Glossary of terms

Allele: the specific version of a gene. An individual typically inherits two alleles for each gene (unless those genes are located on the sex chromosomes in males), one from each biological parent.

Amino acids: the building blocks of protein.

Autosomal: related to the numbered chromosomes that are not sex chromosomes (X and Y).

Benign/likely benign: a type of variation in DNA that does not lead to known genetic conditions. DNA contains many variants and most are benign. Likely benign describes a genetic variant that is not expected to lead to a genetic condition, but the scientific evidence is not as strong as for the variants that are called benign.

Benign (pseudodeficiency allele): genetic variants that are not known to cause genetic conditions, but can alter the protein products or change the gene’s expression. Some of these variants may be associated with abnormal biochemical test results, but do not cause a genetic condition. Some biochemical studies can’t differentiate between pathogenic/likely pathogenic variants and pseudodeficiency alleles, so these must be distinguished with genetic testing.

Carrier: an individual with a single genetic variant (pathogenic or likely pathogenic) in a gene that causes a recessive condition. Two pathogenic or likely pathogenic genetic variants in a gene are needed to cause a recessive condition, but a carrier only has one of these. Being a carrier does not typically impact that individual’s health, but can impact reproductive risk and family planning.

Chromosome: a large piece of DNA that carries many genes. Humans typically have 23 pairs of chromosomes (22 pairs of autosomal or numbered chromosomes and 1 pair of sex chromosomes). Chromosomes are in pairs because one is inherited from each parent. Chromosome pairs 1-22 are the same, regardless of biological sex. The sex chromosomes are X and Y; a female has two X chromosomes and a male has one X chromosome and one Y chromosome.

DNA: deoxyribonucleic acid (DNA) is the material inside of each cell that contains all the genetic information the body needs to function.

Deletion or duplication: large sections of DNA that are missing (deletion) or extra (duplication). They can range in size from a small section within a gene to a larger section containing multiple genes. These are also called copy number variations (CNV).

De novo variant: a genetic variant that was not passed from a parent to a child, but arose new in an individual’s DNA.

Dominant inheritance: a genetic condition would only occur with a single pathogenic/likely pathogenic variant in a gene.

Exome: the part of our genetic material that consists of all the exons within our DNA and codes for proteins.

Exon: the portion of a gene that codes for amino acids and is typically the parts of the gene that are expressed in the final product (the protein).

Family variant testing (FVT): a service at Invitae through which blood relatives of individuals who pursued genetic testing may be eligible for genetic testing to clarify their personal or reproductive risk. For more information regarding eligibility, requirements, and details for this family member testing service, click here.

Gene: a section of DNA that instructs our body how to make a certain protein. Genes are made up of introns and exons and are arranged along chromosomes. Humans have approximately 20,000 genes and typically have two copies of each gene (unless those genes are located on the sex chromosomes in males).

Genetic counseling: an appointment with a healthcare provider specifically trained in medical genetics and counseling to help individuals understand the process of genetic testing, what their genetic test results mean, and the implications for themselves and their family members.

Genetic testing: the process of analyzing an individual’s DNA to look for variants in their genes that could be associated with genetic conditions.

Hemizygous: variant is present in a biological male’s single copy of the X chromosome.

Heterozygous: variant is present in only one of the two copies of a gene.

Homozygous: variant is present in both copies of the gene.

In-cis: when more than one genetic variant is located on the same copy of the gene.

In-trans: when more than one genetic variant is located on opposite copies of the gene.

Increased risk allele: the variant is not expected to directly cause a genetic condition on its own, but there is scientific evidence that it can lead to an increased risk/predisposition to develop the genetic condition in combination with other genetic variants or factors.

Intron: the portion of the gene that does not code for amino acids or expressed in proteins. Introns are located in between the exons.

Inheritance pattern: how a genetic condition is inherited through a family. This includes recessive, dominant, and X-linked.

Inherited variant: a genetic variant that was passed from a parent to a child.

MedGen UID: an identifier within the MedGen database. MedGen is an online database primarily used by healthcare professionals to obtain more information about a specific genetic condition. The MedGen UID is a number that correlates to information about a specific genetic condition.

Mosaic: when the cells studied from one individual have different genetic makeups. For example, a genetic variant may be present in some cells of the body and not present in others. There are different types of mosaicism and the level of mosaicism for a particular individual could influence the symptoms experienced with a genetic condition.

Multifactorial: a combination of factors (genetic and environmental) that lead to a predisposition to, or diagnosis of, a genetic condition.

Mutation: another term for a genetic variant. See definition of “variant” for additional information.

Next generation sequencing (NGS): a laboratory technique that allows for analysis of the exact sequence of letters within a gene and can analyze multiple genes at once.

Pathogenic/likely pathogenic: variants in DNA that are expected to lead to a known genetic condition. A likely pathogenic variant has a high likelihood of causing a known genetic condition and should be managed in the same manner as a pathogenic variant.

Pathogenic (low penetrance): variants in DNA that can cause a genetic condition, but some individuals who have this genetic variant don’t develop the condition or have milder symptoms. The reason why some people develop symptoms and others don’t is not fully known at the current time and not able to be predicted.

Pedigree: a chart showing the family tree of an individual that can be used to analyze inheritance of a genetic condition.

Penetrance: describes the likelihood that an individual with a pathogenic or likely pathogenic genetic variant(s) will actually develop symptoms of the condition. Full or complete penetrance means that every individual with the genetic variant is expected to develop symptoms. Incomplete or reduced penetrance indicates that not every individual with the genetic variant will develop symptoms. This is thought to be due to a combination of both known and unknown factors.

PIN network: Invitae specific service that allows individuals to connect with researchers, clinicians, pharmaceutical companies, and advocacy organizations. There is not a PIN for every genetic condition at this time, but a directory can be found here.

PMID: an abbreviation for PubMed ID. PubMed is an online database used primarily by healthcare professionals and scientists to access medical and scientific articles. A PMID is a number that correlates to a specific article for easier searching.

Potentially positive: a result that could be associated with a diagnosis of, or predisposition to, a genetic condition, but Invitae needs additional information before it can be confirmed. This additional information can include family member testing to determine segregation of variants (in-cis or in-trans) or that more scientific evidence about the pathogenicity of a specific variant is needed. This result type would apply to individuals with one of the following two scenarios: 1. More than 1 pathogenic/likely pathogenic variant in a gene associated with a recessive condition but the segregation of the variants are unknown 2. At least one pathogenic/likely pathogenic variant and at least one variant of uncertain significance (VUS) in a gene associated with a recessive condition but the segregation of the variants is unknown.

Preliminary evidence gene: a gene that the scientific community has found to have some evidence to be associated with a genetic condition, but more information is needed to confirm or rule out this association.

Proband: the first person in a family to receive genetic testing, often prompted by this person’s health concerns. A proband’s genetic test result can have implications for their biological family members, especially if they have a genetic condition.

Protein: a molecule that is composed of amino acids and plays an important role in the structure, function, and regulation of our body.

Recessive inheritance: a genetic condition would occur only with pathogenic/likely pathogenic variants in both copies of the gene. A single pathogenic variant would confer carrier status (see definition of “carrier” for more information) and is unlikely to cause the genetic condition.

Segregation: analysis through family member testing to help determine how a variant or variants were inherited and could help clarify if the particular variant(s) is responsible for causing the genetic condition. This can lead to the variants being called in-cis (same copy of the gene) or in-trans (opposite copy of the gene).

Syndrome: a genetic condition that can cause health concerns in different body systems.

Transcript (reference sequence): the version of the genetic sequence for a particular gene that is evaluated through genetic testing. For example, NM_206933.2.

Variable expressivity: when individuals with the same genetic variant (within families or among different families) have different symptoms, age of onset, and progression associated with the same condition.

Variant: a genetic “spelling” change in the sequence of the DNA that may or may not affect the function of the gene(s) or product(s). Variants can be pathogenic, likely pathogenic, likely benign, benign, have unknown significance, or be considered an increased risk allele.

Variant classification: a process for analyzing the available evidence for a particular genetic variant(s) and applying a formal variant classification based on this information. A formal classification is meant to help answer the clinical significance of the variant. Variants can be pathogenic, likely pathogenic, likely benign, benign, have unknown significance, or be considered an increased risk allele. For more information regarding Invitae’s specific variant classification click here.

Variant of uncertain significance (VUS): a variation in DNA that has an uncertain or unknown impact on health. If someone has a VUS, they do not necessarily have an increased risk of developing a certain genetic condition. Over time, the scientific and medical community will identify new evidence about each particular VUS and the classification of the variant may be changed to benign/likely benign, or less commonly, to likely pathogenic/pathogenic.

VUS resolution: a service at Invitae to gather more evidence about a particular variant of uncertain significance by testing additional biological relatives to potentially help reclassify that variant. For more information regarding eligibility, requirements, and details for this family member testing service click here.

X-inactivation: a normal process in females (who typically have two X chromosomes) by which one X chromosome is randomly inactivated (turned off) during fetal development. This process occurs by chance and can sometimes impact health conditions with genes located on the X chromosome. This is also known as “lyonization.”

X-linked inheritance: means that the gene associated with the condition is located on the X chromosome. Females typically have two X chromosomes, while males typically have one X and one Y chromosome. As males typically have only one X chromosome, pathogenic or likely pathogenic variants in genes on the X chromosome usually affect males more often than females.

Zygosity: indicates the number of times a specific variant is present in the copy or copies of a gene. Zygosity can be described as heterozygous, homozygous, and hemizygous (see applicable definitions for more information on each term).