Patterns of Inheritance

- Chromosomal Patterns of Inheritance It is important to clarify at the outset the difference between chromosome abnormalities and single gene disorders. Chromosome abnormalities are errors that result in an abnormal chromosome number or an abnormal chromosome structure. These abnormalities lead to the loss or gain of chromosome material. All the genes within these chromosomes, however, are normal. Most chromosome abnormalities are sporadic with a small to negligible risk of recurrence. Of those that are familial, the risk of recurrence is usually less than 15%.

In the case of single gene disorders, the error lies in a mutation or change within the DNA sequence. Errors that occur within a gene can result in absent, deficient or abnormal protein products. The chromosomes, or karyotype, of a patient with a single gene disorder are expected to be normal, 46,XX or 46,XY. Therefore, chromosome studies are not recommended for patients who are thought to have a single gene disorder such as cystic fibrosis or muscular dystrophy.

- Mendelian Patterns of Inheritance Mendelian genetic disorders are disorders caused by a single gene mutation that leads to an abnormality that is usually confined to an organ system (e.g., skeletal as in achondroplasia, CNS as in Huntington disease). The units of heredity, or genes, are DNA sequences that code for the synthesis of proteins. Genes are submicroscopic segments of DNA and cannot be detected by chromosome analysis. Like chromosomes, genes are inherited in pairs, one from each parent.

A gene may be altered by an event that causes a change in the nucleotide bases, a mutation. The different forms of a gene are called alleles (e.g., the gene for eye color has blue, brown, 1

hazel, etc. alleles). If the pair of alleles is alike, the individual is said to be homozygous. If the pair of alleles is different, the individual is said to be heterozygous.

There are approximately 25,000 genes on the 23 pairs of chromosomes. It is estimated that every individual has several altered genes. In most cases these altered genes are recessive and the normal dominant allele results in expression of the normal trait. There are thousands of different single gene disorders. If a condition is due to an alteration in a gene on an autosomal chromosome (1 through 22), it is inherited in an autosomal dominant or autosomal recessive fashion. If the altered gene is located on the X chromosome, it is inherited in an Xlinked fashion.

For a dominant trait to be expressed, one dominant gene will suffice. A gene mutation behaves in a dominant manner if it acquires a new or different function that is disadvantageous (or advantageous) to the cell. In effect, the mutation results in a "gain of function."

For a recessive trait to be observed, however, two recessive genes must be present. A gene mutation behaves in a recessive manner if it produces a non-functional protein. If a cell contains at least one gene that codes for normal protein production, the presence of the recessive gene will be masked. When a cell has two recessive genes and is not able to produce a functional protein, then the recessive trait will be expressed. In effect, the mutation results in "loss of function."

- Autosomal Recessive Inheritance The concept of one gene, one enzyme was introduced by Beadle and Tatum. This resulted in the identification of numerous inborn errors of metabolism, most of which are recessive traits.

A classic example of an autosomal recessive inborn error of metabolism is phenylketonuria (PKU). PKU is caused by a deficiency of the enzyme phenylalanine hydroxylase ( PAM) produced in the liver. The deficiency of PAH results in accumulation of phenylalanine and metabolites such as phenylpyruvic acid in the blood and cerebrospinal fluid. Patients are relatively healthy and survive into adult life. However, without treatment there is significant brain damage with severe to profound mental retardation.

On occasion there are PKU patients who do not respond to dietary control and continue to have elevated blood phenylalanine levels with associated seizures and progressive mental retardation. This variant of PKU is the result of another gene mutation. In these patients, the PAH gene is normal. The problem is caused by a mutation in a gene involved in the synthesis of tetrahydrobiopterin, a co-factor of phenylalanine hydroxylase. This is an example of locus heterogeneity (allele heterogeneity). In this example, PKU can be caused by abnormalities in two different genes at two different sites or loci on the chromosomes.

Mutations can occur anywhere along the length of the gene, affecting introns, exons or the immediate flanking regions. These mutations can affect the amount of protein or enzyme that is produced or the protein or enzyme function. Mutations within a gene can result in the following:

The gene can be completely deleted resulting in the absence of the protein. There can be a partial deletion of the gene resulting in the formation of an abbreviated protein.

The mutation may affect the enzyme's active site and reduce or abolish catalytic activity.

The mutation may affect the stability of the enzyme so that it is degraded more rapidly.

There can be an abnormality of the immediate flanking region affecting messenger RNA transcription and, therefore, protein synthesis.

Individuals with one normal gene and one mutated gene are often unaffected, suggesting that the enzyme product of one normal gene is sufficient to supply the needs of an individual. This is why biochemical assays often show 50% enzymatic function among carriers when compared with non-carriers.

- Autosomal Dominant Inheritance In conditions that are inherited in an autosomal dominant fashion, affected individuals are heterozygous for an autosomal dominant disease gene and a normal gene. In such cases, the presence of the abnormal gene results in the clinical expression of a disease or a condition.

Roughly, there are four times more dominant traits than recessive traits recognized in humans. This is because a recessive trait can be carried through generations "hidden" from view. A dominant trait is invariably expressed in the phenotype. All individuals with a dominant trait must carry the abnormal gene with a 50% chance that they will pass this gene on to their offspring. An example is Huntington disease (HD) where individuals with the abnormal gene will invariably develop clinical signs and symptoms.

There are, however, several variations to this relatively simple inheritance pattern. It is not uncommon to find pedigrees where an index case has an autosomal dominant trait and clearly normal parents.

New (de novo) mutation refers to a DNA change that transforms the gene from normal to abnormal in the egg or sperm that forms the zygote. Realize that the other germ cells of the parent are usually unaffected or normal and the risk of recurrence in future offspring is virtually the same as the general population. The affected individual, however, will have a 50% risk of having affected offspring. A good example is achondroplasia. Eight out of 10

cases of achondroplasia are secondary to new mutations. Only two out of 10 individuals with achondroplasia have a similarly affected parent.

On occasion, two or more sibs with an autosomal dominant trait have normal parents. This can be explained on the basis of germline or gonadal mosaicism. Conceivably, early in development, an individual could have a mutation that is limited to the germline (germ cells egg or sperm) while sparing the somatic cells. Such individuals are phenotypically normal; however, they have a greater risk of recurrence than the general population. This phenomenon has been described in osteogenesis imperfecta, achondroplasia and Duchenne muscular dystrophy.

Finally, an affected child with normal parents can be explained on the basis of incomplete penetrance. The premise in autosomal dominant inheritance is that an individual who carries an abnormal gene will have an observable abnormal phenotype, however, there are exceptions. On occasion, a person who carries an autosomal dominant gene may be physically normal. For autosomal dominant traits, the term "penetrance" refers to the number of gene carriers who are affected, divided by the total number of gene carriers who are affected and unaffected. Thus, a gene can have an 80% penetrance rate (80 affected people among 100 with the gene).

The non-penetrant carrier is a loose term used to describe an individual who carries the abnormal gene, but does not express the disease or the trait. About 20% of individuals who carry the gene for retinoblastoma (Rb) are nonpenetrant carriers. This lack of penetrance can be explained as follows:

Variable expressivity refers to the severity of the disease or trait: mild, moderate, or severe. Very often, variable penetrance and expressivity are used synonymously. Penetrance is an

all or none phenomenon - either the abnormal phenotype is present or it is absent. If the phenotype is absent, then it is nonpenetrant. If the phenotype is apparent, then it is penetrant and can have variable expressivity.

The explanations for variable expressivity of a gene include:

The presence of modifier genes, (i.e., other genes within an individual's genome can interact with the abnormal gene to either increase or decrease its expression.

Heterogeneity, as previously discussed in recessive inheritance, can affect expression. A particular disease phenotype could be due to mutations in several different genes from different loci (locus heterogeneity) or it could be due to different mutations within one gene (allele heterogeneity), both causing different degrees of clinical severity.

Environmental factors can ameliorate or aggravate the disease process. Another explanation is pleiotrism. Pleiotropism refers to the multiple effects of a gene in different tissues or organs. Autosomal dominant traits are commonly pleiotropic. The diagnosis of Marfan syndrome is made based a triad of cardiovascular (aortic aneurysm, aortic insufficiency), skeletal (long limbs, fingers and toes, loose-jointedness), and eye (dislocated lens) findings. Although several organ systems are involved, the basic defect is an abnormality in the fibrillin protein, which is found in connective tissue. Multi-organ system involvement is also seen in such conditions as osteogenesis imperfecta (bones, teeth, sclera of the eye).

In autosomal dominant traits with complete penetrance, the chance that an affected person will have an affected child is 50%, providing the affected individual has an unaffected partner. There is also a 50% chance that the affected individual will have an unaffected child.

- X-Linked Inheritance Diseases caused by genes on the X-chromosome are said to be X-linked. Most X-linked diseases are recessive, but a few are X-linked dominant. In contrast to the X chromosome, the Y-chromosome is mostly inactive heterochromatin with a small active portion coding for the testis-determining factor.

Females have two X chromosomes and males have only one. In the XX female, one X chromosome in each cell becomes genetically inactive at an early stage in embryogenesis. The inactive X becomes a Barr body. The inactivation of the X chromosome is random. Generally, maternally and paternally derived X chromosomes are inactivated in equal numbers. Therefore, females produce X-linked gene products (e.g., factor VIII protein in hemophilia, creatine phosphokinase enzyme in Duchenne muscular dystrophy) in quantities roughly similar to males (dosage compensation).

Because males have only one X chromosome (hemizygous), the presence of an abnormal gene on the X chromosome is invariably expressed. However, in females who have two X chromosomes, the presence of one abnormal recessive gene is usually compensated by the presence of a normal gene on the other X chromosome (heterozygous). For this reason, Xlinked conditions like hemophilia or muscular dystrophy are expressed in sons and transmitted by physically normal carrier mothers.

The concept of dominance and recessiveness is not particularly relevant in X-linked inheritance. Whether dominant or recessive, an abnormal gene on the X chromosome in males is invariably expressed. A recessive gene in a carrier female is occasionally expressed due to the inactivation of a significant number of the X chromosomes containing the normal gene. By the same token, a dominant trait in a carrier female can escape expression because of inactivation of a majority of the X chromosomes with the abnormal gene.

Since the X chromosome inactivation is random, it is just as likely that either the normal X or the abnormal X is inactivated. At the gene level, the cell either does or does not produce a gene product. Since an organ (e.g., the liver) originates from a small cluster of cells, by chance alone, a large number of the cells within the organ could have a normal functioning X (or an abnormal functioning X). Thus, X chromosome inactivation, or lyonization, creates normal cells and abnormal cells depending on whether the normal X or the abnormal X is active, on average, 50% of each. The extreme, however, is possible. While unlikely, it is possible that X chromosome inactivation will result in the formation of 90% abnormal cells and 10% normal cells. There are well-documented reports of female hemophilia carriers who produce very low levels of factor VIII and for practical purposes can be considered mild hemophiliacs. Thus lyonization can modify the expression of abnormal genes, whether dominant or recessive, on the X chromosomes in females.

In most cases women who carry X-linked recessive disease genes are physically normal. There is a 50% chance with each pregnancy that a carrier female will pass on the abnormal recessive gene. With a Y-chromosome from her partner, she will have an affected son. With an X-chromosome from her partner, she will have a carrier daughter. There is also a 50% chance that a carrier female will pass on the normal X gene. If this is the case, her son will not be affected and her daughter will not be a carrier. Affected males have normal offspring. Their sons, receiving the Y, are free of the trait. Their daughters, receiving the abnormal X, are obligate carriers.

- Non-traditional (Non-Mendelian) Patterns of Inheritance

The rules set by Mendel have survived the test of time. Concepts of autosomal dominant, autosomal recessive, and X-linked genetic patterns of transmission remain valid. However, numerous inconsistencies have been observed, and the recent discoveries provide insight into the genetic basis of some of these concepts.

1- Mosaicism Mosaicism refers to the presence of two or more distinct cell lines, one normal and one abnormal. This was first recognized in chromosomal disorders. Fifty percent of women with Turner syndrome, for instance, have 45,X in all of their cells. The other 50% have mosaicism, with chromosomally normal cells and abnormal cells in varying proportions. Conditions associated with hemihypertrophy or hemihyperplasia, where one side of the body is bigger than the other side, have also been shown to be caused by chromosomal mosaicism.

2- Imprinting Imprinting refers to modification of the gene as it is transmitted through the father or the mother. In mice studies, imprinting is well recognized, probably as a mechanism to guard against parthenogenesis (self-fertilization). Using pronucleus transplantation, mouse zygotes can be constructed containing both paternal (sperm) pronuclei, or both maternal (egg) pronuclei. With both paternal pronuclei, a relatively well developed placenta, but poorly developed embryo, results. With both maternal pronuclei, an embryo develops with a very small placenta leading to early loss. The human counterpart is ovarian teratoma or dermoid tumors when the two sets of chromosomes are maternal in origin, or a hydatidiform mole when the two sets of chromosomes in the fertilized egg are paternal in origin.

Prader-Willi (PWS) and Angelman (AS) syndromes exemplify the concept of imprinting. Both conditions are due to a deletion of the same chromosomal segment, 15q11-12. If the 9

deleted chromosome 15 is paternal in origin, the patient will have PWS. If the deleted chromosome is maternal in origin, the patient will have AS. For the deletion to have a different clinical effect, when transmitted from the father or the mother, suggests that there must be some modification of the chromosome segment that occurs as it passes through paternal or maternal meiosis.

3- Uniparental Disomy Uniparental disomy (UPD) refers to a pair of chromosomes being inherited from one parent. Uniparental isodisomy refers to both chromosomes coming from one parent carrying identical genes (from one grandparent). Uniparental heterodisomy refers to a pair of chromosomes coming from one parent but carrying different genes (from both grandparents). About 20-30% of individuals with PWS show no deletion on chromosome analysis, FISH or DNA studies. In these instances, both number 15 chromosomes are of maternal origin, i.e., no paternal contribution. This makes it analogous to PWS, which occurs, secondary to a paternal deletion of 15q11. The maternal uniparental disomy (and, therefore, the absence of a paternally imprinted chromosome 15) creates clinical features of Prader-Willi syndrome.

Uniparental disomy is presumed to occur in a zygote that, at conception, had three copies of chromosome 15. These trisomic conditions are ordinarily not compatible with life. Survival of the embryo occurs following the random loss of the third chromosome with resulting UPD.

4- Triplet Repeats A number of conditions have been associated with triplet repeats (3 DNA bases), a feature normally present in the genome. The three bases (e.g., CAG, CTG or CGG) are repeated sequentially and are of varying lengths in normal individuals. However, the number of triplet sequences increases above the expected range in individuals with certain genetic conditions. These triplet repeats are found close to the beginning, within, or close to the end of a gene.

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The function of these repeated DNA sequences is not clearly defined. As the triplet repeat is passed on to subsequent generations, it can undergo expansion in size and result in earlier onset (anticipation) or more severe disease in the offspring.

1- Fragile X syndrome is associated with CGG repeats. Among normal individuals, the number of CGG repeats is between 6 and 40. Unaffected carriers, who carry a premutation, have between 50-200 copies of the CGG repeats. Affected individuals with the full mutation, have over 200-1,000 CGG repeats.

2- Huntington disease (HD), associated with CAG repeats, is an adult onset neurodegenerative condition affecting mainly the basal ganglia. Persons with HD develop a movement disorder (choreoathetoid or dance-like movement) and dementia. Their life span, on average, is 15 years after the onset of symptoms. The number of triplet repeats in normal individuals is 11-34. Individuals with HD have 39 repeats or more. Those with repeats in the 60 70 range have a juvenile onset HD. Most individuals with juvenile expression of HD inherit the gene from their father, following an expansion of the triplet repeat, which is more likely to occur in male meiosis.

3- Myotonic dystrophy is associated with an increase in the number of CTG repeats. Myotonia refers to the inability to relax following muscle contraction, (i.e., opening a clenched hand or extending a flexed elbow). Often, there is associated frontal balding, testicular atrophy, and subsequent weakness. Considered a dominant trait, both males and females are affected. The normal number of CTG repeats is 5-30. There is a gray zone of 3070 repeats where there is potential for expansion during meiosis. Affected individuals have more than 70 repeats. The peculiarity of this condition is the occurrence of congenital myotonic dystrophy among newborns inheriting the condition from the mother, a phenomenon not observed when the condition is inherited from the father.

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5- Contiguous Gene Syndromes Contiguous gene syndromes are conditions that occur secondary to microdeletions or microduplications involving several neighbouring genes. The occurrence of mental retardation in individuals with syndromes normally associated with normal psychomotor development (the gene for neurofibromatosis was discovered on 7q because a chromosome abnormality was seen in a mentally retarded person with NF), or the association of ordinarily distinct entities (Di-George syndrome and velo-cardio-facial syndrome on 22q), should trigger a request for a high resolution chromosome study and/or FISH or molecular DNA studies to rule out a microdeletion or microduplication. Examples of contiguous gene syndromes are: cri-du-chat, Wolf-Hirschhorn syndrome, , retinoblastoma, Miller-Dieker syndrome, DiGeorge syndrome, velo-cardio-facial syndrome, and Smith-Magenis syndrome.

6- Mitochondrial Inheritance There are a few rare conditions due to abnormalities of mitochondrial DNA (mtDNA). Mitochondria are organelles in the cytoplasm that provide energy for cellular metabolism through a process called oxidative phosphorylation. There are several hundred mitochondria per cell, which replicate independent of the nucleus. Mitochondrial inheritance is characterized by great variability depending on the number of abnormal versus normal mitochondria within the cell. Since the mitochondria are inherited from the cytoplasm of the egg, it has a vertical mode of inheritance. Mitochondrial DNA abnormalities can affect both males and females; however, they are inherited solely from the mother. Examples of mitochondrial DNA abnormalities include: LHON - Leber hereditary optic neuropathy; MELAS - mitochondrial encephalomyopathy, lactic acidosis, and stroke like episodes; and MERRF - myoclonic epilepsy with ragged red fibers.

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7- Multifactorial Inheritance The most common cause of genetic disorders is multifactorial or polygenic inheritance. Traits that are due to the combined effects of multiple genes are polygenic (many genes). When environmental factors also play a role in the development of a trait, the term multifactorial is used to refer to the additive effects of many genetic and environmental factors. Expression of these traits may follow a normal, or "bell-shaped," curve. Examples of multifactorial traits include cleft lip and palate, congenital hip dislocation, schizophrenia, diabetes and neural tube defects such as spine bifida.

Multifactorial conditions tend to run in families, but the pattern of inheritance is not as predictable as with single gene disorders. The chance of recurrence is also less than the risk for single gene disorders. The degree of risk of a multifactorial disorder occurring in relatives is related to the number of genes they share in common with the affected individual. The closer the degree of relationship, the more genes in common. The degree of risk also increases with the degree of severity of the disorder.

Although multifactorial conditions run in families, the risk is generally less than the 25% or 50% seen in Mendelian conditions. Identical twins, who are exactly alike genetically, do not always have the same condition when inheritance is multifactorial. This indicates that there are non-genetic factors that also play a role in the expression of multifactorial traits. For instance, the risk of coronary heart disease increases with smoking or obesity. The risk of emphysema in individuals with alpha-1-antitrypsin deficiency increases greatly with smoking. Maternal ingestion of valproic acid increases the risk of spine bifida. Maternal alcohol abuse or uncontrolled diabetes increases the risk of having a child with a congenital heart defect. Empiric risks are used to predict the recurrence of a multifactorial disorder. This is a risk that is based on epidemiologic and population studies and on mathematical models.

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