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Understanding Genetic Variance and Phenotype Expression

VARIANTS

A sequence variant¹ can be a permanent alteration in the DNA sequence that makes up a gene in such a way that the sequence differs from what is found in most people. Variants range in size; they can affect anywhere from a single DNA building block (base pair) to a large segment of a chromosome that includes multiple genes. Several types of variants can cause disease. A single-base modification is a change in a single DNA base—a single-nucleotide polymorphism—and is the most common kind of variant. The change can be a missense, nonsense, or frameshift mutation. A missense mutation is the replacement of one base with another that can cause disease if the variant results in the substitution of a different amino acid in the resulting protein and a consequent change in function. A nonsense mutation changes one base of a three-base codon for an amino acid to a premature stop codon and results in a truncated and usually nonfunctional protein. A frameshift mutation is caused by insertions or deletions of a number of nucleotides not divisible by 3 and changes the reading frame of the gene in such a way that the original amino acid sequence of the protein is lost from the mutation onward (Guttmacher and Collins, 2002). Variants found in germline cells are inherited because gametes are derived from those cells.

Variants can have several effects on function. A variant in the protein-coding region that does not change the specific amino acid sequence specified is not expected to have a phenotypic effect. However, although one might not think that a given variant would directly change an encoded amino acid sequence, it might change pre-mRNA splicing (processing of the RNA that carries protein sequence information from the DNA) and thereby indirectly have profound effects on the encoded amino acid sequence—and it is not always easy to predict whether or how splicing will be changed. Some variants that call for different amino acids might affect the function of the protein only slightly, and others might cause major changes in protein function; the effect would depend on the nature of the specific amino acid change and its position in the protein. Health effects are caused by such changes in protein function. Most common is the loss of function of a protein. Sometimes, the function of a mutant protein changes in such a way that it acquires a new toxic role, in some cases even antagonizing the normal protein. In some rare cases, variants can reduce the risk of disease; an example is a frameshift mutation in the CCR5 gene that results in resistance to HIV type 1 infection (although the beneficial effect may be accompanied by a more subtle deleterious effect). In addition to affecting protein function, variants can disrupt parts of DNA that control the regulation of gene expression—time, place, and so on (Guttmacher and Collins, 2002).

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¹ The neutral term variant is used instead of mutation or polymorphism to avoid confusion about pathogenicity (Richards et al., 2015).

Somatic Variants and Cancer

Although a predisposition to cancer can be inherited through the germline cells, variants in somatic cells (the “dead-end” cells of the body as opposed to germline cells that pass on DNA to offspring) can accumulate throughout a lifetime and cause sporadic cancer. Variants occur as cells multiply and tissues grow, especially in highly proliferative tissues, such as intestinal epithelia, providing a selective growth advantage to mutant cells. Variants that affect cellular proliferation, survival, or invasive potential can cause cells to multiply uncontrollably to form a neoplasm.

Penetrance and Expressivity

The degree to which a given genetic variant has consequences for a particular person’s phenotype reflects the qualities of penetrance and expressivity. Penetrance is the probability that a person who has the variant will express a phenotypic difference; expressivity is the magnitude of the phenotypic difference (Nussbaum et al., 2016). Those issues are important in diseases that are associated with single-gene disorders, specifically autosomal dominant and sometimes autosomal recessive diseases. Both kinds of diseases reflect the variability in phenotypes associated with a given genetic variant, which can be caused by uncontrolled environmental differences, differences in other modifier genes, or simply stochastic effects (NIH, 2016).

A genetic variant with reduced penetrance will cause disease only in some people. For example, many people carry variants in the BRCA1 and BRCA2 gene, but not all will develop cancer. Reduced penetrance makes the use of genetic information for risk prediction difficult (NIH, 2016). Most genes that have been associated with common diseases have been identified as a result of their high degree of penetrance, such as the genes that contribute to the development of hereditary nonpolyposis colorectal cancer and Huntington’s disease, but they are relatively rare (low in prevalence) in the general population. In contrast, some genes that have been associated with diseases have low penetrance but are more frequent (high in prevalence) in the population), such as variants in the APC gene associated with increased risk of colorectal cancer (Gutmacher and Collins, 2002).

A gene or variant can also express different signs or symptoms in different people (variable expressivity) and can lead to mild symptoms in some people and severe complications in others (NIH, 2016).

Single-Gene Diseases

Single-gene diseases are caused by pathogenic variants in individual genes on one or both chromosome and follow a pattern of autosomal recessive, autosomal dominant, or X/Y-linked Mendelian inheritance in families (Nussbaum et al., 2016). Examples of disorders caused by changes in single genes are Huntington’s disease (caused by a change in HTT), cystic fibrosis (a change in CFTR2), and sickle-cell anemia (a change in HBB). Single-gene pathogenic variants often can result in many phenotypic effects on a variety of organ systems; for example, a variant in the VHL gene² could result in effects in the brain, spinal cord, retina, kidney, pancreas, and reproductive system (Nussbaum et al., 2016).

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² The VHL gene provides instructions for making a protein that functions as part of a complex (a group of proteins that work together) called the VCB-CUL2 complex. This complex targets other proteins to be broken down (degraded) by the cell when they are no longer needed. Protein degradation is a normal process that removes damaged or unnecessary proteins and helps to maintain the normal functions of cells (NLM, 2016).

Dominant and Recessive

A variant is considered dominant if its phenotype is expressed in heterozygotes. Truly dominant variants are rare, but they are observed when heterozygotes and homozygotes for a variant have the same phenotype, such as Huntington’s disease. Semidominant and incompletely dominant are used to describe a situation in which heterozygotes have an abnormal phenotype but the phenotype is less severe than the phenotype expressed in homozygotes. In codominant inheritance, two alleles of a gene are expressed, and each version makes a slightly different protein with the potential to have a measurable influence on the genetic trait or to determine the characteristics of the genetic condition (e.g., ABO blood group). The term recessive is used to describe a trait that is expressed only in homozygotes in which both copies of a defective allele are present (Nussbaum et al., 2016). It should be noted that characterization of variants as recessive or dominant can depend on the particular phenotypic or molecular assay one uses and especially on its sensitivity.

Autosomal Recessive

Autosomal recessive single-gene diseases occur in people who have two mutant alleles of the disease-associated gene (no wild-type allele) (Chial, 2008). A person who has an autosomal recessive single-gene disease inherits one mutant allele of the disease-associated gene from each parent. Examples are phenylketonuria, cystic fibrosis, and sickle-cell anemia (Nussbaum et al., 2016).

Autosomal Dominant

Autosomal dominant single-gene disorders occur in people who have a single mutant copy of the disease-associated gene and a normal copy. One mutated copy of the gene in each cell is sufficient for a person to be affected by an autosomal dominant disorder. In some cases, an affected person inherits the condition from an affected parent (such as Huntington’s disease). In others, the condition may result from a variant in the gene that did not get transmitted from a parent with the disorder, either because of variable penetrance (the parent had the gene but not the phenotype of the disorder) or because the DNA change arose in the parental germline or the very young embryo (such as Marfan syndrome).

X-Chromosome–Linked Recessive

Single-gene diseases that involve genes found on the sex chromosomes have somewhat different inheritance patterns from ones that involve genes found on autosomes. The reason for the differences lies in the genetic distinction between males and females. Females have two copies of the X chromosome, and they receive one copy from each parent, as is true of autosomes. Therefore, females who have an X-chromosome–linked recessive disease inherit one copy of the mutant gene from an affected father and one copy from the mother, who is most often a carrier (heterozygous) but who might be affected (homozygous). Males, in contrast, have only one copy of the X chromosome, always from the mother, and the Y chromosome from the father is what makes them male, but it lacks copies of most genes present on the X chromosome. Therefore, males who have an X-chromosome–linked disease always receive the mutant copy of the gene from the mother. Because males do not have a second copy of the X chromosome to potentially “cancel out” the adverse effects of recessive X-linked variants, they are far more likely than females to be affected by X-chromosome–linked recessive diseases. X-linked recessive diseases include hemophilia and Duchenne muscular dystrophy (Chial, 2008).

X-Chromosome–Linked Dominant

X-linked dominant disorders are caused by variants in genes on the X chromosome. In females, a variant in one of the two copies of the gene in each cell is sufficient to cause the disorder. In males, a variant in the only copy of the gene in each cell causes the disorder. In most cases, males experience more severe symptoms of the disorder than females (e.g., fragile X syndrome). A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons, whether dominant or recessive (there is no male-to-male transmission). X-linked disease can occur rarely in females through a process called X-chromosome dosage compensation.

Y-Chromosome–Linked

A condition is considered Y-linked if the mutated gene that causes the disorder is on the Y chromosome. Only males have a Y chromosome, so Y-linked inheritance can be passed only from father to son, and it does not make a difference whether the Y-chromosome–linked variant is dominant or recessive, inasmuch as only one copy of the mutated gene is ever present. Examples of Y-linked disorders are nonobstructive spermatogenic failure, a condition that leads to infertility problems in males (Chial, 2008), and Swyer syndrome.

Mitochondrial

Mitochondrial inheritance is a form of strict maternal inheritance. It applies to genes in mitochondrial DNA that do not demonstrate typical patterns of Mendelian inheritance. Most of the cell’s DNA is contained in the nucleus, but mitochondria contain 37 genes that encode for molecules involved in oxidative phosphorylation. Because only egg cells contribute mitochondria to the developing embryo, only females can pass on mitochondrial variants to their offspring. Conditions that result from variants in mitochondrial DNA can appear in every generation of a family and can affect both males and females, but fathers do not pass the disorders to their daughters or sons (e.g., Leber hereditary optic neuropathy).

Chromosomal Disorders

Chromosomal disorders occur when there are extra, missing, or broken chromosomes or segments of chromosomes, as opposed to errors in the genes themselves. Chromosomal disorders affect about 0.7% of live births and cause about half of all spontaneous abortions (Nussbaum et al., 2016). The patterns of inheritance followed by chromosomal disorders carried in parents can be complex, but most chromosomal disorders are not carried in the parents but rather are generated by spontaneous changes in one parent’s germ cells (NIH, 2016).

Chromosomal abnormalities can be described as either numerical or structural (NHGRI, 2016b). For example, when a chromosome is missing from the pair, the condition or disorder is referred to as a monosomy, as in Turner syndrome, in which females are born with only one X chromosome (NLM, 2016). Most cases of monosomy X are not inherited and result from a nondisjunction event—the failure of paired chromosomes to separate during cell division in a parent’s reproductive cells—in which either both chromosomes or neither chromosome ends up in the daughter cell. In contrast with X-chromosome monosomy, autosomal monosomies are invariably lethal to the developing fetus. A trisomy occurs when three copies of the same chromosome are in the same cell rather than only the usual pair, as in trisomy 21 (Down syndrome). Most trisomies are lethal to the developing fetus.

Structural chromosomal abnormalities can be categorized as deletions, duplications, translocations, inversions, or rings (NHGRI, 2016b). A deletion is the loss of DNA from a chromosome whether large (such as a segment) or small (such as a single base). When a portion of a chromosome or a segment of a chromosome is duplicated, extra copies of the region or chromosome can produce different phenotypes and act as gene variants (Griffiths et al., 2000). A translocation occurs when a piece of one chromosome is relocated to another chromosome in a reciprocal translocation (segments from two chromosomes are exchanged) or in a Robertsonian translocation (an entire chromosome attaches to the centromere of another chromosome) (NHGRI, 2016b). In an inversion, a chromosome segment is reversed end to end (Nussbaum et al., 2016). Rings can form from a broken chromosome when telomeres of each arm are deleted and the broken arms reform as a circle (Nussbaum et al., 2016). In some cases, a parent who carries a chromosomal abnormality can have a normal balance of genes and show no abnormal phenotype, but genetic recombination or chromosome segregation in that parent’s germline generates gametes that have unbalanced complements of genes and thereby causes problems for the progeny.

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