Glossary

Affected: An individual who manifests symptoms of a particular condition

Allele: One version of a gene at a given location (locus) along a chromosome

Alternate paternity: (synonyms: false paternity, nonpaternity) The situation in which the alleged father of a particular individual is not the biological father

Analysis of the entire coding region: Sequence analysis: (synonyms: gene sequencing, sequence analysis, sequencing) The process by which the nucleotide sequence is determined for the entire coding region of a gene

Autosomal: Refers to any of the chromosomes other than the sex-determining chromosomes (i.e., the X and Y) or the genes on these chromosomes

Autosomal dominant: Describes a trait or disorder in which the phenotype is expressed in those who have inherited only one copy of a particular gene mutation (heterozygotes); specifically refers to a gene on one of the 22 pairs of autosomes (non-sex chromosomes)

Autosomal recessive: Describes a trait or disorder requiring the presence of two copies of a gene mutation at a particular locus in order to express observable phenotype; specifically refers to genes on one of the 22 pairs of autosomes (non-sex chromosomes)

Background risk: (synonym: population risk) The proportion of individuals in a given population who are affected with a particular disorder or who have mutations in a certain gene; often discussed in the genetic counseling process as a comparison to the patient's personal risk given his/her family history or other circumstances

Benign variant: (synonym: polymorphism) An alteration in a gene distinct from the normal, wild-type allele that does not appear to have a deleterious effect

Carrier: An individual who has a recessive, disease-causing gene mutation at a particular locus on one chromosome of a pair and a normal allele at that locus on the other chromosome; may also refer to an individual with a balanced chromosome rearrangement

Carrier testing: (synonyms: carrier detection, heterozygote testing) Testing used to identify usually asymptomatic individuals who have a gene mutation for an autosomal recessive or X-linked recessive disorder , or who have a chromosome rearrangement (eg, translocation, inversion)

Chromosome: Physical structure consisting of a large DNA molecule organized into genes and supported by proteins called chromatin

Cis configuration: (synonyms: cis, coupling) Term which indicates that an individual who is heterozygous at two neighboring loci has the two mutations in question on the same chromosome

Coding region: (synonym: open reading frame) All exons of a gene that contribute to the protein product(s) of the gene

Compound heterozygote: An individual who has two different abnormal alleles at a particular locus, one on each chromosome of a pair; usually refers to individuals affected with an autosomal recessive disorder

Congenital: Present from birth, but not necessarily genetic

Consanguinity: Genetic relatedness between individuals descended from at least one common ancestor

De novo mutation: (synonyms: de novo gene mutation, new gene mutation, new mutation) An alteration in a gene that is present for the first time in one family member as a result of a mutation in a germ cell (egg or sperm) of one of the parents or in the fertilized egg itself

Deletion: Absence of a segment of DNA; may be as small as a single base or as large as one or more genes

Deletion/duplication analysis: Molecular genetic testing using methods such as MLPA, PCR, or Southern blot to identify deletions or duplications between about 40 bp and 10 Kb of DNA within a gene. These methods typically exclude detection of smaller deletions or duplications of a few base pairs (identified by sequencing, mutation scanning or targeted mutation analysis). These methods also exclude detection of subchromosomal microdeletions or microduplications (identified by FISH or array genomic hybridization), and chromosome deletions or duplications (identified by standard chromosome analysis)

Diagnostic testing: Testing designed to confirm or exclude a known or suspected genetic disorder in a symptomatic individual or, prenatally, in a fetus at risk for a certain genetic condition

Direct DNA analysis: (synonym: direct DNA) The use of any test method, such as sequence analysis,mutation scanning, or mutation analysis to detect a mutation in a gene

Disease-causing mutation: A gene alteration that causes or predisposes an individual to a specific disease

DNA: (synonym: deoxyribonucleic acid) The molecule which encodes the genes responsible for the structure and function of an organism and allows for transmission of genetic information from one generation to the next

Double heterozygote: An individual who is heterozygous for a mutation at each of two separate genetic loci

Duplication: The presence of an extra segment of DNA, resulting in redundant copies of a portion of a gene, an entire gene, or a series of genes, usually caused by unequal crossing-over during gene replication when gametes are formed in meiosis

Exon: Coding sequence of DNA present in mature messenger RNA

Familial: A phenotype that occurs in more than one family member; may have genetic or non-genetic etiology

Family history: The genetic relationships and medical history of a family; when represented in diagram form using standardized symbols and terminology, usually referred to as a pedigree

Family-specific mutation: In a family, the sequence alteration observed that causes or predisposes to a particular disease; the mutation may be rare or common

Family-specific mutation analysis: Testing for the specific disease-causing mutation(s) previously identified in a family member. Note: Family-specific mutation analysis is different from targeted mutation analysis

First-degree relative: Any relative who is one meiosis away from a particular individual in a family (i.e., parent, sibling, offspring)

Founder effect: A gene mutation observed in high frequency in a specific population due to the presence of that gene mutation in a single ancestor or small number of ancestors

Frameshift mutation: (synonyms: out-of-frame deletion, out-of-frame mutation) An insertion deletion involving a number of base pairs that is not a multiple of three and consequently disrupts the triplet reading frame, usually leading to the creation of a premature termination (stop) codon and resulting in a truncated protein product

Full penetrance allele: In autosomal dominant,autosomal recessive, and X-linked disorders caused by nucleotide repeat expansion, an abnormally large allele that is associated with disease manifestations

Gene: The basic unit of heredity, consisting of a segment ofDNA arranged in a linear manner along a chromosome. A gene codes for a specific protein or segment of protein leading to a particular characteristic or function.

Gene product: Genes are transcribed into segments of RNA (ribonucleic acid), which are translated into proteins. Both RNA and proteins are products of the expression of the gene.

Gene symbol: A unique abbreviation of a gene name consisting of italicized uppercase Latin letters and Arabic numbers formally assigned by the by HUGO Gene Nomenclature Committee after a gene has been identified (Note: a putative gene may be referred to by itslocus name prior to its identification)

Gene therapy: Experimental treatment of a genetic disorder by replacing, supplementing, or manipulating the expression of abnormal genes with normally functioning genes

Genetic counseling: A process, involving an individual or family, comprising: evaluation to confirm, diagnose, or exclude a genetic condition, malformation syndrome, or isolated birth defect; discussion of natural history and the role of heredity; identification of medical management issues; calculation and communication of genetic risks; provision of or referral for psychosocial support

Genetic predisposition: (synonym: genetic susceptibility) Increased susceptibility to a particular disease due to the presence of one or moregene mutations associated with an increased risk for the disease and/or afamily history that indicates an increased risk for the disease

Genome: The completeDNA sequence, containing all genetic information and supporting proteins, in the chromosomes of an individual or species

Genotype: The genetic constitution of an organism or cell; also refers to the specific set of alleles inherited at a locus

Genotype-phenotype correlation: The association between the presence of a certain mutation or mutations (genotype) and the resulting pattern of abnormalities (phenotype)

Genotyping: Testing that reveals the specific alleles inherited by an individual; particularly useful for situations in which more than one genotypic combination can produce the same clinical presentation, as in the ABO blood group, where both the AO and AA genotypes yield type A blood

Germline: The cell line from which egg or sperm cells (gametes) are derived

Germline mosaicism: Two or more genetic or cytogenetic cell lines confined to the precursor (germline) cells of the egg or sperm; formerly called gonadal mosaicism

Germline mutation: The presence of an altered gene within the egg or sperm (germ cell), such that the altered gene can be passed to subsequent generations

Hemizygous: The situation in which an individual has only one member of a chromosome pair or chromosome segment rather than the usual two; refers in particular to X-linked genes in males who under normal circumstances have only one X chromosome

Heteroplasmy: The situation in which, within a single cell, there is a mixture of mitochondria (energy producing cytoplasmic organelles), some containing mutant DNA and some containing normal DNA

Heterozygote: An individual who has two different alleles at a particularlocus, one on each chromosome of a pair; oneallele is usually normal and the other abnormal

Homozygote: An individual who has two identical alleles at a particularlocus, one on each chromosome of a pair

Hotspot mutation region: DNA sequences of high susceptibility tomutation due to some inherent instability, tendency toward unequalcrossing over, or chemical predisposition to single nucleotide substitutions; region where mutations are observed with greater frequency

Immunohistochemistry: Testing to detect the presence of specific proteins in cells or tissues by means of a specific antigen/antibody reaction tagged with a visible label

In-frame mutation: Amutation that does not cause a shift in the triplet reading frame; such mutations can, however, lead to the synthesis of an abnormal protein product

Incomplete autosomal dominant: An inheritance pattern in which the phenotypes observed lie on a continuum (differing in degree or kind) depending on whether one or two mutated alleles are present

Informed consent: Permission given by an individual to proceed with a specific test or procedure, with an understanding of the risks, benefits, limitations, and potential implications of the procedure itself and its results

Insertion: A chromosome abnormality in which material from one chromosome is inserted into another nonhomologous chromosome; a mutation in which a segment of DNA is inserted into a gene or other segment of DNA, potentially disrupting the coding sequence

Interfamilial variability: Variability in clinical presentation of a particular disorder among affected individuals from different families

Intrafamilial variability: Variability in clinical presentation of a particular disorder among affected individuals within the same immediate or extended family

Intron: Non-coding sequence of DNA removed from mature messenger RNA prior to translation

Intronic mutation: A mutation (usually a base substitution) within an intron that creates an alternative splice site that competes with the normal splice sites during RNA processing. Such a mutation results in a proportion of mature messenger RNA with improperly spliced intron sequences.

Inversion: A chromosomal rearrangement in which a segment of a chromosome has inverted from end to end, and re-inserted into the chromosome at the same breakage site. Balanced inversions (in which no net loss or gain of genetic material occurs) are usually not associated with phenotypic abnormalities, however, in some cases, gene disruptions at the breakpoints can cause adverse phenotypic effects, including some known genetic diseases. Unbalanced inversions (in which loss or gain of chromosome material occurs) nearly always yield an abnormal phenotype.

Isolated: An abnormality that occurs in the absence of other systemic involvement

Known family-specific mutations: A specific disease-causing mutation identified in an affected family member; testing is recommended for other at-risk family members who might have that specific mutation; for example, if sequence analysis identifies a disease-causing mutation in an affected family member, all at-risk relatives need only to be tested for their family-specific mutation.

Locus: The physical site or location of a specificgene on a chromosome

Locus heterogeneity: The situation in which mutations in genes at different chromosomal loci cause the same phenotype

Locus name: An informally assigned abbreviation used in the process of mapping to designate a putative gene prior to gene identification; once the gene is identified. The locus name is generally replaced by a formally assigned gene symbol (which often differs from the locus name).

Loss of heterozygosity: (synonym: LOH) At a particular locus heterozygous for a deleterious mutant allele and a normalallele, a deletion or other mutational event within the normalallele renders the cell either hemizygous (one deleterious allele and one deleted allele) or homozygous for the deleterious allele

Manifesting carrier: An individual who has, at a particularlocus, a recessive, disease-causing allele on one chromosome and a normalallele on the other chromosome and who manifests some symptoms of the disorder; generally refers to female carriers of an X-linked recessive mutation who are clinically affected, although the phenotype is usually less severe as compared to males with the same mutation

Maternal contamination: The situation which occurs in prenatal testing in which a sample of chorionic villus, amniotic fluid, or umbilical blood becomes contaminated with maternal (usually blood) cells, which can confound interpretation of the results of genetic analysis

Methylation: The attachment of methyl groups to DNA at cytosine bases; correlated with reduced transcription of the gene and thought to be the principal mechanism in X-chromosome inactivation and imprinting

Methylation analysis: Testing that evaluates the methylation status of a gene (attachment of methyl groups to DNA cytosine bases); genes that are methyalted are not expressed; methylation plays a role in X-chromosome inactivation and imprinting

Microdeletion syndrome: (synonym: contiguous gene deletion syndrome) A syndrome caused by a chromosomal deletion spanning several genes that is too small to be detected under the microscope using conventional cytogenetic methods. Depending on the size of the deletion, other techniques, such as FISH or other methods of DNA analysis can sometimes be employed to identify the deletion

Microsatellite: (synonyms: satellite DNA, short tandem repeats) Repetitive segments of DNA two to five nucleotides in length (dinucleotide/trinucleotide/tetranucleotide/pentanucleotid e repeats), scattered throughout the genome in non-coding regions between genes or within genes (introns), often used as markers for linkage analysis because of the naturally occurring high variability in repeat number between individuals. These regions are inherently unstable and susceptible to mutations.

Microsatellite instability: (synonyms: MSI, replication error phenotype, RER) The presence of a discrepancy between the size of microsatellites in DNA from tumor tissue compared to nontumor tissue from the same person, resulting from mutations in a gene in the DNA mismatch repair pathway (MMR) that would normally correct these errors.

Microsatellite instability testing: (synonym: MSI testing) Used to identify tumors caused by defective mismatch repair by comparing the number of nucleotide repeats in a panel of microsatellite markers in normal tissue with the number from tumor tissue from the same individual. Microsatellite stability (MSS) is present if the same number of repeats is present in each marker in both the tumor and the normal tissue. Microsatellite instability (MSI) is present if the number of repeats in the tumor and the normal tissue differs.

Mismatch repair mechanism: (synonym: mismatch repair) The DNA 'proof-reading' system controlled by certain genes that identifies, excises, and corrects errors in the pairing of the bases during DNA replication. Mutations in the genes responsible for this mechanism can lead to certain genetic diseases and some forms of cancer.

Missense mutation: A single base pair substitution that results in the translation of a different amino acid at that position

"Mitochondrial inheritance: Mitochondria, cytoplasmic organelles that produce the energy source ATP for most chemical reactions in the body, contain their own distinct genome; mutations in mitochondrial genes are responsible for several recognized syndromes and are always maternally inherited since ova contain mitochondria, whereas sperm do not

Mode of inheritance: (synonyms: inheritance pattern, pattern of inheritance) The manner in which a particular genetic trait or disorder is passed from one generation to the next. Autosomal dominant, autosomal recessive, X-linked dominant, X-linked recessive, multifactorial, and mitrochondrial inheritance are examples

Molecular genetic testing: (synonyms: DNA testing, DNA-based testing, molecular testing) Testing that involves the analysis of DNA, either through linkage analysis, sequencing, or one of several methods of mutation detection

Mosaicism: Within a single individual or tissue, the occurrence of two or more cell lines with different genetic or chromosomal constitutions

Multifactorial inheritance: (synonym: polygenic) The combined contribution of one or more often unspecified genes and environmental factors, often unknown, in the causation of a particular trait or disease

Mutation: (synonyms: sequence alteration, splicing mutation) Any alteration in a gene from its natural state; may be disease-causing or a benign, normal variant

Newborn screening: Testing done within days of birth to identify infants at increased risk for a specific genetic disorder so that treatment can begin as soon as possible; when a newborn screening result is positive, further diagnostic testing is usually required to confirm or specify the results and counseling is offered to educate the parents

Nonsense mutation: A single base pair substitution that prematurely codes for a stop in amino acid translation (stop codon)

Novel mutation: A distinct gene alteration that has been newly discovered; not the same as a 'new' or 'de novo' mutation

Nucleotide: A molecule consisting of a nitrogenous base (adenine, guanine, thymine, or cytosine in DNA; adenine, guanine, uracil, or cytosine in RNA), a phosphate group, and a sugar (deoxyribose in DNA; ribose in RNA). DNA and RNA are polymers of many nucleotides.

Obligate carrier: (synonym: obligate heterozygote) An individual who may be clinically unaffected but who must carry a gene mutation based on analysis of the family history; usually applies to disorders inherited in an autosomal recessive or X-linked recessive manner

Parent-of-origin studies: An analysis used to determine whether a particular chromosome or segment of DNA was inherited from an individual's mother or father; helpful in the diagnosis of disorders in which imprinting or uniparental disomy is a possible underlying etiological mechanism

Parentage testing: (synonyms: maternity testing, paternity testing) The process through which DNA sequences from a particular child and a particular adult are compared to estimate the likelihood that the two individuals are related; DNA testing can reliably exclude but cannot absolutely confirm an individual as a biological parent

PCR: (synonym: polymerase chain reaction) A procedure that produces millions of copies of a short segment of DNA through repeated cycles of: 1) denaturation, 2) annealing, and 3) elongation; PCR is a very common procedure in molecular genetic testing and may be used to: 1) generate a sufficient quantity of DNA to perform a test (e.g., sequence analysis, mutation scanning), or 2) may be a test in and of itself (e.g., allele-specific amplification, trinucleotide repeat quantification).

Pedigree: A diagram of the genetic relationships and medical history of a family using standard symbols and terminology

Penetrance: The proportion of individuals with a mutation causing a particular disorder who exhibit clinical symptoms of that disorder; most often refers to autosomal dominant conditions.

Phenotype: The observable physical and/or biochemical characteristics of the expression of a gene; the clinical presentation of an individual with a particular genotype

Point mutation: An alteration in DNA sequence caused by a single nucleotide base change, insertion, or deletion

Polygenic: A condition caused by the additive contributions of mutations in multiple genes at different loci

Polymerase chain reaction (PCR): A procedure that produces millions of copies of a short segment of DNA through repeated cycles of: 1) denaturation, 2) annealing, and 3) elongation; PCR is a very common procedure in molecular genetic testing and may be used to: 1) generate a sufficient quantity of DNA to perform a test (e.g., sequence analysis,mutation scanning), or 2) may be a test in and of itself (e.g., allele-specific amplification, trinucleotide repeat quantification).

Polymorphism: Natural variations in a gene, DNA sequence, protein, or chromosome that have no adverse effect on the individual and occur with fairly high frequency in the general population.

Population risk: (synonym: background risk) The proportion of individuals in the general population who are affected with a particular disorder or who carry a certain gene; often discussed in the genetic counseling process as a comparison to the patient's personal risk given his or her family history or other circumstances

Predictive testing: Testing offered to asymptomatic individuals with a family history of a genetic disorder and a potential risk of eventually developing the disorder

Predisposing mutation: (synonym: susceptibility gene) A genemutation that increases an individual's susceptibility or predisposition to a certain disease or disorder. When such a mutation is inherited, development of symptoms is more likely but not certain.

Predispositional testing: Testing of an asymptomatic individual in whom the discovery of a gene mutation indicates that eventual development of findings related to a specific diagnosis is likely but not certain. A negative result may not exclude the possibility of future development of the disease from other causes.

Preimplantation diagnosis: (synonym: preimplantation testing) A procedure used to decrease the chance of a particular genetic condition for which the fetus is specifically at risk by testing one cell removed from early embryos conceived by in vitro fertilization and transferring to the mother's uterus only those embryos determined not to have inherited the mutation in question

Prenatal diagnosis: (synonym: prenatal testing) Testing performed during pregnancy to determine if a fetus is affected with a particular disorder. Chorionic villus sampling (CVS), amniocentesis, periumbilical blood sampling (PUBS), ultrasound, and fetoscopy are examples of procedures used either to obtain a sample for testing or to evaluate fetal anatomy.

Presymptomatic testing: Testing of an asymptomatic individual in whom the discovery of a gene mutation indicates certain development of findings related to a specific diagnosis at some future point. A negative result excludes the diagnosis.

Private mutation: (synonym: unique mutation) A rare disease-causing mutation observed in a few families

Proband: (synonyms: index case, propositus) The affected individual through whom a family with a genetic disorder is ascertained; may or may not be the consultand (the individual presenting for genetic counseling)

Promoter region: A specific region just upstream from a gene that acts as a binding site for transcription factors and RNA polymerase during the initiation of transcription

Protein analysis: One of several different testing methods that reveals either the structure or function of a particular protein product

Protein expression: Testing to examine the expression of a mutation in a recombinant protein to confirm its pathogenicity

Protein truncation testing: (synonym: PTT) Means of identifying the shortened (truncated) proteins that result from mutations which specifically cause premature termination of mRNA translation

Reading frame: (synonym: exon) A sequence of messenger RNA that is translated into an amino acid chain, three bases at a time, each triplet sequence coding for a single amino acid

Rearrangement: A structural alteration in a chromosome, usually involving breakage and reattachment of a segment of chromosome material, resulting in an abnormal configuration; examples include inversion and translocation

Recurrence risk: The likelihood that a trait or disorder present in one family member will occur again in other family members in the same or subsequent generations

Reduced penetrance allele: (synonym: intermediate allele) In autosomal dominant disorders caused by nucleotide repeat expansion, an abnormally large allele that may or may not result in an abnormal phenotype in a normal life span. The abnormal phenotype may be very-late-onset disease and/or a different phenotype. Reduced penetrance alleles are larger than mutable normal alleles and smaller than full penetrance alleles.

Reflex testing: Follow-up testing automatically initiated when certain test results are observed in the laboratory; used to clarify or elaborate on primary test results

Risk assessment: Calculation of an individual's risk, employing appropriate mathematical equations, of having inherited a certain gene mutation, of developing a particular disorder, or of having a child with a certain disorder based upon analysis of multiple factors including family medical history and ethnic background

Risk assessment modification: Alteration of the assessment of an individual's genetic risk based upon previously unknown information about the family history or upon the results of genetic testing; depending on the nature of the new information, risk may be either increased or decreased

RNA: (synonym: ribonucleic acid) The molecule synthesized from the DNA template; contains the sugar ribose instead of deoxyribose, which is present in DNA; three types of RNA exist, messenger RNA (mRNA), transfer RNA (tRNA), and ribosomal RNA (rRNA)

Screening: Testing designed to identify individuals in a given population who are at higher risk of having or developing a particular disorder, or having a gene mutation for a particular disorder

Second-degree relative: Any relative who is two meioses away from a particular individual in a pedigree; a relative with whom one quarter of an individual's genes is shared (i.e., grandparent, grandchild, uncle, aunt, nephew, niece, half-sibling)

Segregation: The separation of the homologous chromosomes and their random distribution to the gametes at meiosis

Sensitivity: The frequency with which a test yields a positive result when the individual being tested is actually affected and/or has the gene mutation in question

Sequence alteration: (synonym: mutation) Any alteration in a gene from its natural state; may be benign (commonly referred to as a "polymorphism"), pathogenic, or of unknown significance

Sequence analysis: (synonyms: gene sequencing, sequencing) Process by which the nucleotide sequence is determined for a segment of DNA

Specificity: The frequency with which a test yields a negative result when the individual being tested is actually unaffected and/or does not have the gene mutation in question

Splice-site mutation: A mutation that alters or abolishes the specific sequence denoting the site at which the splicing of an intron takes place. Such mutations result in one or more introns remaining in the mature messenger RNA and can disrupt the generation of the protein product

Splicing: (synonym: splicing mutation) The process by which introns, non-coding regions, are excised out of the primary messenger RNA transcript and exons (i.e., coding regions) are joined together to generate mature messenger RNA

Sporadic: The chance occurrence of a disorder or abnormality that is not likely to recur in a family

Subtelomeric region: The chromosomal region just proximal to the telomere (end of the chromosome) composed of highly polymorphic repetitive DNA sequences that are typically situated adjacent to gene-rich areas. Microdeletions and subtle rearrangements that disrupt genes in the subtelomeric regions can cause mental retardation; use of fluorescent in situ hybridization (FISH) to evaluate subtelomeric regions is usually required for detection of these abnormalities.

Susceptibility gene: A gene mutation that increases the likelihood that an individual will develop a certain disease or disorder. When such a mutation is inherited, development of symptoms is more likely but not certain

Trans configuration: (synonym: repulsion) Term which indicates that an individual who is heterozygous at two neighboring loci has the two mutations in question on each of the two homologous chromosomes

Transcription: The process of synthesizing messenger RNA (mRNA) from DNA

Translation: The process of synthesizing an amino acid sequence (protein product) from the messenger RNA code

Unaffected: An individual who does not manifest any symptoms of a particular condition

Variable expressivity: Variation in clinical features (type and severity) of a genetic disorder between affected individuals, even within the same family

Wild-type allele: The normal, as opposed to the mutant, gene or allele

X-linked dominant: Describes a dominant trait or disorder caused by a mutation in a gene on the X chromosome. The phenotype is expressed in heterozygous females as well as in hemizygous males (having only one X chromosome); affected males tend to have a more severe phenotype than affected females.

X-linked lethal: A disorder caused by a dominant mutation in a gene on the X chromosome that is observed almost exclusively in females because it is almost always lethal in males who inherit the gene mutation

X-linked recessive: A mode of inheritance in which a mutation in a gene on the X chromosome causes the phenotype to be expressed in males who are hemizygous for the gene mutation (i.e., they have only one X chromosome) and in females who are homozygous for the gene mutation (i.e., they have a copy of the gene mutation on each of their two X chromosomes). Carrier females who have only one copy of the mutation do not usually express the phenotype, although differences in X-chromosome inactivation can lead to varying degrees of clinical expression in carrier females