Clinical Genetics

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).

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.

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.