Mendelian Laws of Inheritance
Gregor Mendel described the basic tenets of inheritance through his studies of peas in the 19th century. Although chromosomes and genes were yet to be discovered, Mendel’s Laws of Heredity are now applied to human traits and disease, many of which follow mendelian inheritance.
The Law of Segregation:
The two copies of an individual’s genes (the two homologous chromosomes) separate during meiosis such that each gamete has only one copy of each chromosome and one copy of each gene.
The Law of Independent Assortment:
Genes that are not linked (i.e., not too close together on the chromosome) are inherited independently of each other, because the maternal and paternal chromosomes exchange genetic material (homologous recombination) during meiosis I. This process ensures genetic diversity in each subsequent generation.
Autosomal Dominant Inheritance
Typical Characteristics of Autosomal Dominant Inheritance
- Successive generations are affected (vertical transmission).
- Males and females are affected with equal frequency and severity.
- The disease is transmitted to subsequent generations by females as well as males (Figs. 5.1 and 5.2).
Figure 5.1.Typical Pedigree of an Autosomal Dominant Disorder.
Figure 5.2.Inheritance Pattern of an Autosomal Dominant Disorder.
- Male-to-male transmission of trait occurs.
As discussed in detail in Section 4.2, a disorder/mutation is called dominant if heterozygosity for a genetic variant causes a clear pathological phenotype. The normal (wild-type) allele, on its own, is not sufficient to secure normal function. Half of the germ cells generated by an individual who is heterozygous for a disease-causing mutation will harbor this mutation, while the other 50% of germ cells will harbor the normal wild-type allele.
Statistically, half of the offspring receive the mutated allele and will also be affected by the disorder. If the partner of the affected person happens to have the same disorder (which is generally unlikely, yet is seen frequently in some disorders such as achondroplasia, Section 26.2), 25% of the offspring will be homozygous (or compound heterozygous) mutation carriers. The clinical consequences depend on the disorder and are, in most cases, considerably more severe than with heterozygous affected individuals (Section 4.2).
Penetrance and Expressivity
As already mentioned in Chapter 4, there is not always a direct connection between the genotype and the manifest phenotype. The term penetrance is used to describe the probability with which a carrier of a “dominant mutation” will actually show signs of the disorder. For example, not all women who carry a BRCA1 gene mutation will develop breast or ovarian cancer, and therefore the penetrance is said to be incomplete.
Incomplete penetrance may explain the occurrence of a dominant disorder in a grandparent and a grandchild, with apparent skipping of one generation. It should be noted that penetrance of some disorders is closely linked to age. An example is Huntington disease (Section 31.1.1), where mutation carriers are normally free of symptoms at a young age but will, with certainty, become symptomatic before they reach old age (complete yet age-dependent penetrance).
The term expressivity refers to the variability of a genetic disorder leading to the spectrum of symptoms in a particular patient. Most dominant disorders show variable expressivity, meaning that the clinical presentation varies between different mutation carriers even within the same family. The clinical picture may be influenced by other (usually unknown) genetic factors (a phenomenon called epistasis), by gene–environment interactions, or by chance events.
For example, whether a BRCA1 gene mutation carrier will develop breast or ovarian cancer may be, to a large degree, due to chance additional mutation events. In most dominant disorders, it is not possible to predict the exact clinical presentation in an affected child.
De novo Mutations
Many autosomal dominant disorders occur sporadically, which means that healthy parents have an affected child. This occurs when the mutation is de novo (new) in the affected child. In some conditions, all affected individuals have de novo mutations, because the disorder is incompatible with life and there are no affected persons who could have an affected child; one example is osteogenesis imperfecta type II (caused by mutations in the gene encoding type I collagen), which is lethal perinatally.
Other conditions do not interfere with reproductive fitness and are frequently inherited from a parent; an example is osteogenesis imperfecta type I, the “mild” form of collagen I deficiency (Section 4.2). It is important to keep in mind that de novo mutations may arise at any stage during germ cell development (more frequently in the male than in the female germ line) and that, because of germline mosaicism (Section 4.4), later siblings of an affected child with a de novo mutation may inherit the same mutation even though it is not found in the blood of either parent.
De novo mutations are not observed in trinucleotide repeat disorders (such as fragile X syndrome); nonaffected ancestors may, however, harbor an unstable repeat and, while not clinically affected, are predisposed to transmit an expanded allele. These individuals are known as premutation carriers.
Examples of Disorders with Autosomal Dominant Inheritance
– most familial cancer predisposition syndromes (e.g., familial breast and colon cancer, retinoblastoma)
– most trinucleotide repeat disorders (e.g., Huntington disease, myotonic dystrophy)
– familial hypercholesterolemia
– most forms of osteogenesis imperfecta
Autosomal Recessive Inheritance
Typical Characteristics of Autosomal Recessive Inheritance
- Horizontal pattern in a pedigree; the disorder occurs only in one generation, not in successive generations. Several children of one couple are affected.
- The disorder affects males and females with equal frequency and severity.
- The disorder is transmitted by phenotypically healthy parents to affected offspring. The parents are heterozygous (carriers) for a disease-causing mutation.
- The disorder occurs in higher frequency in the offspring of consanguineous couples (e.g., first-cousin marriage) (Figs. 5.3 and 5.4).
Figure 5.3.Typical Pedigree of an Autosomal Recessive Disorder.
Figure 5.4.Inheritance Pattern of an Autosomal Recessive Disorder.
A heterozygous carrier for a recessive mutation has a 50% probability of transmitting this mutation to a child. If both partners are heterozygous carriers for the same autosomal recessive disease, the risk for transmission to offspring is as follows: 25% of the offspring of the couple will be homozygous (or compound heterozygous) for the disease-causing allele and thus be affected by the disorder, 50% of the offspring will be healthy heterozygous carriers just as their parents, and 25% will be homozygous for the wild-type allele. When speaking of the children of carrier parents, two-thirds of the healthy siblings of an affected child are heterozygous carriers.
If an individual with an autosomal recessive disorder has children, a disease-causing mutation will be transmitted to all of them (either of the two mutant alleles). The consequences for the child depend on this individual’s partner. If the partner is homozygous for the normal allele of the respective gene (as in the majority of cases), all offspring will be nonaffected heterozygous carriers. If the partner, however, is a carrier (the likelihood is approximately 0.5% to 1% for the more frequent recessive disorders), statistically, half of the offspring will be affected (homozygous or compound heterozygous), and the other half will be carriers. If both partners should have the same recessive disorder (caused by mutations in the same gene), all offspring will be homozygous/compound heterozygous and affected.
The phenomenon that different mutations in the same gene (allelic mutations) may cause the same disorder.
The phenomenon that some clinically defined disorders may be caused by a deficiency of different genes (loci), meaning the absence of different proteins causes the same phenotype.
The possibility of locus heterogeneity is an important phenomenon that needs to be taken into consideration when two persons with the “same” autosomal recessive condition are planning to have children. If the disease in the partners is caused by (homozygous) mutations in different genes, the child will be heterozygous for mutations at both loci but him- or herself will not be affected. This is a common observation in some conditions, such as autosomal recessive deafness.
In rare cases one of the parents of a child with a recessive disorder is not a carrier for the mutation(s) found in the offspring. This can have several causes, including (1) nonpaternity, meaning the assumed father is not the biological father; (2) a de novo occurrence of a deletion, which encompasses the gene of interest; (3) uniparental disomy of a chromosome that contains a recessive mutation; and (4) rarely, a de novo mutation of the gene of interest. The most frequent of these is nonpaternity.
Examples of Disorders with Autosomal Recessive Inheritance
- most inborn errors of metabolism (e.g., phenylketonuria, galactosemia, hemochromatosis, Gaucher disease, Tay-Sachs disease
- Smith-Lemli-Opitz syndrome)
- 21-hydroxylase deficiency (i.e., congenital adrenal hyperplasia)
- cystic fibrosis, spinal muscular atrophy
- sickle cell disease, ?-thalassemia
- ataxia telangiectasia.
Typical Characteristics of X-Chromosomal Inheritance
- Males are severely affected; sometimes the disorder in males is incompatible with life.
- Clinical symptoms in females are variable depending on the disease mechanism and the individual X-inactivation pattern; females may be asymptomatic carriers.
- A heterozygous (carrier) female transmits the disease-causing mutation to 50% of her sons and 50% of her daughters.
- A hemizygous (affected) male transmits the disease-causing mutation to all of his daughters and none of his sons (Figs. 5.5 and 5.6).
Figure 5.5.Typical Pedigree of an X-Chromosomal Disorder with Asymptomatic Carrier Females.
Figure 5.6.Inheritance Pattern of an X-Chromosomal Disorder.
As discussed in Section 2.8, males have only one X chromosome and are therefore hemizygous for all X-chromosomal variants outside the pseudoautosomal region. A mutation in a typical X-linked gene is, thus, expressed in all cells of the body. In contrast, females have two X chromosomes and are, thus, either heterozygous or homozygous for X-chromosomal variants. Because of X inactivation in females, only one X chromosome is active in each cell, and a typical X-linked heterozygous mutation is expressed only in a proportion of cells (on average 50%). Thus, the female is a functional mosaic for X-chromosomal traits.
The clinical picture of an X-chromosomal disorder depends on the pathogenic mechanism and, in females, is influenced by the variability or compensatory mechanism of X inactivation. A mutation that causes cell death will be lethal for male embryos in an early stage of postzygotic development. In females, such a mutation typically causes the loss of all cells that express the mutant copy of the gene, while the other cells may develop normally.
A female may show signs of X-chromosomal mosaicism, as in incontinentia pigmenti (Section 4.4), or may be clinically normal with completely skewed X inactivation (Section 2.8). If (as in fragile X syndrome, Section 31.2.2) the mutation disturbs cellular function but does not cause cell death, hemizygous males are severely affected while females show variable symptoms, ranging from asymptomatic to severe, depending on the individual X-inactivation pattern. Mothers of boys frequently show skewed X inactivation (favoring the wild-type allele), sometimes explained by ascertainment bias, as females with an unfavorable X-inactivation pattern may be less likely to have children.
Different consequences, again, may be expected if a deficiency of an X-chromosomal gene in a cell may be compensated for by neighboring cells, as is the case for secreted proteins or some metabolic functions. Hemizygous males will show the typical disease picture (which, in the individual case, may be variable depending on the specific mutation), while heterozygous females are usually asymptomatic or may show minor disease manifestation due to unfavorable X inactivation. Notable examples are the hemophilias (Section 21.6) and ornithine transcarbamylase deficiency, the most common urea cycle disorder (Section 24.1.3).
Because of the variable clinical presentation in heterozygous females, the terms recessive or dominant should not be used in relation to X-chromosomal disorders. We would also argue, as Mendel did, that these terms refer to the functional relationship of two different alleles in the heterozygous individual and, thus, cannot apply to X-chromosomal genes of a cell, as only one X chromosome is functionally active in males and females alike. The term X linked is sufficient to explain both the peculiarities of disease expression in females and the inheritance patterns within families.
A male patient with an X-chromosomal disorder will transmit his only X chromosome, which contains the mutation, to all of his daughters. All daughters are obligate heterozygotes and may be either asymptomatic carriers or have variable (less severe) symptoms of the disorder. On average, 25% of the daughters’ children (50% of her sons) will be affected with the disorder of their grandfather, 25% of children (50% of her daughters) will be heterozygous females, while 50% of the children will inherit the normal allele from their mother. All sons of an affected male will have inherited the Y chromosome of their father and, therefore, will not be affected and will not transmit the disorder to their children.
As for many conditions, when evaluating an individual with an X-linked disorder, the family’s medical and developmental history may be inconclusive or completely negative for additional persons affected with the disorder. In this instance, the occurrence of a de novo mutation must be taken into consideration. Due to the pathophysiology of spermatogenesis, a new mutation is more likely to occur in the male germ line rather than in the female germ line.
This implies that the mother of an affected boy can be a carrier for the disease. As for any condition, the individual affected with the condition should be tested first. If a mutation is identified in a male affected with an X-linked disorder, his mother should be tested, even in the absence of signs, symptoms, or positive family history. As germline mosaicism can also occur in X-linked disorders, there is a small (?6%) risk of recurrence, even if the mother has a negative DNA analysis; thus, prenatal mutation analysis should be considered.
Examples of Disorders with X-Chromosomal Inheritance
- muscular dystrophy types Duchenne and Becker
- hemophilias A and B
- Lesch-Nyhan syndrome
- ornithine transcarbamylase deficiency
- fragile X syndrome
- color blindness, and incontinentia pigmenti.