Genes and the Genetics of Inherited Diseases
Human cells contain 23 pairs of chromosomes, 46 in total. Each parent contributes one chromosome to each of these pairs. Twenty-two of the chromosome pairs, known as autosomes (chromosomes 1–22), have the same appearance in males and females. Females have two X chromosomes as the 23rd pair, and males have one X and one Y chromosome as their 23rd pair. Reproductive cells (gametes) have 23 chromosomes, 22 autosomes and either one X (oocytes) or one Y (sperm cells) chromosome.
Autosomal genes are therefore present in two copies, one inherited from each parent. Females have two gene copies on their X chromosomes, whereas males have only one copy of genes carried on their X and Y chromosomes. Genetically inherited diseases are usually caused by a mutation within a specific gene, which causes the gene to be inactive or faulty. The mutations that lead to a disease can be caused by a single change, or by more complicated changes within the gene, such as deletions, substitutions or insertions in the base sequence. A single gene may contain “hot spots” that are prone to mutation.
A triplet of bases on a chromosome can sometimes be expanded, and this phenomenon leads to a group of diseases known as triplet repeat disorders. Gross chromosomal abnormalities, such as aneuploidy, translocations and inversions, can also lead to a fetus with an unbalanced chromosome complement. Age-related aneuploidy can also lead to chromosomally abnormal offspring: this is not inherited diseases, and it can occur in any pregnancy.
Single-gene defects may affect the autosomes (chromosomes 1–22) or the sex chromosomes (X and Y). Whether the disease is expressed when both or only a single copy of the gene carry a mutation is determined by the mode of inheritance: autosomal recessive, autosomal dominant or X-linked (sex-linked).
Autosomal Recessive Disease
Autosomal recessive inheritance accounts for the majority of genetic disease. If an individual has one normal and one abnormal gene for a particular disorder, he or she is a carrier of the disease and will usually be unaffected. If both parents of a child carry the same disease-causing mutation, the child will be affected by the disease. For example, if both the mother and the father are carriers of cystic fibrosis, the offspring have a 1 in 4 chance of being affected, 1 in 4 chance of being unaffected, and a 2 in 4 chance of carrying the disease without being affected.
The most common autosomal recessive defect in one gene is beta-thalassemia, caused by a mutation in the beta-globin gene. However, there are many different mutations for beta thalassemia, especially between different ethnic groups: in many couples, each partner may carry a different mutation (compound heterozygotes).
Autosomal Dominant Disorders
Disorders that are dominant in their inheritance will be expressed if a single copy of the mutated gene is present. These diseases are not as life threatening as some recessive diseases, and therefore affected individuals can still reproduce and transmit the disease to their offspring. Many dominant disorders are late in onset. A large number of dominant diseases can now be diagnosed by PGD.
X-linked diseases affect genes that are carried on the X chromosome: more than 400 X-linked diseases have been identified. They can be inherited in a recessive or dominant manner, but almost all severe types have recessive inheritance. Males inherit the X chromosome from their mother, and if this inherited X chromosome is abnormal, they will be affected with the disease. Therefore, carrier mothers transmit the disease to half of their male offspring, and half of a carrier mother’s daughters will be carriers. Embryo biopsy and genetic diagnosis can identify non-carrier female and non-affected male embryos, which can then be selected for transfer.
Triplet Repeat Disorders
A new class of genetic disorders was identified during the 1990s: triplet repeat disorders are caused by the expansion of a triplet of bases that are repeated within a gene, and they are usually associated with neurological disorders. Each disease has a range of repeats associated with a spectrum from normal individuals to affected individuals.
For example, fragile X syndrome, which generally affects males, was originally thought to be an X-linked disease, but it has been reclassified as a triplet repeat disorder. The disease is caused by the unstable expansion of a CGG repeat in the 50-untranslated region of the FMR1 gene, which lies on the X chromosome. This triplet expansion results in mental retardation. A normal individual will have from 6 to 54 triplet repeats, those having the “premutation” will carry between 54 and 200 repeats, and those affected with fragile X will have over 200 repeats.
Females carrying the pre-mutation are at risk of transmitting the full mutation to their offspring, and since males inherit the X chromosome from their mothers and have a single X chromosome, their male offspring are at a 50% risk of inheriting fragile X. Females who inherit the expanded gene from their mothers will also inherit a normal X chromosome from their father, and their disease manifestation is variable. Males carrying the pre-mutation are at risk of transmitting only the pre-mutation to their female offspring, who will be carrier females.
Abnormalities that involve whole chromosomes are usually lethal. Those compatible with life includes Down’s syndrome (three copies of chromosome 21) and those that involve the sex chromosomes, such as Turner’s syndrome (XO) and Klinefelter’s syndrome (XXY).
The most common chromosome abnormality is a translocation, where two chromosomes have broken and rejoined to the opposite chromosome. If the chromosomes are still balanced, i.e., all the genetic material is still present, the patient is described as having a balanced translocation. The majority of patients carrying a balanced translocation do not realize they have abnormal chromosomes until they try to reproduce. During meiosis, the segregation of the chromosomes becomes confused, and unbalanced chromosome complements are formed in the gametes, leading to the formation of an embryo with abnormal chromosomes (unbalanced translocation). Therefore, patients carrying balanced translocations may experience infertility, repeated miscarriage or the birth of a child with abnormal chromosomes.
Robertsonian translocations involve breakages around the centromere of the “acrocentric” chromosomes (13, 14, 15, 21, 22). These chromosomes contain a satellite region on their short arm, and loss of this area has no effect on the phenotype. Since two of the acrocentric chromosomes join together, the patient has only 45 chromosomes. Robertsonian translocations can be diagnosed using PGD to identify the number of chromosomes present.
Reciprocal translocations involve breaks at any location on two chromosomes, and any chromosome can be affected. Every couple may have different chromosome breakpoints, and therefore diagnosis by PGD is difficult.
Chromosome abnormalities can also be caused by chromosome inversions, insertions, deletions or rearrangements (such as ring chromosomes).
Women over the age of 35 are known to be at increased risk of having a fetus with a chromosome abnormality such as Down’s syndrome. However, only 20% of Down’s syndrome babies are born to women over the age of 35. Screening methods have been developed to help identify those pregnancies at risk, as the use of age alone as an indication for prenatal diagnosis of age-related aneuploidy will miss the majority of affected pregnancies.
Biochemical (plasma alpha-fetoprotein, hCG, unconjugated estriol) and ultrasound screening methods are therefore used to determine which pregnancies are at risk. Patients found to be at risk undergo prenatal diagnosis, with a karyotype performed to ascertain the status of the fetus. The chromosomes most commonly involved in age-related aneuploidy are 13, 16, 18, 21, X and Y.
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