Clinical Genetics

Ruth Wheeler

Chapter outline

Outline

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:

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).

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...