement. Older or over-weight women with Turner syndrome are slightly more at risk of developing diabetes. Osteoporosis can develop because of a lack of estrogen, but this can largely be prevented by taking hormone replacement therapy.

(Lymphedema of the feet in an infant is shown. The toes have the characteristic sausagelike appearance.)

(Generalized lymphedema is seen here in an infant with Turner syndrome. The loose skin folds around the neck will form a webbed neck later in life.) How is Turner syndrome diagnosed? A diagnosis of Turner syndrome may be suspected when there are a number of typical physical features observed such as webbed neck, a broad chest and widely spaced nipples. Sometimes diagnosis is made at birth because of heart problems, an unusually wide neck or swelling of the hands and feet. The two main clinical features of Turner syndrome are short stature and the lack of the development of the ovaries. Many girls are diagnosed in early childhood when a slow growth rate and other features are identified. Diagnosis sometimes takes place later when puberty does not occur. Turner syndrome may be suspected in pregnancy during an ultrasound test. This can be confirmed by prenatal testing - chorionic villous sampling oramniocentesis - to obtain cells from the unborn baby for chromosomal analysis. If a diagnosis is confirmed prenatally, the baby may be under the care of a specialist pediatrician immediately after birth. Diagnosis is confirmed by a blood test, called a karyotype. This is used to analyze the chromosomal composition of the female. More information about this will be discussed in the section "Is Turner syndrome inherited?" What is the treatment for Turner syndrome? During childhood and adolescence, girls may be under the care of apediatric endocrinologist, who is a specialist in childhood conditions of the hormones and metabolism. Growth hormone injections are beneficial in some individuals with Turner syndrome. Injections often begin in early childhood and may increase final adult height by a few inches. Estrogen replacement therapy is usually started at the time of normal puberty, around 12 years to start breast development. Estrogen and progesterone are given a little later to begin a monthly 'period,' which is necessary to keep the womb healthy. Estrogen is also given to preventosteoporosis. Babies born with a heart murmur or narrowing of the aorta may need surgery to correct the problem. A heart expert (cardiologist) will assess and follow up any treatment necessary. Girls who have Turner syndrome are more likely to get middle ear infections. Repeated infections may lead to hearing loss and should be evaluated by the pediatrician. An ear, nose and throat specialist (ENT) may be involved in caring for this health issue.

High blood pressure is quite common in women who have Turner syndrome. In some cases, the elevated blood pressure is due to narrowing of the aorta or a kidney abnormality. However, most of the time, no specific cause for the elevation is identified. Blood pressure should be checked routinely and, if necessary, treated with medication. Women who have Turner syndrome have a slightly higher risk of having an under active thyroid or developing diabetes. This should also be monitored during routine health maintenance visits and treated if necessary. Regular health checks are very important. Special clinics for the care of girls and women who have Turner syndrome are available in some areas, with access to a variety of specialists. Early preventive care and treatment is very important. Almost all women are infertile, but pregnancy with donor embryos may be possible. Having appropriate medical treatment and support allows a woman with Turner syndrome to lead a normal, healthy and happy life. Is Turner syndrome inherited? Turner syndrome is not usually inherited in families. Turner syndrome occurs when one of the two X chromosomes normally found in women is missing or incomplete. Although the exact cause of Turner syndrome is not known, it appears to occur as a result of a random error during the formation of either the eggs or sperm. Humans have 46 chromosomes, which contain all of a person's genes and DNA. Two of these chromosomes, the sex chromosomes, determine a person's gender. Both of the sex chromosomes in females are called X chromosomes. (This is written as XX.) Males have an X and a Y chromosome (written as XY). The two sex chromosomes help a person develop fertility and the sexual characteristics of their gender. In Turner syndrome, the girl does not have the usual pair of two complete X chromosomes. The most common scenario is that the girl has only one X chromosome in her cells. Some girls with Turner syndrome do have two X chromosomes, but one of the X chromosomes is incomplete. In another scenario, the girl has some cells in her body with two X chromosomes, but other cells have only one. This is called mosaicism.

Klinefelter syndrome
What is Klinefelter syndrome? Klinefelter syndrome, also known as the XXY condition, is a term used to describe males who have an extra X chromosome in most of their cells. Instead of having the usual XY chromosome pattern that most males have, these men have an XXY pattern. Klinefelter syndrome is named after Dr. Henry Klinefelter, who first described a group of symptoms found in some men with the extra X chromosome. Even though all men with Klinefelter syndrome have the extra X chromosome, not every XXY male has all of those symptoms. Because not every male with an XXY pattern has all the symptoms of Klinefelter syndrome, it is common to use the term XXY male to describe these men, or XXY condition to describe the symptoms. Scientists believe the XXY condition is one of the most common chromosome abnormalities in humans. About one of every 500 males has an extra X chromosome, but many don't have any symptoms.

What are the symptoms of the XXY condition? Not all males with the condition have the same symptoms or to the same degree. Symptoms depend on how many XXY cells a man has, how muchtestosterone is in his body, and his age when the condition is diagnosed. The XXY condition can affect three main areas of development 1) physical, 2) language, and 3) social.

Physical development As babies, many XXY males have weak muscles and reduced strength. They may sit up, crawl, and walk later than other infants. After about age four, XXY males tend to be taller and may have less muscle control and coordination than other boys their age. As XXY males enter puberty, they often don't make as much testosterone as other boys. This can lead to a taller, less muscular body, less facial and body hair, and broader hips than other boys. As teens, XXY males may have larger breasts, weaker bones, and a lower energy level than other boys. By adulthood, XXY males look similar to males without the condition, although they are often taller. They are also more likely than other men to have certain health problems, such as autoimmune disorders, breast cancer, vein diseases, osteoporosis, and tooth decay.

XXY males can have normal sex lives, but they usually make little or nosperm. Between 95 percent and 99 percent of XXY males are infertilebecause their bodies don't make a lot of sperm.

Language development As boys, between 25 percent and 85 percent of XXY males have some kind of language problem, such as learning to talk late, trouble using language to express thoughts and needs, problems reading, and trouble processing what they hear. As adults, XXY males may have a harder time doing work that involves reading and writing, but most hold jobs and have successful careers. Social development As babies, XXY males tend to be quiet and undemanding. As they get older, they are usually quieter, less selfconfident, less active, and more helpful and obedient than other boys. As teens, XXY males tend to be quiet and shy. They may struggle in school and sports, meaning they may have more trouble "fitting in" with other kids. However, as adults, XXY males live lives similar to men without the condition; they have friends, families, and normal social relationships. What are the treatments for the XXY condition? The XXY chromosome pattern can not be changed. But, there are a variety of ways to treat the symptoms of the XXY condition.

Educational treatments - As children, many XXY males qualify for special services to help them in school. Teachers can also help by using certain methods in the classroom, such as breaking bigger tasks into small steps. Therapeutic options - A variety of therapists, such as physical, speech, occupational, behavioral, mental health, and family therapists, can often help reduce or eliminate some of the symptoms of the XXY condition, such as poor muscle tone, speech or language problems, or low self-confidence. Medical treatments - Testosterone replacement therapy (TRT) can greatly help XXY males get their testosterone levels into normal range. Having a more normal testosterone level can help develop bigger muscles, deepen the voice, and grow facial and body hair. TRT often starts when a boy reaches puberty. Some XXY males can also benefit from fertility treatment to help them father children.

Down syndrome
What is Down syndrome? Down syndrome is a chromosomal disorder caused by an error in cell division that results in an extra 21st chromosome. The condition leads to impairments in both cognitive ability and physical growth that range from mild to moderate developmental disabilities. Through a series of screenings and tests, Down syndrome can be detected before and after a baby is born. The only factor known to affect the probability of having a baby with Down syndrome is maternal age. That is, less than one in 1,000 pregnancies for mothers less than 30 years of age results in a baby with Down syndrome. For mothers who are 44 years of age, about 1 in 35 pregnancies results in a baby with Down syndrome. Because younger women generally have more children, about 75 - 80% of children with Down syndrome are born to younger women. What causes Down syndrome? Down syndrome occurs because of an abnormality characterized by an extra copy of genetic material on all or part of the 21st chromosome. Every cell in the body contains genes that are grouped along chromosomes in the cell's nucleus or center. There are normally 46 chromosomes in each cell, 23 inherited from your mother and 23 from your father. When some or all of a person's cells have an extra full or partial copy of chromosome 21, the result is Down syndrome. The most common form of Down syndrome is known as Trisomy 21, a condition where individuals have 47 chromosomes in each cell instead of 46. This is caused by an error in cell division called nondisjunction, which leaves a sperm or egg cell with an extra copy of chromosome 21 before or at conception. Trisomy 21 accounts for 95% of Down syndrome cases, with 88% originating from nondisjunction of the mother's egg cell. The remaining 5% of Down syndrome cases are due to conditions called mosaicism and translocation. Mosaic Down syndrome results when some cells in the body are normal while others have Trisomy 21. Robertsonian translocation occurs when part of chromosome 21 breaks off during cell division and attaches to another chromosome (usually chromosome 14). The presence of this extra part of chromosome 21 causes Down some syndrome characteristics. Although a person with a translocation may appear physically normal, he or she has a greater risk of producing a child with an extra 21st chromosome. What are characteristics of people with Down syndrome? Individuals with Down syndrome often have distinct physical characteristics, unique health issues, and variability in cognitive development. Physical characteristics include:

Eyes that have an upward slant, oblique fissures, epicanthic skin folds on the inner corner, and white spots on the iris Low muscle tone Small stature and short neck Flat nasal bridge Single, deep creases across the center of the palm Protruding tongue Large space between large and second toe A single flexion furrow of the fifth finger

Individuals with Down syndrome usually have cognitive development profiles indicative of mild to moderate mental retardation. However, cognitive development in children with Down syndrome is quite variable. Children with Down syndrome often have a speech delay and require speech therapy to assist with expressive language. In addition, fine motor skills are delayed and tend to lag behind gross motor skills. Children with Down syndrome may not walk until age 4, but some will walk at age 2. Although many with the condition experience developmental delays, it is not uncommon for those with Down syndrome to attend school and become active, working members in the community. Individuals with Down syndrome can have abnormalities affecting general health that may affect any organ system or bodily function. They have an increased risk for congenital heart defects, respiratory and hearing problems, Alzheimer's disease, childhood leukemia, epilepsy, and thyroid conditions. However, people with Down syndrome also have a lower risk of hardening of the arteries, diabetic retinopathy, and most kinds of cancer. How is Down syndrome screened and diagnosed? Some families have prenatal exams that indicate various possible problems, and others already know that they have an increased chance of having a child with Down syndrome. These families often receive screening and diagnostic tests for the condition. It is also standard for pregnant women older than 30 or 35 to receive genetic screens because the risk of having a child with Down syndrome is increased as women age. Screening tests are used to estimate the risk that a fetus has Down syndrome, and diagnostic tests can tell whether the fetus actually has the condition. Screening tests are a cost-effective and less invasive way to determine if more invasive diagnostic tests are needed. However, unlike diagnostic tests, screening tests cannot give definite answers as to whether the baby has Down syndrome. Diagnostic tests, which are 99% accurate in detecting Down syndrome and other problems, are usually performed inside the uterus and carry an extra risk of miscarriage, fetal injury, or preterm labor. Screening tests include:

Nuchal translucency testing (at 11 to 14 weeks) - an ultrasound that measures clear space in folds of tissue behind the neck of a developing baby Triple screen or quadruple screen (at 15 to 18 weeks) - measures the quantities of normal substances in the mother's blood Integrated screen - combines first trimester screening tests (with or without nuchal translucency) and blood tests with second trimester quadruple screen Genetic ultrasound (at 18 to 20 weeks) - Detailed ultrasound combined with blood test results Diagnostic tests include:

Chorionic villus sampling (at 8 to 12 weeks) - analysis of a tiny sample of placenta obtained from a needle inserted into the cervix or the abdomen Amniocentesis (at 15 to 20 weeks) - analysis of a small amount of amniotic fluid obtained from a needle inserted into the abdomen Percutaneous umbilical blood sampling (after 20 weeks) - analysis of a small sample of blood from the umbilical cord obtained from a needle inserted into the abdomen Down syndrome can also be diagnosed after a baby is born by inspecting the infant's physical characteristics as well as blood and tissue samples that are stained to show chromosomes grouped by size, number, and shape.

(LONGITUDINAL PRENATAL SONOGRAPH)

Translocation

A chromosomal condition occurs when an individual is affected by a change in the number, size or structure of his or her chromosomes. This change in the amount or arrangement of the genetic information in the cells may result in problems in growth, development and/or functioning of the body systems.Chromosomal changes may be inherited from a parent. More commonly, chromosomal changes occur when the egg or sperm cells are forming or during or soon after the babys conception: these occur for unknown reasons (spontaneous occurrence). Chromosome translocations Translocation (trans = across; location = place) is the term used to describe a rearrangement of chromosome material involving two or more chromosomes. There are two different types of translocations: Reciprocal translocation - material is exchanged between two chromosomes Robertsonian translocation - involves exchange between chromosomes 13, 14, 15, 21 and 22 Types of chromosome translocations a. Reciprocal translocations Reciprocal translocations are the most common type of translocation About 1 in 930 people in the general population have a reciprocal translocation These translocations can occur between any of the chromosomes and involve pieces of any size.The translocation arises when an exchange of chromosomal material takes place between two different chromosomes; for example, where there is an exchange of chromosomal material between chromosomes number 1 and number 9. Pieces of each of these chromosomes have changed places and the pieces have become attached to the other chromosome. In this case, where there does not appear to have been any loss or gain of chromosome material, the Translocation is described as balanced b. Robertsonian translocations Robertsonian translocations, named after an American cytogeneticist, are relatively common About 1 in 1000 people in the general population have a Robertsonian translocations only involve exchanges between chromosome numbers 13, 14, 15, 21 and 22. These chromosomes are different from the other chromosomes as their centromeres lie very near the tip of the chromosome, giving a chromosome with a long arm and a very tiny short arm (acrocentric chromosomes) The exchange involves loss of the short arms of two chromosomes and fusion of the remaining two long arms at their centromeres The result is one long chromosome that consists of two long arms of either The same numbered chromosome Two different chromosomes and containing either one or both centromeres There is therefore a loss of the short arm of the chromosomes. The loss of the genes that are located there, however, seems to have little or no effect on the health of the individual carrying a Robertsonian translocation is a diagrammatic representation of a Robertsonian translocation between chromosomes 13 and 15. Chromosomes 13 and 15 have joined together to produce one long chromosome. One copy of chromosome 21 is attached to chromosome 14 so the individual has two copies of chromosome 14 and two copies chromosome 21 - a balanced chromosome complement, simply rearranged. Robertsonian translocations can also occur between the two chromosomes of the same pair, e.g. a Robertsonian translocation where the two chromosomes 21 fuse so the person has 45 chromosomes in total but with all the genetic material present (balanced).

Translocation leading to diseases

Inversion
Paracentric chromosome: A basic type of chromosome rearrangement in which a segment that does not include the centromere (and so is paracentric) has been snipped out of a chromosome, turned through 180 degrees (inverted), and inserted right back into its original location in chromosome. The feature that makes it paracentric is that both breaks are on the same side of the centromere so that the centromere (the point at which the chromosome attaches to the spindle) is not affected. Any chromosome inversion can be inherited and have come from one of the parents to a child. Or the inversion can appear for the first time in a child. An inversion can be "balanced", meaning that it has all the genes present in the normal uninverted chromosome. Or an inversion can be "unbalanced", meaning that genes been have deleted (lost) or duplicated. A balanced inversion in a child causes no problems. An unbalanced inversion is abnormal and is often associated with problems such as development delay (and later, mental retardation) and multiple congenital anomalies (birth defects). Inversions can also be acquired in a body cell (a somatic cell) and be a step involving that cell in a precancerous and cancerous process.

DUPLICATION
When extra copies of chromosomal regions are formed, resulting in different copy, no. of genes within that area of chromosome. If duplicated section are adjacent to original process is known as tandeem duplication, if they are separated by non-duplicated region, duplication is displaced. Duplication may affect phenotype by altering gene dosages. Duplication results in extra gene copies. E.g.: Drosophila Bar Eye!

CHARCOT MARIE TOOTHT DISEASE CMT is disorder of nerves that takes different forms. It is predominantly characterised by loss of muscle tissue, touch sensation in feet, ankles. High arched canus feet are associated with disorder. Disease is one of the most common inherited neurological disorder. Symptoms: Symptoms of CMT begin in early adulthood. CMT can cause claw toe ( curling of toes), wasting of muscle tissue of lower parts of legs gives rise to inverted bottle appearance. CMT can affect hearing, vision, hips socket can be malformed. Gastrointestinal problems. Neuropathic pain is common symptom of CMT.

CLAW TOES Genetics: CMT disease is caused by mutation that cause defects in neuronal proteins. Mutation of CMT affects myelin sheath. Cause of CMT is by duplication of large region in chromosome 17p12 that includes gene PMP22. Some mutation affects gene MFN2 which codes for mitochondrial protein. Cells contain separate set of genes in their nucleus and in their mitochondria. In nerve cells mitochondria travel down axon. If CMT is mutated MFN2 causes mitochondria to form large cluster which are unable to travel down the axon towards synapses. Thus prevents synapses from functioning.

Ring chromosomes
On rare occasions, ring chromosomes are found as constitutional aberrations in foetuses or new-borns with developmental abnormalities. More commonly, they may arise as acquired genetic abnormalities in cells from tumours or leukaemias. Mechanisms of ring formation Ring chromosomes may be formed in two ways (below):

Ring chromosome formation may occur through breaks in the chromosome arms and fusion of the proximal broken ends, leading to loss of distal material (a). Rings may also be formed by telomere dysfunction triggering fusion of reactive chromosome ends without major loss of genetic material (b). By two DNA breaks, one in each arm of the same chromosome, followed by fusion of the proximal broken ends. The causes of these DNA breaks are usually unknown and so is the mechanism behind ligation of the ends. It is possible that the non-homologous end-joining machinery plays a role in this process (Smith et al., 2001). A ring can also be formed by fusion at two breakpoints in the same chromosome arm. However, only few examples of such rings have been described. Most probably, this is because they are acentric and will lack attachment point for the cell division machinery. Unless there is a different anchorage sequence for the kinetochore complex they will be lost in subsequent mitoses. Such "neocentromere" sequences have, however, been described in rare cases of constitutional (Slater et al., 1999) and acquired (Gisselsson et al., 1999) ring chromosomes. By fusion of dysfunctional telomeres from the same chromosome. Several in vitro and animal models have shown that shortening of telomeric DNA repeats leads to the detachment of protective proteins from the chromosome ends (Counter et al., 1992). This renders the chromosome ends prone to recombination with DNA either from other chromosomes leading to formation of a dicentric or with the other arm of the same chromosome leading to formation of a ring. Ring chromosomes at cell division In contrast to linear chromosomes, rings may undergo cell division in three different ways (McClintock, 1938; Lejeune, 1968). Which of these pathways a ring chromosome will follow depends on the number of sister chromatid exchanges (SCE) that has occurred in the ring before cell division: No SCE or an even number of SCEs in the same direction will enable normal, symmetrical segregation of the chromatids.

An even number of SCEs in different directions will lead to the formation of interlocked rings. An odd number of SCEs will lead to transformation from two parallel chromatids into one continuous ring, similar to a Mobius band with the double size of the original rings.

Breakage-fusion-bridge cycle triggered by a sister chromatid exchange (a) leading to bridge formation (b) and breakage (c), or nondisjunction (d) at anaphase. Broken ends fuse in the daughter cells (e) and form novel ring structures, which can again undergo the same series of events (f). The ring in (1) will undergo a normal mitotic division with equal distribution of chromosome material to the daughter cells at anaphase. In the other situations, the sister chromatids will not be capable of normal separation. Instead the interlocked (2) or continuous (3) ring will be suspended as a chromosome bridge between the two poles of the mitotic spindle at anaphase. Depending on the balance between the pulling forces of the cell division machinery and the chemical bonds within the anaphase bridge, one of the following scenarios will occur ( McClintock, 1938):

Flow chart of potential ring chromosome dynamics. The ring (r1) can either undergo normal mitosis or form a bridge at cell division. If the bridge breaks, the cell may die, arrest, or survive and allow fusion of broken ends into

novel rings (r2 and r3). The bridge can also undergo nondisjunction so that a double-sized ring (r1x2) is formed. All these rings may continue through breakage-fusion-bridge (BFB) cycles, potentially leading to amplification of genes. A. The bridge will break in two or several pieces. Breakage may occur at any point between the chromosome-spindle attachments. Broken fragments that are still attached to the spindle will each be pulled into one of the daughter cells. B. Detachment occurs between one kinetochore and the mitotic spindle. The double-sized ring/interlocked rings will then be pulled into one of the daughter cells, whereas the other cell becomes monosomic for the corresponding chromosome. These dramatic distortions of chromosomal morphology may, however, only be the beginning of a chain of further recombination events. The broken ends in each daughter cell in (A) may heal by fusion to each other (McClintock, 1938; 1940) forming a novel ring chromosome that can again give rise to bridges at the next cell division . The ring chromosome can thus trigger a series of breakage-fusion-bridge (BFB) events, causing continuous DNA breakage and recombination of the chromosomal material. The ring in (B) was not broken but may again form a bridge at any forthcoming cell division. Constitutional ring chromosomes Constitutional ring chromosomes occur in 1/50,000 human foetuses (Jacobs et al., 1975). In most instances, these rings are formed by breakpoints in both arms, followed by fusion of the proximal ends into a ring with loss of the distal material. Such rings may thus result in clinical features mimicking terminal deletion syndromes. Alternatively, congenital ring chromosomes are supernumerary, i.e. they occur together with two normal homologues of the corresponding chromosome (Anderlid et al., 2001), and the consequences will be similar to partial trisomies or duplications. The ring syndromes are thus a very heterogeneous group, with different characteristics depending, not only, on which chromosome is involved, but also on the position of breakpoints within the chromosome. However, ring syndrome patients do not only display diverse symptoms resulting from deletions or duplications. Most of them have one feature in common. In a meta-study including more than two-hundred patients with congenital ring chromosomes it has been demonstrated that the majority of children with rings show a failure to thrive beyond the extent expected from their chromosomal imbalances (Kosztolanyi, 1987). It has been suggested that this is due to the mitotic instability of rings, preventing somatic cells to proliferate normally. The hypothesis is supported by the fact that growth failure is more common among patients with large ring chromosomes, than among those with small ones (Kosztolanyi, 1987). This is in accordance with the BFB model of ring chromosome dynamics. Statistically, large rings will undergo more SCEs per cell cycle than small rings and would thus have a higher propensity for breaking at anaphase. In a normal cell, this provokes a physiological DNA damage response leading to either cell cycle arrest or apoptosis (Cohen-Jonathan et al., 1999). From the reasoning above, it follows that a cell population carrying a ring chromosome would proliferate slower than a population without rings; the population with rings would be less fit and be at a selective disadvantage. Interestingly, ring chromosome loss or size reduction is not uncommon in cases with congenital rings. In particular, cases with small rings often exhibit a subclone without the ring chromosome and these patients are thus ring/monosomy mosaics (Gisselsson et al., 1999). In cases with large rings and prominent growth failure, heterogeneity of ring size is a more common feature. Children with ring chromosomes are thus illustrative examples of how natural selection at the cellular level may play a role for the symptoms and signs of human disease. Acquired ring chromosomes Table 1. Ring chromosome prevalence (%) in human tumours*

Hematological neoplasms Acute lympoblastic leukaemia Chronic lymphocytic leukaemia Acute myelogenous leukaemia Chronic myelogenous leukaemia Carcinomas Breast Colon & rectum Gallbladder Kidney Larynx Liver Lung Mouth Ovary Pancreas Prostate Skin Stomach Thyroid Uterine cervix Urinary bladder Uterus 5.7 4.6 21.1 13.0 5.2 13.0 8.8 1.9 3.9 11.5 0.0 3.7 1.7 1.1 0.0 4.5 2.2 0.7 1.1 2.2 1.0

Sarcomas Chondrosarcoma 5.6

Dermatofibrosarcoma protuberans 70.3 Ewing sarcoma Leiomyosarcoma Liposarcoma Malignant fibrous histiocytoma Mesothelioma Osteosarcoma Central nervous system tumours Astrocytoma Glioma Oligendroglioma Meningioma 0.0 0.0 0.0 4.0 0.6 11.2 21.1 11.5 14.2 12.2

* Data from the Mitelman Database of Chromosome Aberrations in Cancer, October 4, 2001. http://cgap.nci.nih.gov/Chromosomes/Mitelman Tumours with ring frequency >10% are in red. Congenital rings appears to be a burden for normal proliferating cells. The high prevalence of rings in neoplastic cells (Table1) thus appears paradoxical at first glance. Rings are rare in benign tumours, whereas they are common in certain invasive tumours. Rings are even so common in certain subgroups of sarcomas that they may be used as diagnostic indicators for these lesions. Well-differentiated liposarcomas (also referred to as atypical lipomas) are borderline malignant tumours occurring primarily in the thigh and retroperitoneum (Enzinger and Weiss, 1994). More than 90% of these tumours contain large supernumerary ring chromosomes, typically as the sole abnormalities or together with giant marker chromosomes (Fig. below; Heim et al., 1987). They rarely metastasise but show a locally aggressive growth behaviour and frequently recur after surgery. A virtually identical cytogenetic scenario is found in two other low-grade malignancies: parosteal osteosarcomas and well-differentiated malignant fibrous histiocytomas (Orndal et al., 1992; Sinovic et al., 1992).

Ring chromosome (a), giant marker chromosome (b), and anaphase bridge (c) in a well-differentiated liposarcoma. The former metaphase cell also contains telomeric associations between chromosomes. Courtesy of Prof. N. Mandahl. Compared to constitutional rings, the ring chromosomes occurring in these tumours are highly unstable. The rings are rarely lost. Instead, they are frequently present in more than one copy and there is wide variability in ring size and structure within each case (Gisselsson et al., 1998) and chromosome bridges occur frequently at mitosis (Gisselsson et al., 1999). There is also evidence that the rings may break up into large linear marker chromosomes by capturing telomeric sequences from other chromosomes. Thus, BFB events do not seem to have the same negative consequences on cell proliferation as in non-neoplastic cells. Although these tumours all have an indolent growth pattern, they are still able to invade surrounding tissues and frequently reach a considerable size before clinical presentation. Function and origin of ring chromosomes in tumours The mechanism behind the great ring chromosome variability in some neoplastic cells is not completely understood. Several studies have shown that the normal DNA damage response is disrupted in many malignant tumours. BFB events may thus occur at a high frequency without substantial negative consequences for cell proliferation (Artandi and DePinho, 2000; Gisselsson et al., 2001). There are evidence that one common mechanism behind the deficient response to DNA damage is inactivation of the TP53 protein by point mutations (Stark, 1993; Gisselsson et al., 2000). In this context, it is of interest to note that the large unstable rings in the previously mentioned bone and soft tissue

tumours contain amplified sequences from the MDM2 region in 12q14-15 in more than 90% of cases (Fig below; Berner et al., 1996). MDM2 binds to the TP53 protein and either directly inhibits its transcription factor activity or targets it for destruction (Oliner et al., 1993; Haupt et al., 1997; Kubbutat et al., 1997).

Amplification of MDM2 (red), CDK4 (green), and chromosome 9 sequences (blue) in a low-grade malignant fibrous histiocytoma (a). Rings from six different cells from the same tumour showing extensive variability in size and structure (b). Anaphase bridges containing amplified MDM2 sequences (red) in a well-differentiated liposarcoma. It is tempting to suggest that the amplified sequences carried in the rings are also the very prerequisite for ring variability and size expansion. It has been shown that the elevated copy-number of MDM2 genes in the rings correlates with an increased production of the MDM2 protein. Cells with large rings will over-express MDM2 and may thereby, at least partly, disable the DNA damage response. These rings may break at cell division with little, if any, impact on cellular survival and novel rings may form in the daughter cells after fusion of the broken ends . A wide variety of rings may then occur after only a few cell divisions. If MDM2 and/or other genes in the 12q14-15 region are favourable for the growth of the tumours, cells with rings containing several copies of these genes will have a selective advantage. In this way, repeated BFB events could actually contribute to the high-level of gene amplification in low-grade bone and soft tissue tumours. Similar mechanisms have been demonstrated in several in vitro systems with amplification of drug-resistance genes (Smith et al., 1995; Coquelle et al., 1997). However, this reasoning does not resolve the issue of how the rings are originally generated. Recent studies have demonstrated that the initial formation of ring and dicentric chromosomes in malignant tumours can result from telomere shortening and subsequent fusion of chromosome ends (Gisselsson et al., 2001). The same bone and soft tissue tumours that exhibit ring chromosomes also show a high frequency of telomeric fusions. This results in the formation of dicentric chromosomes and it has been suggested that gene amplification is initiated by the involvement of these chromosomes in BFB events, in a way similar to that of the rings (Pedeutour and Turc-Carel, 1997). After a number of BFB cycles, when the amplified arrays have reached a large size, the two ends of some fragments may fuse after anaphase breakage to form ring chromosomes. However, two arguments may be raised against this sequence of events: (1) The rings typically occur together with an apparently normal chromosome complement; at least one of the chromosome 12 homologues should be rearranged if the above

hypothesis is correct. (2) It still does not explain why the tumour cell tolerates chromosome breakage at this early stage of neoplastic development; to claim so would be circular reasoning.

Hypothetical mechanism of gene amplification: Telomeric association between two chromosomes produces a functional dicentric (a), which may form a bridge at mitosis (b) and undergo nondisjunction (c), leading to an extra copy of the MDM2 gene (blue). This renders the cell permissive for structural rearrangements through breakagefusion-bridge events and potential amplification of the gene (d). The dicentric structures may finally convert into a ring and marker chromosomes with a high MDM2 copy-number (e). The ring will, in turn, initiate another series of breakage-fusion-bridge events. A theoretically plausible scenario for the amplification would most probably include an early event leading to increased copy-number of MDM2 sequences without chromosomal breakage. As a first step, one might image that the dicentric chromosome loses the attachment to one of the poles of the mitotic spindle and undergoes nondisjunction, instead of anaphase breakage, which would lead to a trisomy for both chromosomes involved in the dicentric (Fig. above). For a dicentric including chromosome 12, this would imply gain of one MDM2 allele in one daughter cell and loss of one in the other. If we assume that one of the dicentric chromatids remains intact, it may again form a bridge at the next cell division. If the increased copy-number of MDM2 now provides sufficient inhibition of the DNA damage checkpoint, anaphase breakage could occur without apoptosis or cell cycle arrest. Once this threshold of tolerance has been surpassed, additional BFB events could generate large amplified arrays that may break into fragments, which could then close into rings. As such rings will have evolved through a large number of random breakage events their structure would be expected to show a high level of complexity. Indeed, when the structure of rings in well-differentiated liposarcomas and parosteal osteosarcomas was studied in detail, the normal order of loci along the 12q arm was extensively disrupted even below the megabase level (Gisselsson et al., 1998). It has also been demonstrated that genes amplified in the rings may actually be structurally rearranged, having recombined with loci from other parts of chromosome 12 or even other chromosomes (Berner et al., 1997).

Deletion
Deletion (also called gene deletion, deficiency, or deletion mutation)is a mutation (a genetic aberration) in which a part of achromosome or a sequence of DNA is missing. Deletion is the loss of genetic material. Any number of nucleotides can be deleted, from a single base to an entire piece of chromosome. Deletions can be caused by errors in chromosomal crossover during meiosis. This causes several serious genetic diseases. Deletion also causes frameshift.

Causes
Causes include the following:

Losses from translocation Chromosomal crossovers within a chromosomal inversion Unequal crossing over Breaking without rejoining

For synapsis to occur between a chromosome with a large intercalary deficiency and a normal complete homolog, the unpaired region of the normal homolog must loop out of the linear structure into a deletion or compensation loop.

Types
Types of deletion include the following:

Terminal Deletion - a deletion that occurs towards the end of a chromosome. Intercalary Deletion / Interstitial Deletion - a deletion that occurs from the interior of a chromosome.

Cri-du-Chat syndrome
Definition
Cri du Chat Syndrome (CdCS) is a genetic disease resulting from a deletion of the short arm of chromosome 5 (5p-). Its clinical and cytogenetic aspects were first described by Lejeune et al. in 1963 . The most important clinical features are a high-pitched cat-like cry (hence the name of the syndrome), distinct facial dysmorphism, microcephaly and severe psychomotor and mental retardation. The size of the deletion ranges from the entire short arm to the region 5p15 . Simmons et al. reported a deletion size ranging from 5 to 40 Mb.

What is Cri-du-Chat syndrome? The name of this syndrome is French for "cry of the cat," referring to the distinctive cry of children with this disorder. The cry is caused by abnormal larynx development, one of the many symptoms associated with this disorder. It usually becomes less noticeable as the baby gets older, making it difficult for doctors to diagnose cri-du-chat after age two. Cri-du-chat is caused by a deletion (the length of which may vary) on the short arm of chromosome 5. Multiple genes are missing as a result of this deletion, and each may contribute to the symptoms of the disorder. One of the deleted genes known to be involved is TERT (telomerase reverse transcriptase). This gene is important during cell division because it helps to keep the tips of chromosomes (telomeres) in tact.

How do people get Cri-du-Chat syndrome? A deletion is caused by a break in the DNA molecule that makes up a chromosome. In most cases, the chromosome break occurs while the sperm or egg cell (the male or female gamete) is developing. When this gamete is fertilized, the child will develop cri-du-chat syndrome. The parent, however, does not have the break in any other cells of the body and does not have the syndrome. In fact, the break is usually such a rare event that it is very unlikely to happen

again if the parent has another child.It is possible for a child to inherit a broken chromosome from a parent who also had the disorder. Epidemiology CdCS is a rare disease with an incidence ranging from 1:15,000 to 1:50,000 live-born infants. Niebuhr] found a prevalence of around 1:350 among over 6,000 mentally retarded people, Duarte et al. found a prevalence of 1:305 among 916 patients attending genetic counselling services and analysed cytogenetically. Clinical description The clinical features at birth are low weight (mean weight 2614 g), microcephaly (mean head circumference 31.8 cm), round face (83.5%), large nasal bridge (87.2%), hypertelorism (81.4%), epicanthal folds (90.2%), downward slanting palpebral fissures (56.9%), down-turned corners of the mouth (81.0%), low-set ears (69.8%), micrognathia (96,7%), abnormal dermatoglyphics (transverse flexion creases) (92%) and the typical cry (95.9%) [1,5,7-19] (percentages from the Italian CdCS Registry (Fig. below A,B). Neonatal problems are asphyxia, cyanotic crises, impaired suction and hypotonia. Severe psychomotor retardation becomes evident during the first year of life. Malformations, although not very frequent, may be present: cardiac, neurological and renal abnormalities, preauricular tags, syndactyly, hypospadias, and cryptorchidism. Recurrent respiratory and intestinal infections are reported during the first years of life, although higher sensibility to infections is not reported.

The characteristic cat-like cry is probably due to anomalies of the larynx (small, narrow, diamond-shaped) and of the epiglottis (flabby, small, hypotonic), as well as to neurological, structural and functional alterations. Malformations of the cranial base suggest associated anomalies of the brain (rhombencephalic region) and larynx during embryonal development.

Specific growth charts for CdCS, based on a multicentre study carried out on 374 patients from the United States, Italy, the United Kingdom and Australia, confirmed the existence of prenatal and postnatal growth retardation. For all ages, median head circumference and weight are near or below the 2nd and 5thpercentile, respectively. Height is less affected than weight from birth up to 2 years of age in both sexes. This trend continues until later in life, especially in males. The low weight may be attributed to feeding difficulties and gastroesophageal reflux, both of which are frequent in the first years of life. On the other hand, the slender body shape of many adolescent and adult patients may also be related to the syndrome. The following features develop with age: the face becomes long and narrow (70.8%), the supra-orbital arch prominent (31.0%), the philtrum short (87.8%), the lower lip full (45.2%), dental malocclusion (open bite) (75.0%) (Fig above. C,D), palpebral fissures tend to become horizontal (70.2%), divergent strabismus is frequent (44.7%), metacarpi (82.6%) and metatarsi (75.0%) are short resulting in small hands and feet, and prematurely grey hair may be observed (30.4%) (percentages from the Italian CdCS Registry). Myopia and cataract have been reported. Hypersensitivity of the pupil to methacholine and resistance to mydriatics, probably due to a defect of the pupil dilator muscle, have also been described. These features have also been found in four patients with Goldenhar's syndrome associated with CdCS. Scoliosis, flat foot, pes varus, inguinal hernia and diastasis recti are frequent. Two patients with joint hyperextensibility, skin hyperelasticity and other features of Ehlers-Danlos syndrome, and one patient with both clinical manifestations of CdCS and Marfan syndrome have been reported. A patient with a small deletion in 5p15.33 and phenotype suggesting Lujan-Fryns syndrome has been described. Cryptorchidism, sometimes present at birth, is rare in adolescent patients. Sexual development is generally normal in both sexes. A single case of procreation in a CdCS patient (a mother and a daughter with the typical syndrome) has been reported. With age, muscle hypotonia is replaced by hypertonia, and microcephaly becomes more evident. Convulsive crises are rare at all ages. Atrophy of the brainstem mainly involving the pons, cerebellum, median cerebellar peduncles and cerebellar white matter has been revealed by magnetic nuclear resonance imaging. A CdCS child with an arachnoid cyst, causing triventricular hydrocephalus by obstruction of the aqueduct of Silvius, has been reported. Metabolic anomalies have been described in CdCS patients: a defect in the synthesis of purine nucleotides (important neuromediators involved in brain development) and clinical features associated with non-ketotic hyperglycinaemia, infantile spasms, hypsarrhythmia and brain heterotopia have been reported in a patient with a 5p deletion and typical CdCS. Developmental and behavioural profile The limited data available about the psychomotor development indicated a severe psychomotor and mental retardation in all patients. Prognosis is better for home-reared patients who underwent an early educational program. Progress in verbal development is particularly slow]. Patients' ability to comprehend speech is better than their ability to communicate]. A study on psychomotor development was carried out on 91 patients from the Italian Registry, using the Denver Developmental Screening Test II (DDST II). This test showed the percentile distribution of patients on the basis of the age of achievement of developmental milestones. A specific psychomotor development chart has been established. Data from the Italian series show that half of the patients walk by themselves at three years old and that all learn to walk later; with regard to the language, 25% of the children are able to make short sentences at 4.5 years old, 50% at 5.5 and almost all the children make short sentences before the age of 10; 50% of the patients feed themselves with a spoon at 3.5 years old and dress at 5. Although these patients have a range of severe developmental

retardation, they can achieve many skills in childhood and continue to learn. This suggests that today's CdCS patients have a better outcome than those in the past. CdCS children have mostly a gentle and affectionate personality. Hyperactivity is present in about 50% of patients and sometimes coexists with aggressiveness, which can be modified with adequate educational programs. The behavioural profile of 27 patients studied by Cornish and Pigram showed self-injury, repetitive movements, hypersensitivity to sounds, clumsiness and obsessive attachment to objects. Hyperactivity and distractibility seems specific to CdCS, if compared to Prader-Willi and Smith-Magenis syndromes. A survey of the prevalence of stereotypy, self-injury and aggression in CdCS children and young adults has been recently carried out by Collins and Cornish. A low level of object-directed behaviour may be an early precursor of hyperactivity, distractibility and stereotypy in older individuals. Nevertheless, early educational interventions and the involvement of families and caregivers allow these behaviours to be improved. Genotype-phenotype correlation Although CdCS is a well-defined clinical entity, individuals with 5p deletion show phenotypic and cytogenetic variability. A few studies, sometimes giving conflicting results, have been performed to correlate the clinical picture with the deletion size .A more severe phenotype and cognitive impairment was reported to be associated with a larger deletion . The fact that the phenotype is well recognisable, in spite of the variability in deletion size, has led to the hypothesis that a critical region causes the characteristic clinical picture when present in a hemizygous situation: Niebuhr located this region in a narrow area around 5p15.2. Such an assumption was supported by findings of individuals with a deletion that did not include 5p15.2, who either did not display the typical CdCS phenotype, or were completely normal. Molecular-cytogenetic analysis allowed Overhauser et al. and Gersh et al. to identify two distinct regions, one for the typical cry in 5p15.3, and another for the other clinical characteristics in 5p15.2. Church et al. distinguished several critical regions: a region for speech retardation, one for the typical cry, one for face dysmorphisms in childhood and one for face dysmorphisms in adulthood . A genotype-phenotype correlation study has been carried out in 80 patients from the Italian CdCS Registry. All of them underwent FISH analysis. The results confirmed the importance of deletion of the critical region for manifestation of the CdCS clinical features. However, they also showed a clinical and cytogenetic variability and highlighted a correlation between clinical severity, and the size and type of deletion. In fact, in 62 patients with terminal deletion, the degree of severity (for microcephaly, dysmorphism and psychomotor retardation) has been demonstrated to vary between patients with a small deletion in 5p15.2 and 5p15.1, and patients with a larger deletion. The condition of patients with a deletion in 5p13 appeared particularly severe (Fig.below). The variability correlated with the type of deletion in patients with an interstitial deletion, unbalanced translocation resulting in 5p deletion, mosaicism and other rare rearrangements. The study of patients with an interstitial deletion and with a small terminal deletion has enabled the existence of two distinct critical regions (one for dysmorphisms, microcephaly and mental retardation in p15.2, and the other for the typical cry in p15.3) to be confirmed. Moreover, this study allowed the cry region defined by Overhauser et al. to be narrowed distally and supported the hypothesis of a distinct region for speech retardation in p15.3. Furthermore, two patients who showed an interstitial deletion and a terminal deletion that did not include the critical region and did not show CdCS clinical features, confirmed that not all 5p deletions result in the CdCS phenotype.

In patients with an unbalanced translocation resulting in 5p deletion, the partial trisomy of the other involved chromosome may influence the clinical features, even if the CdCS phenotype prevails. Three patients with mosaicism showed two rearranged cell lines: one with both cell lines deleted, the others with a deleted and a duplicated cell line. In the latter, the CdCS phenotype prevailed over the effect of the partial 5p trisomy present in part of the cells. The patient with the largest duplication had a mild clinical picture, suggesting compensation between deleted and duplicated cell lines. Kitsiou et al. reported a patient with three cell lines in the same tissue: del 5p, dup 5p and a normal one. The mild phenotype in this patient could be mainly due to the normal cell line. However, the duplicated cell line may have contributed to the phenotype through the duplication of the critical CdCS region. The deleted chromosome was mainly of paternal origin: no phenotypic differences caused by imprinting effects were observed in the Italian group of patients. The combination of FISH, comparative genome hybridisation (CGH) and cytogenetic analysis of a patient with dup5q/del5p confirmed that the characteristic cry was due to the deletion at 5p15.3. Recently Rossi et al., using FISH analysis with bacterial artificial chromosome (BAC) clones in a patient without typical CdCS features, were able to correlate cat-like cry and mild mental retardation with a deletion in 5p15.31, 8.5 Mb away from the short arm telomere. Zhang et al., by using array CGH, refined the CdC critical regions and confirmed the correlation between the severity of mental retardation and the deletion size and type. Using quantitative polymerase chain reaction (PCR), Wu et al. narrowed the critical region for the cat-like cry to a short 640 Kb region and characterised three candidate genes in this region. Harvard et al. found, in a subject with an autism spectrum disorder, a de novo cryptic microdeletion involving 5p15.2. The identification of phenotypic subsets associated with specific deletions may be of great diagnostic and prognostic relevance. Furthermore, clinical examination combined with molecular analysis of the deletion results in a more personalised evaluation of the patients, which is useful for rehabilitative and educational programs .