Human genetic disorders

The spectrum of inherited or congenital genetic disorders can be classified as the chromosomal disorders, including mitochondrial chromosome disorders, the Mendelian and sex-linked single gene disorders, a variety of non-Mendelian disorders and the multifactorial and polygenic disorders


Chromosomal abnormalities are much more common than generally appreciated. Over half of spontaneous abortions have chromosomal abnormalities, as compared with only 4-{) abnormalities per 1000 live births. Specific chromosomal abnormalities can lead to well-recognized and severe clinical syndromes, although autosomal aneuploidy (a differing from the normal diploid number) is usually more severe than the sex chromosome aneuploidies. Abnormalities may occur in either the number or the structure of the chromosomes.

Prevalence of genetic disease'.
Prevalence of genetic disease’.
Genetic disorders.
Genetic disorders.

Abnormal chromosome numbers If a chromosome or chromatids fail to separate (‘nondisjunction’) either in meiosis or mitosis one daughter cell will receive two copies of that chromosome and one daughter cell will receive no copies of the chromosome. If this non-disjunction occurs during meiosis it can lead to an ovum or sperm having either (i) an extra chromosome, so resulting in a fetus that is ‘trisomic’ and has three instead of two copies of the chromosome; or (ii) no chromosome, so the fetus is ‘monosomic’ and has one instead of two copies of the chromosome. Non-disjunction can occur with auto somes or sex chromosomes.
However, only individuals with trisomy 13, 18 and 21 survive to birth, and most children with trisomy 13 and trisomy 18 die in early childhood. Trisomy 21 (Down’s syndrome) is observed with a frequency of 1 in 700 live births regardless of geography or ethnic background. Full autosomal monosomies are extremely rare and very deleterious. Sex chromosome trisomies (for example Klinefelter’s syndrome, XXY) are relatively common. The sex chromosome monosomy in which the individual has an X chromosome only and no second X or Y chromosome is known as Turner’s syndrome and is estimated to occur in 1 in 2500 live born girls (Table 2.2). Occasionally, non-disjunction can occur during mitosisshortly after two gametes have fused. It will then result in the formation of  two cell lines, each with a different chromosome complement. This occurs more often withthe sex chromosome, and results in a ‘mosaic’ individual.  Very rarely the entire chromosome set will be present in more than two copies, so the individual may be triploid rather than diploid and have a chromosome number of 69. Triploidy and tetraploidy (four sets) result in spontaneous abortion.
Abnormal chromosome structures As well as abnormal numbers of chromosomes, chromosomes can have abnormal structures, and the disruption to the DNA and gene sequences may give rise to a genetic disease.


Deletions of a portion of a chromosome may give rise to a disease syndrome if two copies of the genes in the deleted region are necessary, and the individual will not be normal with just the one copy remaining on the nondeleted homologous chromosome. Many deletion syndromes have been well described, for example a deletion of chromosome 22 gives rise to DiGeorge syndrome.


Duplications occur when a portion of the chromosome is present on the chromosome in two copies, so the genes in that chromosome portion are present in an extra dose. A form of the neuropathy Charcot-Marie-Tooth disease due to a small duplication of a region of chromosome.

Examples of chromosomal disorders in live births.
Examples of chromosomal disorders in live births.


Inversions involve an end-to-end reversal of a segment within a chromosome, e.g. abcdefgh becomes abcfedgh. Translocations Translocations occur when two chromosome regions join together, when they would not normally. Chromosome translocations in somatic cells may be associated with tumorigenesis. Translocations can be very complex involving more than two chromosomes, but most are simple and fall into two categories: 1 Reciprocal translocations. These occur when any two non-homologous chromosomes break simultaneously and rejoin, swapping ends. In this case the cell still has 46 chromosomes but two of them are rearranged. Someone with a balanced translocation is likely to be normal (unless a translocation breakpoint interrupts a gene) but at meiosis, when the chromosomes separate into different daughter cells, the translocated chromosomes will enter the gametes and any resulting fetus may inherit one abnormal chromosome and have an unbalanced translocation with physical manifestations. 2 Robertsonian translocations. These are clinically important and occur when two acrocentric chromosomes join and the short arm is lost leaving only 45 chromosomes. This translocation is balanced as no genetic material is lost and the individual is healthy. However any offspring have a risk of inheriting an unbalanced arrangement. This risk depends on which acrocentric chromosome is involved. Clinically important is the 14/21 Robertsonian translocation and a woman with this karyotype has a 1 : 8 risk of aDown’s baby (a male carrier has a 1 : 50 risk). However, they have a 50% risk of producing a carrier like  themselves, hence the importance of genetic family studies. Relatives should be alerted about the risk of a Down’s offspring and should have their chromosomes checked.

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