2
Clinical Genetics
Ruth Wheeler
Chapter outline
Outline
- Chromosome Abnormalities, 11
- Chromosome Nomenclature, 11
- Numerical Disorders, 12
- Structural Chromosome Abnormalities, 14
- Single Gene Disorders, 16
- Autosomal Dominant Diseases, 17
- Autosomal Recessive Diseases, 17
- Sex-Linked Inheritance, 18
- Mitochondrial Inheritance, 19
- Genomic Imprinting, 19
- Uniparental Disomy, 20
- Multifactorial Inheritance, 20
- Genetic Testing and Interpretation of a Genetic Result, 20
- Cytogenetics, 20
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.
Fig. 2.1 A normal female 46,XX G-banded karyotype illustrating the banding patterns which permit identification of each individual chromosome.
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.
Fig. 2.2 Reciprocal translocation between chromosomes 2 and 3. A portion of the short arm of chromosome 2 has been exchanged with a small portion of the long arm of chromosome 3. The panel on the left shows this in diagrammatic form. The middle panel is the result of G-banding. The right panel shows chromosome painting. This is a balanced translocation.
(Figure provided by Dr L. Willett, East Anglian Genetics Service, Cytogenetics Laboratory.) 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).
Table 2.1
Numerical Abnormalities of Autosomes 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.
Table 2.2
Sex Chromosome Anomalies 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...
