Which disorder is the result of a chromosomal abnormality

For more information about how chromosomal changes occur:

As part of its fact sheet on chromosome abnormalities, the National Human Genome Research Institute provides a discussion of how chromosome abnormalities happen.

The Chromosome Disorder Outreach fact sheet Introduction to Chromosomes explains how structural changes occur.

Additional information about how chromosomal changes happen is available from the University of Rochester Medical Center.

Topics in the Inheriting Genetic Conditions chapter

• What does it mean if a disorder seems to run in my family?
• Why is it important to know my family health history?
• What are the different ways a genetic condition can be inherited?
• If a genetic disorder runs in my family, what are the chances that my children will have the condition?
• What are reduced penetrance and variable expressivity?
• What do geneticists mean by anticipation?
• What are genomic imprinting and uniparental disomy?
• Are chromosomal disorders inherited?
• Why are some genetic conditions more common in particular ethnic groups?
• What is heritability?

Other chapters in Help Me Understand Genetics

The information on this site should not be used as a substitute for professional medical care or advice. Contact a health care provider if you have questions about your health.

Chromosomal disorders fall into two general categories: those involving an incorrect chromosome number, called aneuploidy, and those that result from large chromosomal mutations, as described earlier. Aneuploidy is the result of nondisjunction during meiosis, in which both members of a homologous pair of chromosomes move to the same daughter cell. As a result of nondisjunction, the fertilized egg receives either one or three copies of the chromosome instead of the usual two. Because they involve numerous genes, with disturbance in the normal genomic balance, most disorders affecting chromosome number are embryonic lethal, particularly if the defect is loss of a chromosome. Disorders that are not lethal usually result in sterility, because they prevent meiosis from proceeding normally. The best-known and most common chromosomal disorder is Down syndrome, which generally results from trisomy of chromosome 21 but also can be due to a duplication or translocation of a specific region of chromosome 21. Trisomies of chromosome 13 or 18 also occur but are much less common in live born infants than is Down syndrome. Turner syndrome occurs in women who receive only a single X chromosome, whereas Klinefelter syndrome occurs in men who receive two X chromosomes in addition to the Y chromosome.

Deletions that are too small to be visible using the cytogenetic techniques that were standard before the advent of molecular diagnostics are called microdeletions, and the resulting disorder is termed a microdeletion syndrome or contiguous gene syndrome. Microdeletions can be detected using large arrays of cloned genetic markers covering the entire genome. For some applications, the technique of fluorescence in situ hybridization (FISH) is still used. In the FISH technique, a cloned DNA probe is labeled with a fluorescent molecule and is then hybridized to a standard chromosome preparation on a microscope slide. The presence of two normal chromosomes can be visualized by the appearance of two fluorescent dots, whereas a heterozygous microdeletion appears as a single dot. It is likely that advanced DNA sequencing technologies will supplant all previously used techniques for diagnosing genetic diseases, including microdeletions.

Examples of microdeletion syndromes are DiGeorge syndrome, characterized by T cell immunodeficiency and cardiac anomalies and due to a microdeletion of chromosome 22, and Prader-Willi syndrome, characterized by mental retardation, infantile hypotonia, and a compulsive eating disorder, and frequently due to a microdeletion of chromosome 15. A clinically unrelated disorder, Angelman syndrome, characterized by severe mental retardation, seizures, and a movement disorder, can also be due to a microdeletion in the same region of chromosome 15 as that affected in Prader-Willi syndrome. However, in Prader-Willi syndrome, the deletion is always on the chromosome inherited from the father, whereas in Angelman syndrome, the deletion is always on the maternally inherited chromosome. Both Prader-Willi and Angelman syndromes can arise from uniparental disomy, which means that both chromosomal homologues are derived from one parent, with no contribution from the other. For example, in approximately 15% of patients with Prader-Willi syndrome, both copies of chromosome 15 are maternally derived, whereas in Angelman syndrome, both copies can be inherited from the father.

Parent-of-origin effects on the occurrence of a genetic disease are a reflection of the phenomenon of imprinting. Imprinting refers to a process of transcriptional inactivation of a region of a chromosome derived from only one parent. The mechanism of this transcriptional inactivation involves methylation of cytosine residues during development. The reason for the existence of imprinting is not known, but it is clear that proper imprinting is necessary for normal development.

CHROMOSOMAL DISORDERS AND RECOGNISABLE PATTERNS OF MALFORMATION

Chromosomal disorders are caused by an abnormality in an individual's complement of chromosomes. The normal situation is to possess 23 pairs of chromosomes, of which one pair are sex chromosomes (two X chromosomes in females and an X and a Y in males). Individuals with Down's syndrome have an additional chromosome 21, with most having a total of 47 chromosomes. This disorder occurs in approximately 1 in 800 births and is more common with advancing maternal age (Jones, 1988). Children with Down's syndrome have an increased likelihood of a variety of congenital abnormalities, including cardiac malformations, intestinal atresias and cataracts. The intellectual development of children with Down's syndrome is slower than normal and the average IQ is around 50. Other specific neurological problems include hypotonia, an increased incidence of epilepsy and the occurrence of dementia from 40 years onwards in many individuals.

Physiotherapy alone or as part of a multidisciplinary programme has been used in the management of children with Down's syndrome. There is evidence for improvement in motor skills, particularly following early-intervention programmes that include a series of individualised therapy objectives (Harris, 1981; Connolly et al., 1984). Physiotherapy includes management of low muscle tone (see Ch. 25) and strategies to improve strength, co-ordination, general fitness and functional activities. Many children with Down's syndrome have asymptomatic atlantoaxial instability and around 1% are at increased risk of atlantoaxial subluxation, which may cause quadriplegia. Cervical spine radiographs are not carried out routinely in children with Down's syndrome, but should be taken if there is head tilt or the emergence of neurological signs, or if participation in tumbling or contact sports is planned (American Academy of Pediatrics, 1995).

Other trisomies include Edward's syndrome (trisomy 18) and Pattau's syndrome (trisomy 13), both of which cause profound retardation and usually death in early infancy.

Some chromosomal anomalies can be detected only by high-resolution chromosomal studies or by analysis of dioxyribonucleic acid (DNA). Prader–Willi syndrome, for instance, is due to a deletion of part of chromosome 15. Most affected infants are extremely hypotonic in the neonatal period, often with marked feeding difficulties that require tube feeding. Later they have excessive appetites and obesity, short stature, and moderate learning difficulties. Because of the hypotonia there is an increased risk of scoliosis in early infancy and the role of physiotherapy includes providing advice about positioning and seating to promote good postures and reduce the risk of deformity developing.

3.2.1 Chromosomal Disorders

A chromosomal disorder is classically defined as the phenotype resulting from visible alteration in the number or structure of the chromosomes. Using routine light microscopy and a moderate level of chromosome banding, the frequency of balanced and unbalanced structural rearrangements in newborns has been estimated at about 9.2:1000 [8]. Some of those with unbalanced rearrangements will have congenital anomalies and/or intellectual disabilities. A proportion of those with balanced changes will, in adult life, be at increased risk of either miscarriage or having a disabled child. The incidence of aneuploidy in newborns is about 3:1000, but the frequency increases dramatically among stillbirths or in spontaneous abortions [9]. It is estimated that one in two conceptuses has a chromosome abnormality, usually resulting in miscarriage [10]. Different types of chromosomal abnormalities predominate in spontaneous abortions compared with live-born infants. For example, trisomy 16 is the most common autosomal trisomy in abortions [11], whereas trisomies for chromosomes 21, 18, and 13 are the only autosomal trisomies occurring at appreciable frequencies in live-born infants. Monosomy for the X chromosome (45,X) occurs in about 1% of all conceptions, but 98% of those affected do not reach term. Triploidy is also frequent in abortions but is exceptional in newborns. The high frequency of chromosomally abnormal conceptions is mirrored by results of chromosome analysis in gametes, which reveal an approximate abnormality rate of 4%–5% in sperm [12] and 12%–15% in oocytes [13]. When a family experiences three or more miscarriages, one parent is identified with an autosomal chromosome abnormality in 8.5% of analyses [14].

Routine light microscopy cannot resolve small amounts of missing or additional material (less than 4 Mb of DNA). The advent of cytogenomic microarray analysis has revealed a high frequency of submicroscopic deletions and duplications and other copy number variations, including both apparently benign and pathological changes [15]. Multiple microdeletion and microduplication disorders have been defined in recent years, and undoubtedly more await discovery. Such microdeletions, which epistemologically link “chromosomal disorders” with single-gene disorders, account for a proportion of currently unexplained learning disability and multiple malformation syndromes [16,17].

Sex Chromosome Disorders of Sexual Development.

True sex chromosome DSD is very rare. Cases of X_ (Turner syndrome) and XXY (Klinefelter syndrome) are reported. They usually have gonadal dysgenesis and a female phenotype. Chimerism is more common. Chimeras and mosaics have two or more somatic cell types, each with a different chromosome constitution. Chimeras have two genetically distinct cell types that come from different individuals, whereas mosaicism is a different chromosomal constitution from altered mitosis. The most common chimera in domestic animals is the freemartin calf (Fig. 18-3, B). Blood vessels of the placentas from two different fetuses fuse and exchange blood between fetuses. Each fetus becomes a hematopoietic chimera. Anastomosis of placental vessels occurs most often in bovine species and less frequently in other ruminants and pigs. The freemartin is the female of a set of male and female twins. Gene products from the cells of the male fetus induce fetal Sertoli cells and seminiferous cordlike structures in the ovaries of the female twin. The ovaries are small and can have reduced number of or no germ cells. Some freemartins have ovotestes. The paramesonephric (Müllerian) duct derivatives vary from almost normal to cordlike structures, but their lumens do not communicate with the vagina. The vagina, vestibule, and vulva are hypoplastic. Vesicular glands are always present; other mesonephric (Wolffian) structures are present to varying degrees. Externally, the animal has a female phenotype, but the vestibule and vagina are short, the vulva is hypoplastic, and the clitoris is enlarged. The male twin is minimally affected.

Sex chromosome disorders

Introduction

Several hundred chromosomal disorders are associated with epilepsy and this number rises every year as advances in cytogenetics and molecular genetics allow the detection of more complex and smaller chromosomal re-arrangements, duplications, and deletions (Singh et al., 2002; Dibbens et al., 2009). However there are relatively few conditions in which epilepsy is a consistent feature and even fewer in which the electroclinical phenotype is recognizable (Table 57.1). In these syndromes the seizure types and EEG features can suggest a specific diagnosis and guide the clinician to the appropriate genetic investigation.

Table 57.1. Disorders consistently associated with epilepsy

DisordersEstimated incidenceTerminal deletion chromosome 1p361 in 5000Wolf–Hirschhorn syndrome (4p-)1 in 50 000Angelman syndrome1 in 15 000Inversion duplication 15 syndrome (IDIC 15)1 in 30 000Miller–Dieker syndrome (del 17p13.3)1 in 300 000 (estimates)Ring 14 syndromeUnknownRing 20 syndromeUnknown

Cytogenetic tests can look at the chromosome in varying degrees of detail. High resolution G banding of the karyotype will pick up major lesions in much more detail than a decade ago. Fluorescent in situ hybridization (FISH) probes can be targeted to the gene-rich, telomeric regions of chromosomes and DNA dosage techniques such as multiplex ligation probe amplification (MLPA) or comparative genome hybridization (CGH) have the ability to detect micro-chromosomal lesions (Slavotinek, 2008). Many chromosomal anomalies are mosaic and diagnosis can be made from skin biopsy when lymphocyte studies are negative (Fig. 57.1).

The mechanisms through which chromosome lesions produce epilepsy are not well understood but are likely to be varied and complex. Malformations of cortical development can be consistently associated with chromosomal lesions such as the 17p13.3 deletion and Miller–Dieker lissencephaly, or rarely such as focal polymicrogyria and 22q11 deletions. However the conditions discussed in this chapter are not associated with any consistent neuroimaging or neuropathological findings which may help to explain the development of epilepsy.

Genetic and Chromosomal Disorders

Genetic and chromosomal disorders are known causes of tall stature. Hyperploidy of sex chromosomes predisposes to tall stature. The most common of these disorders is Klinefelter syndrome (47,XXY), which is the most common sex chromosome disorder, affecting 1:500 males. Affected males carry an additional X chromosome, which results in male hypogonadism, androgen deficiency, and impaired spermatogenesis. Some other characteristics include gynecomastia, small testes, sparse body hair, tallness (long-legged proportions), and infertility. In children with Klinefelter syndrome, the tendency toward tall stature becomes evident starting at 5 to 6 years of age; of note, however, men with Klinefelter syndrome usually have normal adult stature. The definite diagnosis of Klinefelter syndrome is made with a karyotype, but a careful history and physical examination, with the hallmark being small, firm testes, would provide sufficient diagnostic clues to make the practitioner suspect the diagnosis. Therapy for patients with Klinefelter syndrome consists of testosterone replacement to correct the androgen deficiency and give the patients appropriate virilization. This therapy cannot reverse infertility.

Children with 47,XYY syndrome are normal sizes at birth, with no congenital defects. The mean adult height in one series was 189 cm, and in other series, final heights of the patients have been greater than the heights of their siblings. Genitalia are normal and plasma testosterone concentrations are in the high-normal ranges. The average IQ is reduced. The diagnosis can be made only by karyotype.

The prototypic genetic syndrome associated with tall stature is Marfan syndrome, an autosomal dominant connective tissue disorder. Marfan syndrome has diverse and even seemingly unrelated manifestations in different organs arising from a single mutation in the fibrillin gene (FBN1) at chromosome 15q21. Organs involved include the skeleton, eyes, cardiovascular system, skin, integument, lungs, and muscle tissue. Diagnosis of Marfan syndrome is largely clinical and pragmatic. Classically, Marfan syndrome is characterized by hyperextensible joints, dislocation of the lens, kyphoscoliosis, mitral valve prolapse, and aortic dilatation and dissection. Patients with Marfan syndrome have long, thin bones that result in arachnodactyly and moderately tall stature with long-legged proportions. Because of the possible lethal complications of the cardiovascular manifestations of Marfan syndrome, awareness of the classic features for early diagnosis by the primary physician is important. Among causes of sudden death among competitive athletes, Marfan syndrome trails behind only hypertrophic cardiomyopathy, congenital anomalies of the coronary arteries, and occlusive coronary disease. Any situation that results in greater catecholamine release increases inotropy and, as a result, the impulse of blood ejected into the aorta, with the risk of dissection of the aorta. Therefore, it is recommended that patients avoid situations of considerable emotional or physical stress. It is currently recommended that all patients with Marfan syndrome be considered for β-adrenergic blockade, because this is believed to have a protective effect from both aortic dilatation and dissection, but this has yet to be conclusively proved. Techniques for repairing all aspects of cardiovascular disease in Marfan syndrome have undergone rapid evolution and today, corrective surgery for the mitral valve and the aortic root (dissected and not dissected) carries a lower risk for the majority of the patients. In regard to the tall stature, treatment with estrogen or testosterone has not been systematically tested for efficacy or toxicity, so its use to reduce ultimate height should be done with caution.

Homocysteinuria, an autosomal recessive disorder of methionine-homocysteine metabolism, is associated with marfanoid features but may also involve mental retardation, seizures, joint contractures, and a tendency for thromboembolism. Early diagnosis by amino acid studies and dietary treatment can prevent mental retardation.

What are the disorders due to chromosomal abnormalities?

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Which are the chromosomal disorders?

What are the 3 most common chromosomal abnormalities?