Glossary

Glossary

Allele

An allele is one of two or more versions of a gene or DNA sequence at a particular place on a chromosome. A person inherits two alleles, one from each parent.

Anticipation

Anticipation describes a situation where a genetic condition appears at an earlier age with successive generations. The severity of the condition can also increase. This phenomenon is often seen in conditions caused by trinucleotide repeat disorders, such as Huntington disease, myotonic dystrophy and fragile X syndrome. In these cases, the number of trinucleotide repeats increase when it is passed from parent to child, which can result in earlier onset and more severe disease. 

For more information, refer to the MedlinePlus’ explanation ‘What do geneticists mean by anticipation?’ and ‘What are the different ways in which a genetic condition can be inherited?’ . 

Autosomal dominant inheritance

When a condition follows an autosomal dominant pattern of inheritance, the family tree will usually reveal multiple affected members in multiple generations on the same side of the family. Dominant conditions or traits are expressed when only a single gene variant Gene variants are small DNA sequence changes (ie additions, duplications, deletions, substitutions). These variants can have a range of effects: some may cause disease (pathogenic variant and gene mutation), while others do not cause disease but may modify an individual’s risk of disease (i.e may increase risk or provide a protective effect). The vast majority of gene variants are benign and do not result in disease but rather contribute to the differences between people.  is inherited. 

Wide variability in clinical expression is common in many autosomal dominant conditions, even within the same family. 

Early onset of conditions, such as cancer, can be indicative of autosomal dominant inheritance within a family. 

Not all dominant conditions show 100% penetrance Penetrance refers to the proportion of people with a particular genetic variant who will go on to develop the condition. For example, people carrying an autosomal dominant variant may not always develop the condition – this is called ‘incomplete penetrance’. If a condition is 100% penetrant, an individual will definitely develop the condition. If penetrance is 80%, most but not all individuals will develop the condition. Other genes and lifestyle factors, such as diet, exercise and smoker status, may affect the penetrance of some conditions. For more information, refer to MedlinePlus’ ‘What are reduced penetrance and variable expressivity?’ (eg BRCA1 gene mutations). 

Autosomal recessive inheritance

Autosomal recessive conditions affect either sex, and often occur in the absence of any family history. Recessive conditions or traits appear when an individual inherits two copies of pathogenic variants in the same gene Gene variants are small DNA sequence changes (ie additions, duplications, deletions, substitutions). These variants can have a range of effects: some may cause disease (pathogenic variant Pathogenic variant and gene mutation), while others do not cause disease but may modify an individual’s risk of disease (i.e may increase risk or provide a protective effect). The vast majority of gene variants are benign and do not result in disease but rather contribute to the differences between people.  (one from each parent).
 
Parents of a child with an autosomal recessive condition are usually asymptomatic carriers Recessive genetic conditions such as cystic fibrosis (CF) occur when a person inherits a particular genetic variant from each parent. A carrier is an individual who only has one copy of the gene variant and generally does not have symptoms, but can pass the variant to their children. Some conditions are due to a pathogenic variant in a gene on the X chromosome (X-linked inheritance). Typically, these conditions affect more males (who have the sex chromosomes XY) than females (who have the sex chromosomes XX). A woman who is a carrier of an X-linked condition has the variation on one of her X chromosomes, which she can pass on to her children. However, if the biological male has a pathogenic variant in an X chromosome gene, he will not pass it to his sons, but will pass it to all of his daughters. . The affected child has two copies of the particular gene change.
 
The recurrence risk of autosomal recessive conditions is one in four for each pregnancy.
 
Wide variability in clinical expression is common in many autosomal recessive conditions. Autosomal recessive conditions are more common when the parents are consanguineous. 

Balanced translocation

A balanced translocation is a rearrangement of the chromosome with no apparent loss or gain of chromosomal material. Individuals with balanced translocations do not usually show any symptoms.

Carrier

Recessive genetic conditions such as cystic fibrosis (CF) occur when a person inherits a particular genetic variant from each parent. A carrier is an individual who only has one copy of the gene variant Gene variants are small DNA sequence changes (ie additions, duplications, deletions, substitutions). These variants can have a range of effects: some may cause disease (pathogenic variant), while others do not cause disease but may modify an individual’s risk of disease (i.e may increase risk or provide a protective effect). The vast majority of gene variants are benign and do not result in disease but rather contribute to the differences between people.   and generally does not have symptoms, but can pass the variant to their children.
 
Some conditions are due to a pathogenic variant in a gene on the X chromosome ( X-linked inheritance Since a male inherits only one X chromosome (from his mother), when he has a pathogenic variant in a gene on the X-chromosome, he will have that condition. Males are usually more often and more severely affected because of X-inactivation in females. Since a male only passes his Y chromosome to his sons, there is no male-to-male transmission of X-linked conditions. With each pregnancy, females who are carriers of a pathogenic variant in a gene on the X-chromosome have a one-in-two chance of passing on the variant to each child. Sons who inherit the variant will be affected and daughters who inherit the variation will be carriers like their mothers. Daughters of affected males can only inherit the pathogenic variant from their father and are known as ‘obligate carriers’. ). Typically, these conditions affect more males (who have the sex chromosomes XY) than females (who have the sex chromosomes XX). A woman who is a carrier of an X-linked condition has the variation on one of her X chromosomes, which she can pass on to her children. However, if the biological male has a pathogenic variant in an X chromosome gene, he will not pass it to his sons, but will pass it to all of his daughters. 

Carrier screening

Carrier screening is a test to determine whether an individual carries a genetic variant that does not generally affect that individual’s health, but increases his or her chance of having children with the condition in question. The outcome of such testing can influence future reproductive decisions. Carrier screening is performed on individuals who are not necessarily known to be at increased risk for a particular genetic condition. Screening tests can be conducted on individuals from specific groups such as those from a common ethnic background (eg: screening for Tay-Sachs disease carrier status in the Ashkenazi Jewish community) or entire populations. 

Cascade screening

Cascade screening involves testing the close biological relatives of an individual who has or is a carrier of a genetic condition in order to determine whether these relatives carry the genetic variant or chromosomal alternation (thereby increasing their chances of developing the condition or having a child with the condition). For example, cascade testing is available under the Medicare Benefits Schedule for genetic testing for familial hypercholesterolaemia

Compound heterozygote, compound heterozygous and compound heterozygosity

A compound heterozygote is an individual with two different alleles at a particular location in a pair of chromosomes. For example, in hereditary haemochromatosis, compound heterozygotes have both a p.Cys282Tyr (previously known as C282Y) and a p.His63Asp (previously known as H63D) variant, and are less likely to develop iron overload than p.Cys282Tyr homozygotes. However, the impact will be assessed on a case-by-case situation as it depends on the variant (allele) and its pathogenicity. 

Consanguinity

Consanguinity describes a relationship between two people who are related to each other because of a common ancestor. Consanguineous relationships occur in all population groups, but occur more frequently in certain cultures. The most common form of consanguineous relationships is between first cousins.
 
Individuals who are blood relatives share a greater proportion of their genes than unrelated people, thus, these individuals potentially share pathogenic variants A pathogenic variant is a genetic variant that increases an individual’s susceptibility or predisposition to certain diseases. Pathogenic variants are also known as mutations. for the same autosomal recessive condition. When individuals are first cousins and there is no family history  of a specific condition, or of other consanguineous relationships in previous generations, the risk of them having a child with a medical condition is approximately 5–6%, compared with 3–4% in the general population. This risk is higher in couples where there is a multi-generational tradition of first-cousin marriages, rendering couples closer in genetic relationship. 

De novo

A de novo variant is a new genetic variation that usually arises in the ova or sperm from which the individual is conceived (ie is not present in either parent). 

Exome

The exome is the part of the genome that contains protein-coding genes only. The exome represents less than 2% of the genome, but contains about 85% of known disease-causing gene variants. 

Gene variants

Gene variants are small DNA sequence changes (ie additions, duplications, deletions, substitutions). These variants can have a range of effects: some may cause disease ( pathogenic variants A pathogenic variant is a genetic variant that increases an individual’s susceptibility or predisposition to certain diseases. Pathogenic variants are also known as mutations.  ), while others do not cause disease but may modify an individual’s risk of disease (i.e may increase risk or provide a protective effect). The vast majority of gene variants are benign and do not result in disease but rather contribute to the differences between people. 

Genome

The genome is the entire set of genetic material, including all coding and non-coding DNA.

Genotyping, genomic profiling and polygenic risk scores

Genotyping (also known as genomic profiling or genomic scanning) is a test to determine an individual’s single nucleotide polymorphism A nucleotide is a single base pair unit of DNA. A single nucleotide polymorphism (SNP or ‘snip’) or single nucleotide variant (SNV) is a variation in a single nucleotide occurring at a particular site in the genome. For example, one individual may have a ‘G’ at a particular location and another individual a ‘T’. If two or more alternative DNA variants occur at a particular location at a population frequency of >1%, it is defined as a SNP or SNV. SNPs/SNVs are the most common type of genetic variation in the human genome and account for approximately 0.02% of the genome. (SNP) profile. A SNP profile may be used to predict disease susceptibility by calculating polygenic risk scores, tailor treatment based on pharmacogenomic variants, or  provide non– health related information (eg paternity, ancestry).Currently polygenic risk score may only be useful for people of European ancestry as there are not yet enough data available to reliably apply them to non-European populations. 

Heterozygote, heterozygous and heterozygosity

Heterozygosity refers to the presence of a different allele (form of a gene variant Gene variants are small DNA sequence changes (ie additions, duplications, deletions, substitutions). These variants can have a range of effects: some may cause disease (pathogenic variant), while others do not cause disease but may modify an individual’s risk of disease (i.e may increase risk or provide a protective effect). The vast majority of gene variants are benign and do not result in disease but rather contribute to the differences between people. ) at a given location on a pair of chromosomes (eg a carrier Recessive genetic conditions such as cystic fibrosis (CF) occur when a person inherits a particular genetic variant from each parent. A carrier is an individual who only has one copy of the gene variant and generally does not have symptoms, but can pass the variant to their children. Some conditions are due to a pathogenic variant in a gene on the X chromosome (). Typically, these conditions affect more males (who have the sex chromosomes XY) than females (who have the sex chromosomes XX). A woman who is a carrier of an X-linked condition has the variation on one of her X chromosomes, which she can pass on to her children. However, if the biological male has a pathogenic variant in an X chromosome gene, he will not pass it to his sons, but will pass it to all of his daughters.  for a pathogenic gene variant is heterozygous for that variant). 

Homozygous, homozygous and homozygosity

Homozygosity refers to the presence of two identical alleles (form of a gene variant) at a given location on a pair of chromosomes. 

Incomplete penetrance

Refer to Penetrant and penetrance Penetrance refers to the proportion of people with a particular genetic variant who will go on to develop the condition. For example, people carrying an autosomal dominant variant may not always develop the condition – this is called ‘incomplete penetrance’. If a condition is 100% penetrant, an individual will definitely develop the condition. If penetrance is 80%, most but not all individuals will develop the condition. Other genes and lifestyle factors, such as diet, exercise and smoker status, may affect the penetrance of some conditions. For more information, refer to MedlinePlus’ ‘What are reduced penetrance and variable expressivity?’ (https://medlineplus.gov/genetics/understanding/inheritance/penetranceexpressivity/).

Multifactorial inheritance and complex inheritance

Multifactorial inheritance, also called complex inheritance, can be attributed to a combination of genetic (ie single or multiple genetic variants), environmental and lifestyle factors.
 
The number of necessary factors, and the impact those factors have on the presence or severity of a condition, will vary for different conditions and individuals.
 
Often, when there are multiple susceptibility genes involved, there is an additive effect on the outcome (e.g. when calculating polygenic risk scores).
 
Early onset of conditions, such as cancer, cardiovascular disease or type 2 diabetes, may be indicative of multifactorial inheritance within a family.
 
This type of inheritance does not follow a characteristic pedigree pattern, but may look like autosomal dominant inheritance When a condition follows an autosomal dominant pattern of inheritance, the family tree will usually reveal multiple affected members in multiple generations on the same side of the family. Dominant conditions or traits are expressed when only a single gene variant is inherited. Wide variability in clinical expression is common in many autosomal dominant conditions, even within the same family. Early onset of conditions, such as cancer, can be indicative of autosomal dominant inheritance within a family. Not all dominant conditions show 100% penetrance (eg BRCA1 gene mutations).  with incomplete penetrance Penetrance refers to the proportion of people with a particular genetic variant who will go on to develop the condition. For example, people carrying an autosomal dominant variant may not always develop the condition – this is called ‘incomplete penetrance’. If a condition is 100% penetrant, an individual will definitely develop the condition. If penetrance is 80%, most but not all individuals will develop the condition. Other genes and lifestyle factors, such as diet, exercise and smoker status, may affect the penetrance of some conditions. For more information, refer to MedlinePlus’ ‘What are reduced penetrance and variable expressivity?’ (https://medlineplus.gov/genetics/understanding/inheritance/penetranceexpressivity/).

Pathogenic variant and gene mutation

A pathogenic variant is a genetic variant that increases an individual’s susceptibility or predisposition to certain diseases. Pathogenic variants are also known as mutations. 

Penetrant and penetrance

Penetrance refers to the proportion of people with a particular genetic variant who will go on to develop the condition. For example, people carrying an autosomal dominant variant may not always develop the condition – this is called ‘incomplete penetrance’. If a condition is 100% penetrant, an individual will definitely develop the condition. If penetrance is 80%, most but not all individuals will develop the condition. Other genes and lifestyle factors, such as diet, exercise and smoker status, may affect the penetrance of some conditions.
 
For more information, refer to MedlinePlus’ ‘What are reduced penetrance and variable expressivity?’. 

Pharmacogenomic tests

Pharmacogenomic tests look for common variants that affect the way an individual responds to medications. They can be used to guide selection and dosage of several commonly used medications.

Pre-symptomatic testing and predictive testing

Pre-symptomatic testing aims to determine whether a person will almost certainly develop a particular genetic condition at some point in the future when symptoms of the condition have not yet manifested (eg Huntington disease).
 
Predictive testing aims to determine whether a person who has no signs or symptoms of a specific condition at the time of testing has a specific pathogenic variant that increases the likelihood they will later develop the condition. Predictive testing is often performed in relation to genetic conditions that are not evident at birth, but have their onset during adulthood, such as some cancers (eg BRCA 1 and 2 testing). Predictive genetic testing in familial cancer syndromes can only be conducted when the family-specific genetic variant is known. Hence, genetic testing must generally first be done on a family member affected with the specific condition. 

Pre-implantation genetic testing

Pre-implantation genetic testing is testing performed on embryos produced by IVF. Prenatal testing of successful pregnancies may be undertaken as pre-implantation genetic testing is less than 100% accurate. 

Single nucleotide polymorphism/single nucleotide variant

A nucleotide is a single base pair unit of DNA. A single nucleotide polymorphism (SNP or ‘snip’) or single nucleotide variant (SNV) is a variation in a single nucleotide occurring at a particular site in the genome. For example, one individual may have a ‘G’ at a particular location and another individual a ‘T’. If two or more alternative DNA variants occur at a particular location at a population frequency of >1%, it is defined as a SNP or SNV. SNPs/SNVs are the most common type of genetic variation in the human genome and account for approximately 0.02% of the genome. 

Variable expressivity

Variable expressivity refers to the range of signs and symptoms that an individual with a particular genetic condition will display.
 
Variable expressivity is a factor that influences the effect of particular genetic variants. While some genetic variants are consistent in terms of the effect they have on a disease or characteristic, other have a more variable effect. For example, Lynch syndrome (hereditary non-polyposis colorectal cancer [HNPCC]) shows variable expressivity. An individual’s presentation of this disease is modified by their genetic, lifestyle and environment factors.
 
Variable expressivity is not the same as reduced penetrance. 

For more information, refer to the MedlinePlus’ ‘What are reduced penetrance and variable expressivity?’. 

Variant(s) of uncertain significance (VOUS/VUS)

A variant in a gene where the association with a particular condition is uncertain.

X-inactivation

Inactivation of most genes on the X chromosome in female somatic cells ensures that males and females have the same number of X chromosome genes instructing the body to perform particular functions.
 
This is usually a random process; thus, females will have a mixture of cells with respect to the inactivated X chromosomes being of maternal or paternal origin.
 
The usual random process of X-inactivation means that female carriers Recessive genetic conditions such as cystic fibrosis (CF) occur when a person inherits a particular genetic variant from each parent. A carrier is an individual who only has one copy of the gene variant and generally does not have symptoms, but can pass the variant to their children. Some conditions are due to a pathogenic variant in a gene on the X chromosome (X-linked inheritance). Typically, these conditions affect more males (who have the sex chromosomes XY) than females (who have the sex chromosomes XX). A woman who is a carrier of an X-linked condition has the variation on one of her X chromosomes, which she can pass on to her children. However, if the biological male has a pathogenic variant in an X chromosome gene, he will not pass it to his sons, but will pass it to all of his daughters. of a mutation in a gene on the X-chromosome will not usually show any signs of the condition as there are enough cells with the functioning copy of the gene to instruct the body to perform particular functions.
 
Rarely, some female carriers may be symptomatic because of unequal or skewed inactivation of the X chromosomes that results in the X chromosome with the pathogenic variant being active in the majority of cells.

X-linked recessive inheritance

Since a male inherits only one X chromosome (from his mother), when he has a pathogenic variant in a gene on the X-chromosome, he will have that condition. Males are usually more often and more severely affected because of X-inactivation in females.
 
Since a male only passes his Y chromosome to his sons, there is no male-to-male transmission of X-linked conditions.
 
With each pregnancy, females who are carriers of a pathogenic variant in a gene on the X-chromosome have a one-in-two chance of passing on the variant to each child. Sons who inherit the variant will be affected and daughters who inherit the variation will be carriers like their mothers.
 
Daughters of affected males can only inherit the pathogenic variant from their father and are known as ‘obligate carriers’.