Clinical genetics is the specialty concerned with the diagnosis and investigation of disorders which are thought to have a genetic basis. The clinical genetics team is multidisciplinary and consists of consultants and specialist registrars working closely with genetic counsellors and laboratory-based diagnostic genetic scientists and cytogeneticists. Genetic risk assessment and non-directive counselling are an important part of the clinical workload and may involve both the proband (the first person to be tested) and also other family members.
Genetic disorders can be broadly classified into the following areas:
- 1.
Chromosomal abnormalities
- 2.
Single gene disorders
- 3.
Familial cancer and cancer-predisposing syndromes
- 4.
Multifactorial disorders
This chapter will deal with each of these types of disorders, with the exception of familial cancer and cancer-predisposing syndromes, and will also cover more unusual mechanisms of disease inheritance, including genetic imprinting and mitochondrial disorders. Diagnostic techniques and interpretation of results will be summarised.
Chromosome Abnormalities
Chromosome abnormalities can be numerical or structural, and it is estimated that they are detected in 50% to 70% of miscarriages. As detailed in Chapter 1 , a normal diploid human cell contains 46 chromosomes (22 pairs of autosomes and 1 pair of sex chromosomes) ( Fig. 2.1 ), and any deviation from this is likely to have consequences.
Chromosome Nomenclature
Chromosome abnormalities are described according to an agreed format which forms the basis of cytogenetic reports. The total number of chromosomes is given first, followed by the sex chromosomes (46,XX). Any structural changes, such as translocations, deletions or duplications, are then indicated by the letter ‘t’ (translocation), del (deletion) or dup (duplication), followed by the number of chromosomes concerned in parentheses, with ‘p’ or ‘q’ relating to the involvement of long or short arms. The regions of the chromosomes involved are indicated by their numerical address. Fig. 2.2 shows a reciprocal translocation described as 46,XY, t(2;3) (p21;q29), indicating an exchange of genetic material between chromosome 2p21 and chromosome 3q29.
Numerical Disorders
Three types of numerical disorder have been described: aneuploidy, polyploidy and mixoploidy.
Aneuploidy
Aneuploidy is defined as an abnormal number of chromosomes and includes trisomy, monosomy and the presence of additional, structurally abnormal (marker) chromosomes ( Table 2.1 ). It is the most common chromosome anomaly. It can involve any chromosome, but abnormal numbers of sex chromosomes are usually considered a separate group ( Table 2.2 and below).
| Condition | Karyotype | Clinical Picture |
|---|---|---|
| Polyploidy | 69,XXX or 69,XXY | Usually spontaneous abortion. Occasional live born, die soon after birth. Growth retardation, congenital malformation, mental retardation. |
| Diandry polyploidy | 69,XXX or 69,XXY extra chromosomes from father | Usually spontaneous abortion. Can lead to partial hydatidiform mole. |
| Trisomy | ||
| Trisomy 21 (Down syndrome) | 47,XX + 21 or 47,XY + 21 | Characteristic facial dysmorphology, mental retardation, congenital cardiac anomalies, duodenal atresia. |
| Trisomy 13 (Patau syndrome) | 47,XX + 13 or 47,XY + 13 | Cleft lip and palate, microcephaly, holoprosencephaly, closely spaced eyes, post-axial polydactyly. Death usually within few weeks of birth. |
| Trisomy 18 (Edward syndrome) | 47,XX + 18 or 47,XY + 18 | Low birth weight, small chin, narrow palpebral fissures, overlapping fingers, rocker bottom feet, congenital heart defects, death usually within few weeks of birth. |
| Monosomy | Monosomy of autosomes not viable. |
| Condition | Karyotype | Clinical Picture |
|---|---|---|
| Triple X syndrome | 47,XXX | Slender body habitus, mild learning difficulties, as a group reduction in IQ, individually may not be noticeable. |
| Tetrasomy X | 48,XXXX | Mental retardation more severe than 47,XXX (mean IQ around 60). |
| Klinefelter syndrome | 47,XXY | 1 in 1000 newborns but often not diagnosed until much later. Tall, small testes, gynaecomastia, sparse facial hair, infertility, mild reduction in IQ. |
| XYY syndrome | 47,XYY | Often undiagnosed, can cause mild learning difficulty, behavioural problems. |
| Turner syndrome | 45,X | Often causes spontaneous miscarriage, short stature, webbing of neck, congenital heart defect, wide-spaced nipples, gonadal dysgenesis leading to delayed or absent puberty. |
Trisomy.
Trisomy is the presence of a single extra chromosome. This occurs when homologous chromosomes fail to separate at meiosis, a process known as non-disjunction, which results in a germ cell containing 24 chromosomes rather than the normal 23. Trisomy of any chromosome can occur, but, with the exception of trisomies 13, 18, 21, X and Y, all are lethal in utero.
Trisomy 21, also known as Down syndrome, is the most common of the viable trisomies and affects around 1 in every 650 live births in the absence of prenatal screening. The clinical features are summarised in Table 2.1 . The risk of having a child with Down syndrome increases with maternal age, with a live-born risk of under 1 in 1000 in a 25-year-old woman rising to 1 in 100 at a maternal age of 40. Screening is offered to all pregnant women in the UK between weeks 10 and 14 of pregnancy. A small number of cases of Down syndrome (~2%) are due to mitotic non-disjunction, which occurs after zygote formation. In such cases, only a percentage of cells will be trisomy 21, and the baby is said to be a mosaic. There is no correlation between the degree of mosaicism and the severity of symptoms.
Trisomies 13 (Patau syndrome) and 18 (Edward syndrome) are much rarer (1 in 12,000 and 1 in 6000 live births respectively). Both these trisomies cause severe congenital malformations (see Table 2.1 ) and mental retardation, and affected babies usually die within the first few months of life. Although the risk also increases with maternal age, it is much lower than for Down syndrome at all ages.
Monosomy.
Monosomy, the absence of one of a pair of chromosomes is usually lethal to the embryo and therefore rare in live-born infants. The only exception is monosomy X or Turner syndrome (see Sex Chromosome Anomalies).
Polyploidy
Polyploid cells possess whole extra copies of the haploid genome (i.e. one set of all chromosomes). The most common polyploidies in humans are triploidy, in which 69 chromosomes are present, and tetraploidy (92 chromosomes). Triploidy occurs in 1% to 3% of conceptions and usually results in spontaneous abortion, although there have been occasional reports of live births of affected infants, who present with growth restriction and congenital malformations and die shortly after birth. The extra set of chromosomes can come from either the father (Type 1 triploidy or diandry) or mother (Type 2 triploidy or digyny). Diandry usually arises due to the fertilisation of a single haploid ovum by two sperm or, less frequently, by a single diploid sperm which has arisen due to an error in meiosis during spermatogenesis (see Table 2.1 ). Digyny is much less common and occurs when a diploid egg or nucleated primary oocyte is fertilised. Diploid ova arise as the result of non-disjunction of all chromosomes during meiosis I or II.
Examples of polyploidy include partial hydatidiform mole and diploid-triploid mosaicism. In both cases some cells have the normal two copies of each chromosome, whilst others have three copies. Partial hydatidiform mole is usually due to fertilisation of an ovum by two sperm and does not result in a viable fetus. Diploid-triploid mosaicism is most frequently due to second polar body incorporation in which the polar body (produced in the ovary at the same time as the egg and containing an extra set of chromosomes) is included in the cells that will become the baby. It is associated with truncal obesity, body/facial asymmetry, hypotonia, growth delay, mild differences in facial features, syndactyly and irregularities in the skin pigmentation. Intellectual impairment may be present but is highly variable, depending on the degree of mosaicism present. Interestingly, triploid cells are not normally present in the blood, so diagnosis relies on the analysis of other cell types, such as skin cells.
Tetraploidy, in which there are four copies of each chromosome per cell, is extremely rare. It is predominantly associated with miscarriage but infants surviving to term present with a severe phenotype characterised by multiple congenital abnormalities, and/or genital malformations and limb defects.
Mixoploidy
Mixoploidy includes mosaicism and chimerism.
Mosaicism.
Mosaicism occurs when an individual has two cell populations, derived from a single zygote, each with a different genotype, such as diploid/triploid mosaicism (see above). Aneuploidy mosaicism is common and is usually caused by non-disjunction during early cleavage of the zygote or the loss of one chromosome due to a failure to travel along the nuclear spindle properly during cell division (anaphase lagging). Turner syndrome is often mosaic and this may explain the occasional reports of fertility in affected women.
Chimerism.
In chimerism, an individual has two or more genetically distinct cell lines originating from different zygotes. The exact frequency of chimerism is not known, but there have been reports in association with the rare pigment disorder hypomelanosis of Ito.
Sex Chromosome Anomalies
The consequences of aneuploidy involving the sex chromosomes are generally less severe than those observed in autosomal aneuploidy. This is thought to be due to the presence of normal mechanisms which control gene dosage effects. In a normal female cell (46,XX), one randomly selected, complete copy of the X chromosome is switched off in a process known as X-inactivation or lyonisation. This ensures that both males and females express the same number of X-encoded genes. There is no such mechanism for Y chromosomes, but, as this contains very few genes, predominantly concerned with determining maleness, there is no impact of dosage differences. The features of sex chromosome aneuploidies are summarised in Table 2.2 . Trisomy of the sex chromosomes is often undetected, particularly in Klinefelter syndrome (47,XXY), unless a karyotype is performed. Monosomy, resulting in Turner syndrome (45,X or 45,X0), is the only viable monosomy and has an incidence of approximately 1 in 2500 in newborn females. The features are summarised in Table 2.2 . A much larger number of affected pregnancies miscarry, and monosomy X accounts for about 18% of chromosomal abnormalities seen in spontaneous abortion. Absence of the X chromosome, leaving only the Y chromosome, is incompatible with embryonic development and will always result in early abortion. Tetrasomy (48,XXXX) and pentasomy (49,XXXXX) of sex chromosomes are compatible with normal physical development, but affected individuals usually have some degree of mental retardation. It appears that the greater the number of X chromosomes, the greater the degree of mental impairment. Whatever the number of X chromosomes, the presence of a normal Y chromosome always produces the male phenotype.
Structural Chromosome Abnormalities
Structural chromosome abnormalities are very variable and occur when breaks in chromosomes are misrepaired. These breakages occur naturally during cell divisions to allow the exchange of genetic material between sister chromatids. Structural abnormalities are described as balanced, if there is no overall loss or gain of genetic material, or unbalanced, which is characterised by the loss or gain of genetic material. Generally, the loss of chromosomal material is more harmful and, due to the high number of genes expressed, the brain tends to be the most vulnerable organ, with affected individuals usually showing some reduction of mental and/or intellectual function.
Chromosome Deletions
The loss of part of a chromosome leads to monosomy for that particular region of deoxyribonucleic acid (DNA). Any part of either the long or the short arm of a chromosome may be lost. Deletions are described as interstitial, if they occur within chromosome arms, or terminal, if they involve the ends of the chromosome, the telomeres. The consequences of a chromosome deletion depend on the genes deleted. Several rare syndromes are associated with specific chromosome deletions, such as cri du chat or 5p deletion syndrome (5p-), a condition associated with severe intellectual disability and a characteristic cry from birth which is said to sound like a cat, and Wolf Hirschhorn Syndrome (4p-), which is characterised by severe intellectual disability, microcephaly, hypertelorism and a characteristic facial appearance.
Large deletions (≥4 Mb) can be identified by conventional karyotyping, but syndromes are increasingly being identified in which the chromosome deletion is too small to be detected using traditional G-banding. These microdeletion syndromes require specific tests, such as fluorescence in situ hybridisation (FISH), for diagnosis (see later). An example of a microdeletion syndrome is 22q- or DiGeorge syndrome, in which affected individuals have heart defects, palate abnormalities, a characteristic facial appearance, learning difficulties and immune problems.
Chromosome Duplications
Duplications (dup on a karyotype report) can involve any chromosomal region and result in one or more copies of a region of DNA. The most common cause of chromosomal duplication is unequal sister chromatid exchange due to chromosomal misalignment during meiosis. The resulting duplicated region can be located immediately adjacent to the normal region, either in the same or opposite orientation to the original (tandem duplication and inverted duplication respectively), elsewhere on the same chromosome or attached to a completely different chromosome. There is usually little or no loss of genetic material, so duplications are more often compatible with life than other chromosomal abnormalities and are therefore found more frequently. Any observed phenotype is due to gene dosage effects and will depend on the region involved and the size of the duplication. Examples of chromosome duplication disorders include chromosome 16p11.2 duplication, a rare disorder associated with developmental delay and behavioural problems, such as attention-deficit/hyperactivity disorder and recurrent seizures, and MECP2 (Methyl-CpG-Binding Protein 2) duplication disorder, which involves duplication of part of the long arm of the X chromosome. The condition is seen mainly in males, although females can be affected, and is characterised by moderate to severe intellectual disability. Some duplications are known to occur without phenotypic effect and can be classified as polymorphisms.
Chromosome Inversions
An inversion is a chromosomal rearrangement in which a region of DNA is reversed with respect to its normal orientation (‘inv’ on the karyotype report). It occurs if there are two breaks in a chromosome, followed by rotation of the region through 180 degrees. It can involve a single arm of the chromosome (paracentric inversion) or both arms on either side of the centromere (pericentric inversion). Inversions may not be associated with a phenotype since there is usually neither loss nor gain of chromosomal material, but if the break occurs within a gene or within the controlling region associated with a gene, then a phenotype may be observed.
Translocations
Translocations occur when chromosomes become broken during meiosis and the resulting fragment becomes attached to another chromosome.
Reciprocal translocations : These are the most common type of translocation and usually involve the exchange of material between non-homologous chromosomes. They are described as balanced or unbalanced (see Fig. 2.2 ). The portions exchanged are known as ‘translocated segments’ and the rearranged chromosome is called a ‘derivative’, reported as ‘der’, and is named according to its centromere. It is estimated that around 1 in 500 individuals carry a reciprocal translocation. Balanced translocations usually result in normal development, unless the break occurs within a gene or separates a gene from its controlling elements, in which case a phenotype may be observed. However, in carriers of balanced translocations, there is an increased risk of recurrent miscarriages or of having a child with congenital abnormalities and/or learning difficulties, as there is a possibility of the fetus inheriting the unbalanced form of the translocation. During meiosis, homologous chromosomes pair. When a reciprocal translocation is present, the four chromosomes (i.e. the two derivatives and two normal chromosomes) come together as a structure known as a ‘quadrivalent’. Two of these chromosomes then pass into the gamete. There are four possible outcomes: the gamete contains the two normal chromosomes and will result in a normal karyotype in the offspring; the gamete contains the two derivative chromosomes and will result in offspring with the reciprocal balanced translocation like the parent or one of the two derivatives, and the other normal chromosomes pass into the gamete (or vice versa), resulting in offspring with monosomy for one region of the genome and trisomy for another. This can result in either miscarriage or, if the chromosome segments involved are small, a viable offspring with congenital abnormalities. The phenotype obviously depends on the genes present on the segments of chromosome involved. The risk of giving birth to a live-born infant with an unbalanced translocation is not one in four, but rather is specific to each reciprocal translocation and is difficult to calculate, as it depends on which segments of chromosomes are involved and how large they are. Reciprocal translocations are found in approximately 3% of couples presenting with recurrent miscarriage, and testing is recommended in women who have had three or more miscarriages.
Robertsonian translocations : These are a specific type of translocations involving only the acrocentric chromosomes 13, 14, 15, 21 and 22, which all have a very short p arm. Robertsonian translocations occur following breakages within the short arms of two acrocentric chromosomes and fusion of the long arms to form a single large, derivative chromosome usually described as rob (1stchrq;2ndchrq) ( Fig. 2.3 ). There is usually loss of the short arms but, as these consist mainly of non-coding satellite DNA, this has little or no effect. An individual carrying a Robertsonian translocation has only 45 chromosomes.
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