Genetic screening

Genetic testing may be used when there is a risk of a particular genetic disorder occurring in a family. Such testing is only acceptable when the genetic inheritance pattern of the disorder is well understood, effective therapy is possible, and reliable, valid, highly sensitive, specific, and harmless testing methods are used. The prevalence in a given generation must be high enough to justify the effort involved in testing.

Genetic testing may be aimed at identifying heterozygotes who carry a gene for a recessive disorder but do not express it (e.g., Tay-Sachs disease in Ashkenazi Jews, sickle cell anemia in blacks, thalassemia in several ethnic groups). If a heterozygous couple also has a heterozygote, the couple is at risk of having an affected child.

Testing may be necessary before symptoms appear if there is a family history of a major inherited disorder that manifests itself later in life (e.g., Huntington's disease, breast cancer). Testing determines the risk of developing the disorder, so a person can take preventive measures later. If a test shows that a person is a carrier of the disorder, they can also make decisions about having offspring.

Prenatal testing may also include amniocentesis, chorionic villus sampling, umbilical cord blood testing, maternal blood testing, maternal serum testing, or fetal incarceration. Common reasons for prenatal testing include the mother's age (over 35); a family history of a disorder that can be diagnosed by prenatal testing; abnormal maternal serum testing; and certain symptoms that occur during pregnancy.

Screening of newborns allows for the use of prophylaxis (special diet or replacement therapy) for phenylpyruvic oligophrenia, galactose diabetes and hypothyroidism.

Creating a family genealogy. Genetic counseling widely uses the creation of a family genealogy (family tree). In this case, conventional symbols are used to designate family members and provide the necessary information about their health. Some family disorders with identical phenotypes have several inheritance models.

[ 1 ], [ 2 ], [ 3 ], [ 4 ]

Mitochondrial DNA abnormalities

The mitochondrion contains a unique round chromosome that carries information about 13 proteins, various RNAs, and several regulatory enzymes. However, information about more than 90% of mitochondrial proteins is contained in nuclear genes. Each cell contains several hundred mitochondria in its cytoplasm.

Mitochondrial disorders may result from mitochondrial abnormalities or nuclear DNA abnormalities (e.g., disruptions, duplications, mutations). High-energy tissues (e.g., muscle, heart, brain) are at particular risk of dysfunction due to mitochondrial abnormalities. Different types of tissue dysfunction correlate with specific mitochondrial DNA abnormalities.

Mitochondrial abnormalities are seen in many common disorders, such as some forms of Parkinson's disease (which can cause widespread mitochondrial deletion mutations in basal ganglia cells) and many other types of muscle disorders.

Mitochondrial DNA abnormalities are determined by maternal inheritance. The entire mitochondria is inherited from the cytoplasm of the egg, so all offspring of an affected mother are at risk of inheriting the disorder, but there is no risk of inheriting the disorder from an affected father. The diversity of clinical manifestations is a rule, which can be partly explained by the variability of combinations of inherited mutations and normal mitochondrial genome (heteroplasm) of cells and tissues.

Mitochondrial disorders

Violation	Description
Chronic progressive external ophthalmoplegia	Progressive paralysis of the extraocular muscles, usually preceded by bilateral, symmetrical, progressive drooping, beginning months or years before the paralysis
Kearns-Sayre syndrome	A multisystem variant of chronic progressive external ophthalmoplegia that also causes cardiac block, retinal pigment degeneration, and CNS degeneration
Leber's hereditary optic neuropathy	An intermittent but often devastating bilateral vision loss that most often occurs in adolescence due to a single point mutation in mitochondrial DNA
Murph syndrome	Myoclonic seizure, rough red fibers, dementia, ataxia and myopathy
Molasses Syndrome	Mitochondrial encephalomyopathy, lactic acidosis and stroke-like attacks
Pearson's syndrome	Sideroblastic anemia, pancreatic insufficiency and progressive liver disease that begins in the first months of life and often ends in the death of the child

Single gene defects

Genetic disorders that are caused by a defect in only one gene ("Mendelian disorders") are the simplest to analyze and the most thoroughly studied to date. Science has described many specific disorders of this kind. Single-gene defects can be autosomal or X-linked, dominant or recessive.

[ 5 ], [ 6 ], [ 7 ], [ 8 ]

Autosomal dominant trait

Only one autosomal allele of a gene is required to express an autosomal dominant trait; this means that both the heterozygote and the homozygote of the abnormal gene are affected.

In general, the following rules apply here:

• A sick person has a sick parent.
• A heterozygous affected parent and a healthy parent have, on average, the same number of affected and healthy children, meaning that the risk of developing the disease is 50% for each child.
• Healthy children of a sick parent do not pass the trait on to their offspring.
• Men and women are at equal risk of developing the disease.

[ 9 ], [ 10 ], [ 11 ], [ 12 ]

Autosomal recessive trait

An autosomal recessive trait requires two copies of the abnormal allele to be expressed. In some generations, the percentage of heterozygotes (carriers) is high because of an initiator effect (i.e., the group was started by several people, one of whom was a carrier) or because carriers have a selective advantage (e.g., heterozygosity for sickle cell disease protects against malaria).

In general, the following rules of inheritance apply:

• If healthy parents have a sick child, both parents are heterozygous and, on average, one in four of their children will be sick, one in two will be heterozygous, and one in four will be healthy.
• All children of the affected parent and the genotypically normal individual are phenotypically normal heterozygotes.
• On average, 1/2 of the children of a sick person and one heterozygous carrier are infected, 1/3 are heterozygous.
• All children of two sick parents will become sick.
• Men and women are equally at risk of infection.
• Heterozygote carriers are phenotypically normal but are carriers of the trait. If the trait is caused by a defect in a specific protein (such as an enzyme), a heterozygous person usually has a limited amount of that protein. If the disorder is known, molecular genetic techniques can identify heterozygous, phenotypically normal individuals.

Relatives are more likely to inherit the same mutant allele, which is why marriages between close relatives (consanguineous marriages) increase the likelihood of having sick children. In a parent-child or brother-sister pair, the risk of having a sick child increases due to the presence of 50% of the same genes.

[ 13 ], [ 14 ]

X-linked dominant

X-linked dominant traits are carried on the X chromosome. Most are very rare. Men are usually more severely affected, but women who carry only one abnormal allele are also affected, but less severely.

In general, the following rules of inheritance apply:

• A sick man passes the trait on to all his daughters, but not to his sons; however, if a sick man marries a sick woman, they may have a sick son.
• Affected heterozygous females pass the trait on to half of their children, regardless of gender.
• Affected homozygous females pass the trait on to all their children.
• Twice as many sick women as men carry the trait, unless it has caused death in men.

X-linked dominant inheritance can be difficult to distinguish from autosomal dominant inheritance without the use of molecular tests. This requires large pedigrees with special attention to the children of affected parents, since male-to-male transmission of the trait excludes X-linkage (men pass only Y chromosomes to their sons). Some X-linked dominant disorders cause mortality in males.

X-linked recessive gene

X-linked recessive traits are carried on the X chromosome.

In general, the following rules of inheritance apply:

• Almost all patients are male.
• Heterozygous females are usually phenotypically normal, but as carriers they can pass the abnormality on to their children (however, the trait may represent a new mutation in the male's body).
• A sick man never passes this trait on to his sons.
• All daughters of a sick man are carriers of the trait.
• A female carrier passes the devil on to half of her sons.
• The trait is not passed on to the daughters of a carrier mother (unless they inherited the trait - such as color blindness - from their father), but half of them are carriers.

An affected female must usually be the owner of the abnormal gene on both X chromosomes (homozygous) for the trait to be expressed, i.e. she must have an affected father and a mother with the mutation in either a heterozygous or homozygous manner.

Occasionally, the gene is expressed to some extent in women who are heterozygous for X-linked mutations, but such women are rarely as severely affected as men who have only one pair of genes (hemizygous). Heterozygous women can become affected if there is a structural chromosomal rearrangement (e.g., X-autosome translocation, missing or destroyed X chromosome) or skewed X-inactivation. The latter occurs early in development and usually involves random but balanced inactivation of the X chromosome inherited from either the father or the mother. Sometimes, however, most of the inactivation occurs in the X chromosome inherited from one parent; this phenomenon is called skewed X-inactivation.

Codominance

In codominant inheritance, the phenotype of heterozygotes is different from the phenotype of both homozygotes. Each allele at a genetic locus usually has a distinct effect. For example, codominance is recognized in blood group antigens (e.g., AB, MN), leukocyte antigens (e.g., DR4, DR3), serum proteins with different electrophoretic mobilities (e.g., albumin, tactile globulin), and enzymatic processes (e.g., paraoxonase).

[ 15 ], [ 16 ]

Multifactorial inheritance

Many traits (such as height) are distributed along a parabolic curve (a normal distribution); this distribution is consistent with the polygenic definition of a trait. Each trait adds to or subtracts from the trait, independent of other genes. In this distribution, very few people are at the extremes, and most are in the middle, since people do not inherit multiple factors all acting in the same direction. Various environmental factors that speed up or slow down the end result contribute to the normal distribution.

Many relatively common congenital disorders and familial diseases are the result of multifactorial inheritance. In an affected person, the disorder is the sum of genetic and environmental factors. The risk of developing the trait is significantly higher in first-degree relatives (who share 50% of the affected person's genes) than in more distant relatives, who are likely to inherit only a few abnormal genes.

Common disorders caused by multiple factors include hypertension, atherosclerosis, diabetes, cancer, spinal cord disease, and arthritis. Many specific genes can be diagnosed. Genetic predisposition factors, including family history, biochemical, and molecular parameters, can help identify people at risk for developing a disease so that preventive measures can be taken.

Unconventional inheritance

Mosaicism. Mosaicism is the presence of two or more cell lines that differ in genotype or phenotype but originate from the same zygote. The likelihood of mutation is high during cell division in any large multicellular organism. Each time a cell divides, an estimated four or five changes occur in the genome. Thus, any large multicellular organism has subclones of cells with slightly different genetic makeups. These somatic mutations—mutations that occur during mitotic cell division—may not result in a clearly defined trait or disease, but can be classified as disorders that result in patchy changes. For example, McCune-Albright syndrome causes patchy dysplastic changes in bone, endocrine gland abnormalities, patchy pigmentary changes, and, very rarely, cardiac or hepatic abnormalities. If such a mutation occurred in all cells, it would cause early death, but mosaics (chimeras) survive because normal tissues support the abnormal tissues. Sometimes a parent with a single gene disorder appears to have a mild form of the disease but is actually a mosaic. Offspring may be more severely affected if they inherit an embryonic cell with a mutation in the allele and therefore have an abnormality in every cell. Chromosomal mosaicism occurs in some embryos and can be detected in the placenta by chorionic villus sampling. Most embryos and fetuses with chromosomal abnormalities are spontaneously miscarried. However, the presence of normal cells early in development may support some chromosomal abnormalities, allowing the baby to be born alive.

Genomic imprinting. Genomic imprinting is the differential expression of genetic material depending on whether it is inherited from the mother or the father. The difference in expression results from differential activation of the gene. Genomic imprinting is tissue and developmental stage dependent. Biallelic, or biparental, expression of an allele may occur in some tissues, with expression of the allele inherited from one parent occurring in other tissues. Depending on whether the genetic expression is maternally or paternally inherited, a new syndrome may result if the gene has been genomically imprinted. Particular attention should be paid to genomic imprinting if disorders or diseases have been transmitted across generations.

Uniparental disomy. Uniparental disomy occurs when two chromosomes of a pair are inherited from only one parent. This is extremely rare and is thought to be due to trisomic escape. This means that the zygote originally had three chromosomes, but one was lost, resulting in the disomy in question in one-third of cases. Imprinting effects may occur because there is no information about the other parent. Also, if there are copies of the same chromosome (isodisomy) that contain an abnormal allele for an autosomal recessive disorder, affected individuals are at risk of acquiring the disorder even though only one parent carries it.

Triplet (trinucleotide) repeat disorders. A nucleotide triplet occurs frequently and sometimes has many repeats. It happens that the number of triplets in a gene increases from generation to generation (a normal gene has relatively few triplet repeats). When a gene is passed from one generation to the next, or sometimes as a result of cell division in the body, the triplet repeat can grow and increase, preventing the gene from functioning normally. This increase can be detected by molecular testing, this type of genetic change is not common, but occurs in some disorders (eg, dystrophic myotonia, fragile X mental retardation), especially those involving the central nervous system (eg, Huntington's disease).

Anticipation. Anticipation occurs when the disease has an early onset phase and is more pronounced in each subsequent generation. Anticipation can occur when the parent is a mosaic (chimera) and the child has a complete mutation in all cells. It can also manifest itself in a triplet repeating expansion if the number of repetitions, and therefore the severity of the phenotype damage, increases with each subsequent offspring.