Autosomal dominant

In an autosomal dominant mode of inheritance, only one copy of the variant gene is required for expression of the trait, and the individual is said to be heterozygous for the trait. There are more than 4000 known autosomal dominant conditions, and most occur in the heterozygous form in affected individuals. With a few exceptions, autosomal dominant conditions occurring in the homozygous form (two copies of the affected gene) are rare, the phenotype is more severe, and the conditions are often lethal. An example is achondroplasia, in which two copies of the variant gene result in a lethal condition.

The general characteristics of autosomal dominant inheritance are illustrated in Fig. 2.4 and summarized as follows:

• 1.
  

  Every affected individual has an affected parent (unless this is a new pathogenic variant—to be discussed later). The inheritance pattern is vertical.

  
  
• 2.
  

  If reproductively fit, the affected person has a 50% risk of transmitting the gene with each pregnancy.

  
  
• 3.
  

  The sexes are affected equally.

  
  
• 4.
  

  There is father-to-son transmission.

  
  
• 5.
  

  An individual who does not carry the pathogenic variant will have no risk of transmission to his or her offspring.

Example of autosomal dominant inheritance.

(Courtesy Edith Cheng, MD.)

Three additional properties associated with, but not exclusive to, autosomal dominant traits are variable expressivity, penetrance, and new pathogenic variants. Variable expressivity describes the severity of the phenotype in individuals who have the pathogenic variant. Some autosomal dominant conditions have a clear clinical demarcation between affected and unaffected individuals. However, some conditions express the clinical consequences of the pathogenic variant in varying degrees among members of the same family and between different families. These differences in expression are modified by age, the sex of the affected individual, the individual’s genetic background, and the environment. Variable expression of a condition can lead to difficulties in diagnosis and interpretation of inheritance pattern. Penetrance refers to the probability that a gene will have any clinical manifestation at all in a person known to have the pathogenic variant. A condition is 100% penetrant if all individuals with the pathogenic variant have any clinical feature of the disease (no matter how minor). A number of autosomal dominant conditions are the result of new pathogenic variants. For example, about 70% of achondroplasia cases occur as new variants. Because this condition has 100% penetrance, the recurrence risk in subsequent pregnancies in the normal parents of an affected child is extremely low, but the risk to the offspring of the affected is 50%. If an autosomal dominant condition is associated with poor reproductive fitness, then the likelihood that the cases occurred because of a new pathogenic variant is greater.

Autosomal recessive

Autosomal recessive conditions are rare and require the affected individual to have two copies of the pathogenic variant allele (homozygous) to manifest the condition. In the heterozygote carrier, the product of the normal allele is generally able to compensate for the pathogenic variant allele and prevent occurrence of the disease. Fig. 2.5 is a typical pedigree illustrating autosomal recessive inheritance. The following general statements can be made about an autosomal recessive trait:

• 1.
  

  The characteristic will occur equally in both sexes.

  
  
• 2.
  

  For an offspring to be at risk, both parents must have at least one copy of the pathogenic variant.

  
  
• 3.
  

  If both parents are heterozygous (carriers) for the condition, on average 25% of the offspring will be homozygous for the pathogenic variant and will manifest the condition and 50% will be carriers and will be unaffected. The remaining 25% will not have inherited the variant at all, will be unaffected, and will not be at risk of transmitting the variant to any offspring.

  
  
• 4.
  

  Consanguinity is often present in families demonstrating rare autosomal recessive conditions.

  
  
• 5.
  

  If the disease is relatively rare, it will be clustered among the siblings and will not be seen among other family members such as ancestors, cousins, aunts, and uncles.

Pedigree illustrating autosomal recessive inheritance. Here the parents of the affected children are first cousins, as denoted by the double line connecting them.

(Courtesy Edith Cheng, MD.)

Because autosomal recessive conditions require two copies of the pathogenic variant allele, and because most matings are not consanguineous, counseling couples about the risk for an autosomal recessive condition requires knowledge of the carrier frequency of the condition in the general population . Cystic fibrosis exemplifies the importance of knowing the population in which screening or counseling is being provided ( Table 2.2 ). Depending on the ethnic group of the mother and father, the risk for a child having cystic fibrosis could be as high as 1 in 1936 (1/22 × 1/22 × 1/4) if they are of Northern European descent or considerably less so if they are of Asian descent.

X-linked trait

The human X chromosome is quite large, containing about 160 million bps, or about 5% of the nuclear DNA. Of the 500 genes that have been mapped to the X chromosome, 70% are known to be associated with disease phenotypes. Diseases caused by genes on the X chromosome are said to be X linked, and most are recessive. In contrast, the Y chromosome is quite small, about 70 million bps, and contains only a few genes.

The expression of genes located on the X chromosome demonstrate a unique characteristic known as dosage compensation, a concept that was described by Mary Lyon in the 1960s to explain the equalization of X-linked gene products in men and women ( ). Achievement of dosage compensation is through the principles of X inactivation, also known as the Lyon hypothesis . The tenets of the Lyon hypothesis are as follows:

• 1.
  

  One X chromosome in each cell is randomly inactivated in the early female embryo (soon after fertilization).

  
  
• 2.
  

  The inactivation process is random: Either the paternally or maternally derived X chromosome is chosen. The woman is thus a mosaic for genes located on the X chromosome.

  
  
• 3.
  

  All descendants of the cell will have the same inactive X chromosome.

The Lyon hypothesis is supported by clinical evidence derived from animal and human observations of traits located on the X chromosome, such as the calico cat pattern of red and black patches of fur on female cats but not on male cats. In humans, men and women have equal quantities of the enzyme glucose-6-phosphate dehydrogenase (G6PD), which is encoded by a gene on the X chromosome. The mechanism for X inactivation is unknown at this time but clearly requires the presence of the X inactivation center, which has been mapped to the proximal end of the long arm of the X chromosome (Xq). This center contains an unusual gene called the X-inactive specific transcript (XIST), which seems to control X inactivation, a process that cannot occur in its absence .

The principles of the Lyon hypothesis remain true for the majority of genes located on the X chromosome. The silencing of these genes appears to occur as a function of DNA methylation at the promoter regions of these genes. However, several regions remain genetically active on both chromosomes. They include the pseudoautosomal regions located at the tips of the long and short arms , which are the regions that contain the genes for steroid sulfatase, the Xg blood group, and Kallmann syndrome (hypogonadism and anosmia). The pseudoautosomal region on the short arm shares extensive homology with the Y chromosome and is the region involved in the pairing of the X and Y chromosome at meiosis.

Another exception to the Lyon hypothesis is that one X chromosome is nonrandomly, preferentially inactivated. This is observed for most cases of translocations between an X chromosome and an autosome. If the translocation is balanced, the structurally normal X chromosome is preferentially inactivated. If the translocation is unbalanced, then the structurally normal X chromosome is always active. These nonrandom patterns of inactivation functionally minimize the clinical consequences of the chromosomal rearrangement. Studies can be done to look at patterns of inactivation, as in the case of prenatal diagnosis, to predict the clinical consequences of a de novo X/autosome translocation in the fetus.

Random inactivation confers a mosaic state for the female carrier. The normal allele is able to compensate for the abnormal allele (as in autosomal recessive traits), and female carriers of X-linked recessive conditions usually do not have clinical manifestations of the disease. Occasionally, however, there is a skewed, or less than 50/50, chance of inactivation such that the X chromosome carrying the normal allele is inactivated more frequently. In such cases, female carriers display some features of the condition and are referred to as manifesting heterozygotes . Manifesting heterozygotes have been described for hemophilia A, Duchenne muscular dystrophy, ornithine transcarbamylase deficiency, and X-linked color blindness. Genetic counseling of recurrence risks for an X-linked recessive condition depends on the sex of the affected parent and of the offspring. Fig. 2.6 is a pedigree illustrating X-linked recessive inheritance, the characteristics of which are the following:

• 1.
  

  Affected individuals are usually male unless X-chromosome activation is skewed in the female carrier or the individual is homozygous for the trait.

  
  
• 2.
  

  The affected men in a kindred are related through women.

  
  
• 3.
  

  The gene is not transmitted from father to son.

  
  
• 4.
  

  All daughters of affected men will be carriers.

  
  
• 5.
  

  Daughters of female carriers have a 50% chance of being carriers; sons of female carriers have a 50% chance of being affected.

Pedigree illustrating X-linked recessive condition.

(Courtesy Edith Cheng, MD.)

X-linked dominant inheritance

The major feature of X-linked dominant inheritance is that all heterozygotes, both male and female, manifest the condition . Although the pedigree may resemble autosomal dominant inheritance, the distinguishing feature is that affected men never have affected sons, and all daughters of affected men are affected. There are usually more affected women than men, and the majority of the women are heterozygotes. Examples of diseases with this mode of inheritance are hypophosphatemic rickets and Rett syndrome.

Trinucleotide-repeat disorders: Unstable repeated sequence variants

In the early 1990s a new class of genetic conditions was recognized as being caused by unstable dynamic variants in a gene. In classic genetic inheritance the diseases and their inheritance patterns are due to pathogenic variants that are passed on from generation to generation in a stable form. That is, all affected members in a family have the identical inherited variant. In 1991, however, a number of reports began to describe a new class of genetic condition in which the gene sequence variation was dynamic and changed with different affected individuals within a family. The most common group of disorders is known as triplet, or trinucleotide repeat, disorders. More than a dozen diseases are now known to be associated with unstable trinucleotide repeats ( Table 2.3 ) ( ).

These conditions are characterized by an expansion of variable size, within the affected gene, of a segment of DNA that contains a repeat of three nucleotides such as CAGCAGCAG (CAG)n, or CCGCCG (CCG)n. These triplet repeats are unstable in that they tend to expand as the gene is passed on from generation to generation. The molecular mechanism is most likely misalignment at the time of meiosis. The result of increasing triplet expansion is progressively earlier onset and/or more severe manifestation of disease with each successive generation. This phenomenon is known as anticipation.

The commonality of this group of genetic conditions stops at the shared molecular mechanism. Each disease, otherwise, has its own features. Some, such as myotonic dystrophy, are inherited in an autosomal dominant pattern, but others, such as Friedrich ataxia, are autosomal recessive conditions. The susceptibility of the triplet repeat to expansion also may depend on the parent of origin: It is typically more severe with paternal inheritance in Huntington disease and exclusively maternal in fragile X syndrome.

Fragile X syndrome

Fragile X syndrome, a disease within the unstable triplet repeat disorder group, is the most common heritable form of moderate intellectual disabilities and is second to Down syndrome among causes of intellectual disabilities in men. The affected gene (fragile X mental retardation 1, FMR1 ) is located on the X chromosome at Xq27.3, and triplet repeat expansion in the gene causes a pattern of abnormalities, including intellectual disabilities, characteristic facial features, and autistic behaviors. Disease frequency is approximately 1 in 4000 men and 1 in 8000 women. The condition is due to an expansion of the triplet repeat CGG located in the untranslated region of the first exon of the gene. The triplet expansion blocks normal function of the FMR1 gene, thus causing the syndrome. Fragile X is associated with maternal anticipation, meaning female carriers are at increased risk of passing on expanded repeated sequence variants to their children, whereas the repeated sequence variants in male carriers will not typically expand when passed on to their daughters . Risk of expansion may also be associated with the original size of the repeated sequence variant and the presence or absence of AGG repeats within the CGG expanded region ( ).

Individuals with normal X chromosome alleles have CGG repeats in the 6 to 44 range, whereas affected individuals have expanded “full mutations” of 200 to more than 1000 repeats. Individuals with 55 to 200 repeats are known as premutation carriers. Men are more likely to be affected with fragile X than women, and features of the condition tend to be milder in women than men. Individuals with 45 to 54 CGG repeats are known as intermediate carriers. Intermediate carriers are not at an increased chance to have children affected with fragile X syndrome. However, female intermediate carriers are at an increased chance to have children who are premutation carriers (14% risk of expansion). Premutation carriers are not usually affected with features of fragile X syndrome, but they are at increased risk for having affected children or descendants if the premutation expands to a full mutation in successive generations. Conversely, intermediate and premutation alleles can be passed on without expanding, and in rare instances, expanded alleles may even contract when inherited.

Long-term follow-up of premutation carriers has revealed that these individuals are at increased risk for certain adult-onset conditions separate from the fragile X syndrome. Male premutation carriers are at increased risk for fragile X–associated tremor/ataxia syndrome (FXTAS) later in life ( ). FXTAS may also occur in female premutation carriers, though more rarely. Female premutation carriers are also at increased risk for premature ovarian insufficiency (POI), which is the cessation of menses before age 40. In contrast, intermediate carriers are not at any increased risk to develop FXTAS or POI ( ).

Although the unstable triplet is transmitted in an X-linked pattern, the probabilities of the different phenotypes are far from traditional X-linked inheritance. Understanding the features of fragile X syndrome is crucial for genetic counseling and assessment of recurrence risks. The possible outcomes of the offspring of a premutation female carrier are the following:

• 1.
  

  Male offspring—three possibilities:

  
  
  
  
  • a.
    

    Unaffected: does not inherit the X chromosome with the premutation.

    
    
  • b.
    

    Unaffected: inherits the X chromosome with the premutation that did not expand. At risk for FXTAS and at risk for passing the premutation to daughters, who in turn will be at risk for having children who are premutation carriers or affected.

    
    
  • c.
    

    Affected: inherits an expanded full mutation.

  
  
  
  
• 2.
  

  Female offspring—four possibilities:

  
  
  
  
  • a.
    

    Unaffected: does not inherit the X chromosome with the premutation.

    
    
  • b.
    

    Unaffected: inherits the X chromosome with the premutation that did not expand to a full mutation. At risk for POI and FXTAS and at risk for having children who are premutation carriers or affected.

    
    
  • c.
    

    Unaffected: inherits the X chromosome with an expanded full mutation; about 50% of women with a full mutation appear to be clinically unaffected.

    
    
  • d.
    

    Affected: inherits the X chromosome with an expanded full mutation.

  
  

Genomic imprinting and uniparental disomy

Genomic imprinting and uniparental disomy refers to the differential activation or expression of genes depending on the parent of origin. In contrast to Mendel’s hypothesis that the phenotype of a gene is no different if inherited from the mother or the father, we now understand that there is a group of diseases in which the parent of origin of a gene or chromosome plays a role in the phenotype of the affected individual. The best-studied examples of this mechanism are Prader-Willi syndrome (PWS) and Angelman syndrome (AS). Both diseases arise from loss of function of the same gene on chromosome 15, but two different disease phenotypes arise depending on which parental allele is affected. PWS is characterized by obesity, hyperphagia, small hands and feet, hypogonadism, and mental retardation ( ). In about 70% of cases, cytogenetic deletion of the proximal arm of the paternally inherited chromosome 15 is observable (15q11-q13). In contrast, the same deletion of the maternally inherited chromosome 15 results in the Angelman phenotype of severe mental retardation, short stature, spasticity, and seizures ( ). Interestingly, 30% of subjects with PWS do not have a cytogenetic deletion but rather inherit two intact chromosomes 15 from the mother. No genetic information on chromosome 15 is inherited from the father. This is referred to as maternal uniparental disomy. Individuals with Angelman syndrome without a cytogenetic deletion have two copies of the paternally derived chromosome 15 and no chromosome 15 from the mother, a condition termed paternal uniparental disomy . These findings indicate that for the region of 15q11-q13, the expression of the PWS phenotype is brought on by the absence of a paternal contribution of the genes in this region. Likewise, the expression of Angelman syndrome is due to the absence of the maternal contribution of genes located at 15q11-q13. The genes in this region are said to be “imprinted” because their parent of origin has been “marked.”

Many regions of the human genome have now demonstrated evidence of imprinting. Knowledge of diseases that occur as a result of imprinting are important for clinical care because they have implications for prenatal diagnosis, especially when mosaicism is encountered.

Germline mosaicism

Mosaicism is defined as the presence of two or more genetically different cell lines in the same individual or in tissue derived from a single zygote. All women, because of X inactivation, are mosaics for genes on the X chromosome. Mosaicism, however, is not necessarily evenly or randomly distributed throughout the body. In other words, using the entire body as the whole organism, an individual is mosaic either because different organs or tissues have genetically different cells but each organ or tissue has the same cell line or because the genetically different cell lines are dispersed throughout many tissues in the body. The distinction between these two types of mosaicism is particularly important in making a prenatal diagnosis in cases in which mosaicism is identified in amniotic fluid cells. For instance, one cannot be confident that a fetus identified as having trisomy 21 mosaicism would necessarily have a less severe mental retardation phenotype because of mosaicism. The brain cells could potentially all contain full trisomy 21, but the cells of the skin could all be normal diploid. In germline mosaicism, the implication is that the pathogenic variant is present in only one parent and arose during embryogenesis in all or some of the germ line cells but few or none of the somatic cells of the embryo. This concept was developed to explain recurrence of a genetic condition in a sibship (usually autosomal dominant) in which incorrect diagnosis, autosomal recessive inheritance, reduced penetrance, or variable expression could not be the reason for the recurrence. The best example of germline mosaicism is osteogenesis imperfecta type II (lethal form). At the molecular level, the pathogenic variant causing the condition is dominant—that is, only one copy of the abnormal gene is necessary to cause this perinatal lethal condition. Yet there are families in which multiple affected pregnancies are seen in the same couple or one parent has recurrences with different partners. If the spontaneous pathogenic variant rate for an autosomal dominant variant is 1 chance in 10 ⁵ , then the probability of two independent spontaneous variants for the same lethal autosomal dominant condition is (1/10 ⁵ ) ² , a highly unlikely event. Germline mosaicism is now well documented for about 6% of cases of osteogenesis imperfecta type II ( ). Unfortunately, the exact recurrence risk in an individual family is difficult to assess because the proportion of gametes containing the pathogenic variant is unknowable.

Mitochondrial inheritance: Maternal inheritance

Most inherited conditions occur as a result of variants in the DNA of the nucleus (nuclear genome). However, mitochondria have their own DNA molecules, which contain a small fraction of genes whose products are vital to the function of the cell. Mitochondrial DNA (mtDNA), which was completely sequenced in 1981, is small, about 16.5 kilobase pairs (kb), and is packaged as a circular chromosome located in the mitochondria. A growing number of conditions resulting from abnormalities of the mitochondria have now been identified. Because the mitochondrial apparatus and its function are under the control of both nuclear and mitochondrial genes, many diseases affecting the mitochondria do not follow the typical Mendelian pattern of inheritance. Each human cell contains a population of several hundred or more mitochondria in its cytoplasm. Most of the subunits that make up the mitochondrial apparatus are encoded by the nuclear genome.

Because the primary function of the mitochondria is to provide energy for the cell in the form of adenosine triphosphate (ATP), genetic variants that affect the genes that code for oxidative phosphorylation will likely result in cell dysfunction and death. The organs most affected would be those that depend heavily on mitochondria. The diseases that result are generally neuromuscular in nature, such as encephalopathies, myopathies, ataxias, and retinal degeneration, but the genetic variants have pleiotropic effects, meaning multiple different clinical traits are caused by a single gene defect ( ).

The most significant characteristic of mitochondrial diseases caused by pathogenic variants in mtDNA is that they are all maternally inherited . This is because the cytoplasm of the ovum is abundant with mitochondria, but the sperm contain very few mitochondria. Therefore an individual’s mitochondria (and mtDNA) are essentially all inherited from the mother. If the mother has a mtDNA pathogenic variant, then all of her children will inherit that variant. When a pathogenic variant arises in the DNA of a mitochondrion in the cytoplasm of the ovum, it begins as one variant in one mitochondrion. However, as replication and division of this variant mitochondrion occur, they become randomly distributed among the normal mitochondria and between the daughter cells. One daughter cell by chance may contain a large population of mitochondria with the pathogenic variant, but the other may have none or very little. Fertilization of the egg with a large proportion of mitochondria containing the variant would result in an offspring at risk for manifesting a mitochondrial disease. Leber hereditary optic neuropathy (LHON) is a well-known mitochondrial disease in which rapid, bilateral loss of central vision occurs as a result of a pathogenic variant in mitochondrial DNA. Men and women are affected equally, and all affected individuals are related through maternal lineage.

A second feature of mitochondrial diseases is that of variable expression. Within each cell and tissue, there is a threshold for energy production below which the cells will degenerate and die. Organ systems with large energy requirements are most susceptible to mitochondrial abnormalities. Thus if an mtDNA pathogenic variant is present, the severity of the mitochondrial disease will depend on the proportion of mitochondria with the variant that the individual inherited from his or her mother and the susceptibility of different tissues to altered ATP metabolism.

In contrast, abnormalities of mitochondrial function caused by pathogenic variants of genes encoded in the nuclear genome will exhibit traditional Mendelian inheritance patterns; autosomal dominant, autosomal recessive, and X-linked patterns of mitochondrial disorders have been observed. A few mitochondrial diseases occur as sporadic somatic pathogenic variants and have little or no recurrence risk. Table 2.4 lists some of the known diseases of mitochondrial function and their inheritance patterns.

TABLE 2.4

Features of Some Disorders of Mitochondrial Function

Disease	Features	Genetics	Inheritance Pattern
Barth syndrome	Dilated cardiomyopathy, cyclic neutropenia, skeletal myopathy, growth deficiency, abnormal mitochondria	Nuclear DNA encoding mitochondrial protein tafazzin ( TAZ gene)	X linked
Friedreich ataxia	Limb movement abnormalities, dysarthria, absent tendon reflexes	Nuclear DNA encoding mitochondrial protein frataxin ( FXN gene, triplet repeat)	Autosomal recessive
Leber hereditary optic neuropathy (LHON)	Blindness, rapid optic nerve death in young adulthood	Mitochondrial DNA	Maternal
Leigh disease (subacute necrotizing encephalomyelopathy)	Infant-onset progressive psychomotor regression after viral illness, hypotonia, peripheral neuropathy, lactic acidosis	Many genes: 20%-25% mitochondrial DNA (includes neuropathy, ataxia, and retinitis pigmentosa [NARP])	Mitochondrial DNA: maternal
		75%-80% nuclear DNA	Nuclear DNA: autosomal recessive or X linked
MERRF	Myotonic epilepsy, ragged red fibers in muscle, ataxia, sensorineural deafness	Mitochondrial DNA	Maternal
MELAS	Mitochondrial encephalopathy, lactic acidosis, strokelike episodes, sensorineural deafness	Mitochondrial DNA	Maternal
MIDD	Maternally inherited diabetes and deafness	Mitochondrial DNA	Maternal
MNGIE	Mitochondrial neurogastrointestinal encephalopathy, childhood-onset gastrointestinal dysmotility, peripheral neuropathy	Nuclear DNA ( TYMP gene) causes destabilization of mitochondrial DNA	Autosomal recessive

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