Genetics

Published on 21/03/2015 by admin

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Genetics

Genetic disorders are:

There has recently been an unprecedented growth in knowledge about the genetic basis of diseases :

• The Human Genome Project resulted in the first publication of the human genome sequence in 2001.

• It is now estimated that the human genome contains 20 000–25 000 genes, although the function of many of them remains unknown. Greater diversity and complexity at the protein level is achieved by alternative mRNA splicing and post-translational modification of gene products.

• Microarray techniques and high throughput sequencing are increasing the volume and speed of genetic investigations and reducing their costs, leading to a greater understanding of the impact of genetics on health and disease.

• Access to genome browser databases containing DNA sequence and protein structure has greatly enhanced progress in scientific research and the interpretation of clinical test results (Fig. 8.1).

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Figure 8.1 Ensembl Genome Browser. The image shows part of chromosome region 22q11, involved in 22q11 deletion syndrome (Di George syndrome). Although only part of the commonly deleted region is shown, the image shows several genes that are deleted in 22q11 deletion syndrome. The online Ensembl browser can be used to ‘zoom in’ on specific areas, showing the genes present in different chromosome regions, and can also be used to show the gene sequence itself.

• Genetic databases are available on thousands of multiple congenital anomaly syndromes, on chromosomal variations and disease phenotypes and on all Mendelian disorders.

• Clinical application of these advances is available to families through specialist genetic centres that offer investigation, diagnosis, counselling and antenatal diagnosis for an ever-widening range of disorders.

• Gene-based knowledge is entering mainstream medical and paediatric practice, especially in diagnosis and in therapeutic guidance, such as for the treatment of malignancies.

Genetically determined diseases include those resulting from:

Chromosomal abnormalities

Genes are composed of DNA that is wound around a core of histone proteins and packaged into a succession of supercoils to form the chromosomes. The human chromosome complement was confirmed as 46 in 1956. The chromosomal abnormalities in Down, Klinefelter and Turner syndromes were recognised in 1959 and thousands of chromosome defects have now been documented.

Chromosomal abnormalities are either numerical or structural. They occur in approximately 10% of spermatozoa and 25% of mature oöcytes and are a common cause of early spontaneous miscarriage. The estimated incidence of chromosomal abnormalities in live-born infants is about 1 in 150; they usually cause multiple congenital anomalies and cognitive difficulties. Acquired chromosomal changes play a significant role in carcinogenesis and tumour progression.

Down syndrome (trisomy 21)

This is the most common autosomal trisomy and the most common genetic cause of severe learning difficulties. The incidence (without antenatal screening) in live-born infants is about 1 in 650.

Clinical features

Down syndrome is usually suspected at birth because of the baby’s facial appearance. Most affected infants are hypotonic and other useful clinical signs include a flat occiput, single palmar creases, incurved fifth finger and wide ‘sandal’ gap between the big and second toe (Fig. 8.2a–c, Box 8.1). The diagnosis can be difficult to make when relying on clinical signs alone and a suspected diagnosis should be confirmed by a senior paediatrician. Before blood is sent for analysis, parents should be informed that a test for Down syndrome is being performed. The results may take 1–2 days, using rapid FISH (fluorescent in situ hybridisation) techniques. Parents need information about the short- and long-term implications of the diagnosis. They are also likely, at some stage in the future, to appreciate the opportunity to discuss how and why the condition has arisen, the risk of recurrence and the possibility of antenatal diagnosis in future pregnancies.

Down syndrome

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Figure 8.2a Characteristic facies seen in Down syndrome. Her posture is due to hypotonia.

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Figure 8.2b Single palmar crease.
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Figure 8.2c Pronounced ‘sandal’ gap between the big and second toe.

Box 8.1

Characteristic clinical manifestations of Down syndrome

It is difficult to give a precise long-term prognosis in the neonatal period, as there is individual variation in the degree of learning difficulty and the development of complications. Over 85% of infants with trisomy 21 survive to 1 year of age. Congenital heart disease is present in 30% and, particularly atrioventricular canal defect, is a major cause of early mortality. At least 50% of affected individuals live longer than 50 years. Parents also need to know what assistance is available from both professionals and family support groups. Counselling may be helpful to assist the family to deal with feelings of grief, anger or guilt.

The Child Development Service will provide or coordinate care for the parents. This will include regular review of the child’s development and health. Children with Down syndrome are at increased risk of hypothyroidism, impairment of vision and hearing and of atlanto-axial instability.

Cytogenetics

The extra chromosome 21 may result from meiotic non-disjunction, translocation or mosaicism.

Meiotic non-disjunction (94%)

In non-disjunction trisomy 21:

The incidence of trisomy 21 due to non-disjunction is related to maternal age (Table 8.1). However, as the proportion of pregnancies in older mothers is small, most affected babies are born to younger mothers. Furthermore, meiotic non-disjunction can occur in spermatogenesis so that the extra 21 can be of paternal origin. All pregnant women are now offered screening tests measuring biochemical markers in blood samples and often also nuchal thickening on ultrasound (thickening of the soft tissues at the back of the neck) to identify an increased risk of Down syndrome in the fetus. When an increased risk is identified, amniocentesis is offered to check the fetal karyotype. After having one child with trisomy 21 due to non-disjunction, the risk of recurrence of Down syndrome is given as 1 in 200 for mothers under the age of 35 years, but remains similar to their age-related population risk for those over the age of 35 years.

Table 8.1

Risk of Down syndrome (live births) with maternal age at delivery, prior to screening in pregnancy

Maternal age (years) Risk of Down syndrome
All ages 1 in 650
20 1 in 1530
30 1 in 900
35 1 in 385
37 1 in 240
40 1 in 110
44 1 in 37

Translocation (5%)

When the extra chromosome 21 is joined onto another chromosome (usually chromosome 14, but occasionally chromosome 15, 22 or 21), this is known as a Robertsonian translocation. This may be present in a phenotypically normal carrier with 45 chromosomes (two being ‘joined together’) or in someone with Down syndrome and a set of 46 chromosomes but with three copies of chromosome 21 material. In this situation, parental chromosomal analysis is recommended, since one of the parents may well carry the translocation in balanced form (in 25% of cases) (Fig. 8.4).

In translocation Down syndrome:

Mosaicism (1%)

In mosaicism, some of the cells are normal and some have trisomy 21. This usually arises after the formation of the chromosomally normal zygote by non-disjunction at mitosis but can arise by later mitotic non-disjunction in a trisomy 21 conception. The phenotype is sometimes milder in Down syndrome mosaicism.

Inheritance of Down syndrome

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Figure 8.3 Non-disjunction Down syndrome.

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Figure 8.4 Translocation Down syndrome. There is a Robertsonian translocation involving chromosomes 21 and 14, which has been inherited from a parent.

Summary

Down syndrome (trisomy 21)

Edwards syndrome (trisomy 18) and Patau syndrome (trisomy 13)

Although rarer than Down syndrome (1 in 8000 and 1 in 14 000 live births, respectively), particular constellations of severe multiple abnormalities suggest these diagnoses at birth; most affected babies die in infancy (Fig. 8.5, Boxes 8.2 and 8.3). The diagnosis is confirmed by chromosome analysis. Many affected fetuses are detected by ultrasound scan during the second trimester of pregnancy and diagnosis can be confirmed antenatally by amniocentesis and chromosome analysis. Recurrence risk is low, except when the trisomy is due to a balanced chromosome rearrangement in one of the parents.

Edwards syndome and Patau syndrome

Box 8.2   Clinical features of Edwards syndrome (trisomy 18)

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Figure 8.5 Overlapping of the fingers in Edwards syndrome.

Box 8.3

Clinical features of Patau syndrome (trisomy 13)

Turner syndrome (45, X)

Usually (>95%), Turner syndrome results in early miscarriage and is increasingly detected by ultrasound antenatally when fetal oedema of the neck, hands or feet or a cystic hygroma may be identified. In live-born females, the incidence is about 1 in 2500. Figure 8.6 and Box 8.4 show the clinical features of Turner syndrome, although short stature may be the only clinical abnormality in children.

Treatment is with:

In about 50% of girls with Turner syndrome, there are 45 chromosomes, with only one X chromosome. The other cases have a deletion of the short arm of one X chromosome, an isochromosome that has two long arms but no short arm, or a variety of other structural defects of one of the X chromosomes. The presence of a Y chromosome sequence may increase the risk of gonadoblastoma.

The incidence does not increase with maternal age and risk of recurrence is very low.

Turner syndrome

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Figure 8.6 Turner syndrome. The woman on the left has marked short stature but no other clinical features; the adolescent female on the right has neck webbing and has received growth hormone and is 150 cm in height.

Box 8.4

Clinical features of Turner syndrome

Reciprocal translocations

An exchange of material between two different chromosomes is called a reciprocal translocation. When this exchange involves no loss or gain of chromosomal material, the translocation is ‘balanced’ and usually has no phenotypic effect. Balanced reciprocal translocations are relatively common, occurring in 1 in 500 of the general population. A translocation that appears balanced on conventional chromosome analysis may still involve the loss of a few genes or the disruption of a single gene at one of the chromosomal breakpoints and result in an abnormal phenotype, often including cognitive difficulties. Studying the breakpoints in such individuals has been one way of identifying the location of specific genes.

Unbalanced reciprocal translocations contain an ‘incorrect’ amount of chromosomal material and often impair both physical and cognitive development, leading to dysmorphic features, congenital malformations, developmental delay and learning difficulties. In a newborn baby, the prognosis is difficult to predict but the effect is usually severe. The parents’ chromosomes should be checked to determine whether the abnormality has arisen de novo, or as a consequence of a parental rearrangement. Finding a balanced translocation in one parent indicates a recurrence risk for future pregnancies, so that antenatal diagnosis by chorionic villus sampling or amniocentesis should be offered as well as testing relatives who might be carriers.

Deletions

Deletions are another type of structural abnormality. Loss of part of a chromosome usually results in physical abnormalities and cognitive impairment. The deletion may involve loss of the terminal or an interstitial part of a chromosome arm.

An example of a deletion syndrome involves loss of the tip of the short arm of chromosome 5, hence the name 5p- or monosomy 5p. Because affected babies have a high-pitched mewing cry in early infancy, it is also known as cri du chat syndrome. Parental chromosomes should be checked to see if one parent carries a balanced chromosomal rearrangement. The clinical severity varies greatly, depending upon the extent of the deletion. It is now possible to specify the genes involved in chromosomal deletions as molecular methods are replacing standard cytogenetic investigations.

An increasing number of syndromes are now known to be due to chromosome deletions too small to be seen by conventional cytogenetic analysis. Submicroscopic deletions can be detected by FISH studies using DNA probes specific to particular chromosome regions. FISH studies are useful when a specific chromosome deletion is suspected.

DiGeorge syndrome is associated with a deletion of band q11 on chromosome 22 (i.e. 22q11) (Fig. 8.7). Williams syndrome is another example of a microdeletion syndrome due to loss of chromosomal material at band q11 on the long arm of chromosome 7 (i.e. 7q11) (Fig. 8.18, see also Box 8.12).

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Figure 8.7 Fluorescent in situ hybridisation (FISH) demonstrating a microdeletion on chromosome 22 associated with DiGeorge syndrome. Hybridisation signals are seen on one chromosome 22 but not on the other because of the presence of a deletion. (Courtesy of L. Gaunt, St Mary’s Hospital, Manchester.)

Mendelian inheritance

Mendelian inheritance, described by Mendel in garden peas in 1866, is the transmission of inherited traits or diseases caused by variation in a single gene in a characteristic pattern. These Mendelian traits or disorders are individually rare but collectively numerous and important: over 6000 have been described. For many disorders, the Mendelian pattern of inheritance is known. If the diagnosis of a condition is uncertain, its pattern of inheritance may be evident on drawing a family tree (pedigree), which is an essential part of genetic evaluation (Fig. 8.8).

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Figure 8.8 Examples of pedigree symbols.

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