What causes genetic disorders?
enetics is the science of inheritance. It aims to understand the mechanism by which the blueprints for life are passed through generations and how variations in these blueprints are essential for evolution, yet can cause disease. This article aims to deﬁne the major types of geneticdisorder and provide examples of each.
The GP curriculum and genetic disorders Statement 6 of the GP curriculum is concerned with genetics in primary care. It requires GPs in training to have a basic knowledge about genetics, and in particular about deoxyribonucleic acid (DNA) as genetic material and how mutations and variants contribute to human disease, and patterns of inheritance.
Thebasis of human genetic disorders
Genetic diseases can be due to an alteration in one gene, several genes in combination with environmental factors or due to imbalance of many genes. These are the basis of the three main classes of genetic disorders: single-gene disorders—mutations in single genes often causing loss of function multifactorial conditions—variants in genes interacting with theenvironment and causing alteration of function chromosomal disorders—causing chromosomal imbalance and alteration in gene dosage.
Figure 1. The DNA double helix.
collagen, enzymes and hormones) and special RNA molecules which regulate gene expression. Different genes are read or ‘expressed’ at different times in different cells in response to requirements. A change to the DNA sequence can changethe gene product’s structure and behaviour, and this can have dramatic consequences in the cell and on the individual as a whole. Each human cell nucleus holds about 2 m of DNA and about 25 000 genes. In order to be able to manage this DNA and pass it from cell to cell, it is organized into smaller units—chromosomes. Each chromosome is made up of a long strand of DNA and contains thousands of genes,arranged in a linear order along the chromosome. Chromosomes also contain histone proteins that are involved in chromosome structure and packing and in gene regulation.
DNA, genes and chromosomes
The clinical effects of human genetic disorders can be explained by understanding how our DNA is organized and copied. Genes are encoded in DNA which is composed of two strands of combinations offour chemical bases, which face in opposite directions and connect pairwise to form a double helix shape—Fig. 1. These chemicals are adenine (A), thymine (T), cytosine (C) and guanine (G). Genetic information exists in the sequence of these nucleotides— genes direct the synthesis of proteins involved in cell structure, metabolism and cell communication (for instance
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Humans have 23 pairs of chromosomes (Fig. 2), 22 matching pairs with matching genes called the autosomes and one pair of sex chromosomes (XX—female or XY—male). We inherit one of each pair from our mother and one from our father. Familymembers inherit blocks of genes in common with each other. It is possible to use DNA markers to identify a particular
gene or block of genes in a family. This can then allow predictions to be made about whether another family member is at risk of being affected or of being a carrier depending on whether or not they have inherited the DNA marker (Fig. 3). Although chromosomes can be seen downthe microscope, genes are too small and so chemical methods have to be used
Figure 2. Twenty-three pairs of chromosomes arranged according to size with chromosome 1 being the largest. The ﬁnal two chromosomes are the sex chromosomes. Reproduced with permission from the Genetic Interest Group www.gig.org.uk.
Figure 3. The chromosome theory of inheritance.
to determine the DNA...