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Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017.

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GeneReviews Glossary

Terms and Definitions

A · B · C · D · E · F · G · H · I · K · L · M · N · O · P · Q · R · S · T · U · V · W · X

A

affected

Referring to an individual who manifests signs and/or symptoms of a particular condition

allele

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

Related terms: allele frequency; benign variant; compound heterozygous; heterozygous; homozygous; likely benign variant; likely pathogenic variant; locus; pathogenic variant; polymorphism; variant of uncertain significance; wild-type

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allele frequency

The proportion of individuals in a population who have inherited a specific variant

allelic heterogeneity

Synonym: molecular heterogeneity

Presence of different pathogenic variants in the same gene and at the same chromosome locus that cause a single disease phenotype

Related term: allele

alternate maternity

Synonym: non-maternity

The situation in which the presumed mother of a particular individual is not the biological mother

alternate paternity

Synonym: non-paternity

The situation in which the presumed father of a particular individual is not the biological father

analyte

A chemical substance of interest; a biologic component whose properties (e.g., concentration, presence, absence) can be indicators of human disease; in inherited conditions properties of analytes of interest are often measured in a biochemical/metabolic specialty laboratory to identify abnormalities in a metabolic pathway.

aneuploidy

The occurrence of one or more extra or missing chromosomes leading to an unbalanced chromosome complement, or any chromosome number that is not an exact multiple of the haploid number

anticipation

The tendency in certain genetic disorders for individuals in successive generations to present at an earlier age and/or with more severe manifestations; often observed in disorders resulting from the expression of a nucleotide repeat expansion that tends to increase in size and have a more significant effect when passed from one generation to the next

Related terms: intrafamilial variability; nucleotide repeat; trinucleotide repeat; variable expressivity

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Ashkenazi Jewish

Synonym: Eastern European Jewish

The Eastern European Jewish population primarily from Germany, Poland, and Russia, in contrast to the Sephardic Jewish population primarily from Spain, parts of France, Italy, and North Africa

autosomal

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

autosomal dominant

Referring to a trait or disorder in which the phenotype can be expressed in individuals who have one copy of a pathogenic variant at a particular locus (heterozygotes); specifically refers to a gene on one of the 22 pairs of autosomes (non-sex chromosomes)

Related terms: de novo; germline mosaicism; heterozygous; mode of inheritance; penetrance; variable expressivity

autosomal recessive

Referring to a trait or disorder requiring the presence of biallelic pathogenic variants (i.e., homozygous or compound heterozygous variants) at a particular locus in order to express an observable phenotype; specifically refers to genes on one of the 22 pairs of autosomes (non-sex chromosomes)

Related terms: allele frequency; carrier; carrier testing; compound heterozygous; consanguineous; heterozygous; homozygous; mode of inheritance

B

background risk

The proportion of individuals in a given population who are affected with a particular disorder or who have pathogenic variants in a certain gene; often discussed in the genetic counseling process as a comparison to the proband's personal risk given his/her family history or other circumstances

Related terms: allele frequency; carrier rate

base pair

Synonym: bp

Two nitrogenous bases paired together in double-stranded DNA by weak bonds; specific pairing of these bases (adenine with thymine and guanine with cytosine) facilitates accurate DNA replication; when quantified (e.g., 8 bp), refers to the physical length of a sequence of nucleotides

benign variant

Synonym: polymorphism

An alteration in DNA (distinct from the reference sequence) that is not associated with an abnormal phenotype or increased disease risk. A benign variant meets criteria to be classified as benign according to the five-tier system of describing the clinical significance of genetic variants (see Related terms).

Related terms: likely benign variant; likely pathogenic variant; pathogenic variant; variant of uncertain significance

biallelic

Referring to both alleles of a gene. Biallelic variants may be homozygous or compound heterozygous.

Related terms: compound heterozygous; homozygous; trans

C

carrier

An individual with a recessive pathogenic variant at a particular locus on one chromosome of a pair who is not expected to develop manifestations of the related condition; in GeneReviews, generally reserved for autosomal recessive conditions; may also refer to an individual with a balanced chromosome rearrangement. Note regarding autosomal dominant disorders: GeneReviews does not consider a heterozygote (who has – or is at risk of developing – manifestations of a disorder) to be a carrier.

Related terms: autosomal recessive; carrier rate; carrier testing; heterozygous; obligate heterozygote

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carrier rate

Synonym: carrier freqency

The proportion of individuals in a population who have a single copy of a recessive variant that is pathogenic for a specific condition

Related terms: allele frequency; carrier; heterozygous

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carrier testing

Synonyms: carrier detection, heterozygote testing

Testing used in the course of reproductive counseling to identify (typically) asymptomatic individuals who are heterozygous for a pathogenic variant associated with a specific autosomal recessive or X-linked disorder

Related terms: autosomal recessive; carrier; heterozygous; molecular genetic testing; pathogenic variant; X-linked

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cDNA

Complementary DNA; the reverse-transcribed mRNA. The cDNA sequence of a gene differs from the genomic sequence of the gene in that it does not include the introns; cDNA does not occur in nature but can be synthesized from mRNA using a series of chemical reactions and may be analyzed to determine mRNA sequence. The nomenclature system used to annotate sequence variants in the context of the coding sequence is based on complementary DNA.

Related terms: gDNA; mRNA

chromosomal microarray

Synonym: CMA

Term that refers to methods used to detect copy number variants (losses or gains of chromosome material), which may be benign, pathogenic, or of uncertain clinical significance. A far more sensitive method than traditional karyotyping, CMA detects both large and small copy number variants. Depending on the method used, CMA may involve scanning of the whole genome, targeted regions of the genome, or a specific chromosome or chromosome segment. The CMA methods used most commonly in clinical practice include oligo (oligonucleotide) array, SNP (single-nucleotide polymorphism) array, and oligo/SNP combination array.

Related terms: comparative genomic hybridization; copy number variant; SNP array

chromosome

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

Related terms: aneuploidy; autosomal; cytogenetic; karyotype

chromosome breakage studies

Cytogenetic testing to detect an increased rate of chromosome breakage or rearrangement in metaphase cells by exposing cell cultures to clastogenic agents such as diepoxybutane (DEB) or mitomycin C (MMC); cell cultures not exposed to the DNA clastogenic agent are used as controls to measure the spontaneous rate of chromosome breakage or rearrangement.

cis

Synonyms: cis configuration, coupling

Referring to two variants on the same chromosome (typically used to describe variants within the same gene)

Related term: trans

coding region

Synonyms: open reading frame, ORF

DNA sequence that has the potential to be transcribed into RNA and translated into protein; must include a start codon and termination codon

Related terms: exome sequencing; exon; intron; promoter region

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comparative genomic hybridization

Method in which two DNA samples (a control and a test sample), labeled in different fluorescent colors, are hybridized to a single target to assay for relative losses (deletions) or gains (duplications) in the DNA of the test sample compared to the control

Related terms: chromosomal microarray; SNP array

compound heterozygous

Referring to two heterozygous variants present in trans configuration within the same genomic region of interest (typically within the same gene)

Related terms: biallelic; heterozygous; trans

congenital

Present at birth; not necessarily genetic

consanguineous

Referring to reproductive partners who have a relatively close genetic relationship (e.g., cousins)

Related terms: autosomal recessive; pedigree

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consanguinity

See consanguineous.

Related terms: autosomal recessive; pedigree

contiguous gene deletion

Deletion of a chromosome segment that encompasses two or more adjacent genes

Related terms: deletion; deletion syndrome

contiguous gene deletion syndrome

A constellation of clinical findings caused by deletion of a chromosome segment that encompasses two or more adjacent genes

Related terms: deletion syndrome; FISH

copy number variant

Synonym: CNV

Duplication or deletion of a section of DNA. CNVs can be benign (normal), pathogenic, or of uncertain clinical significance. The method used to detect a CNV varies based on its size (see deletion/duplication analysis).

Related term: single-nucleotide variant

critical region

The specific portion of a chromosome or a gene that, when altered in some way (deleted, duplicated, or otherwise mutated), produces the characteristic set of phenotypic abnormalities associated with a particular syndrome or disorder

custom prenatal testing

Prenatal testing offered to families in which (a) pathogenic variant(s) have been identified in an affected family member in either a research or clinical laboratory; testing is not otherwise clinically available for prenatal diagnosis.

custom testing

Testing offered to families in which (a) pathogenic variant(s) have been identified in an affected family member in either a research or clinical laboratory; testing is not otherwise clinically available.

cytogenetic

Referring to chromosome abnormalities such as aneuploidies, deletions, duplications, and translocations

Related terms: chromosome; contiguous gene deletion; deletion; deletion syndrome; duplication; FISH; karyotype

D

de novo

Referring to a gene variant that does not occur in either parent; present for the first time in the proband

deletion

Absence of a segment of DNA; may be as small as a single base or as large as one or more genes. The method used to detect a deletion depends on the size of the deletion.

Related term: deletion/duplication analysis

deletion/duplication analysis

Synonym: copy number analysis

Testing that identifies deletions/duplications not routinely detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes the gene/chromosome segment of interest.

Related terms: chromosomal microarray; deletion; duplication; FISH; next-generation sequencing; PCR; Sanger sequencing; targeted analysis for pathogenic variants

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deletion syndrome

Synonym: microdeletion syndrome

A recognizable phenotype caused by a chromosome deletion that spans one or more genes and may be too small to be detected using conventional cytogenetic methods; the deletion is typically detected by chromosomal microarray (CMA). Depending on the size of the deletion, other techniques including FISH and quantitative PCR can sometimes be employed to identify the deletion.

Related terms: chromosomal microarray (CMA); chromosome; contiguous gene deletion syndrome; FISH; quantitative PCR

digenic

Referring to expression of a phenotype that requires the presence of pathogenic variants in two different genes

Related terms: oligogenic; trigenic

domain

A specific region or amino acid sequence in a protein associated with a particular function or corresponding segment of DNA

dominant-negative

Referring to a single, heterozygous pathogenic variant which produces a protein that interferes with (i.e., dimerizes or combines with, or blocks) the normal protein produced by the other allele, adversely affecting protein function. In cases of polymeric molecules, such as collagen, dominant-negative variants are often more deleterious than variants resulting in no gene product (null variants).

duplication

The presence of one or more additional copies of a segment of DNA; may be as small as a single base or as large as one or more genes. The method used to detect a duplication depends on the size of the duplication.

Related term: deletion/duplication analysis

dysmorphic

Referring to visible morphologic findings that differ from those commonly seen in the general population or that are expected from the family background

E

exome

The part of the genome that includes all coding nuclear DNA sequences. The human exome comprises approximately 180,000 exons that are transcribed into mature RNA.

Related terms: coding region; exome sequencing; exon; genome sequencing; next-generation sequencing

exome sequencing

Sequence analysis of the exons of protein-coding genes in the genome typically performed by target enrichment or capture of exons followed by next-generation sequencing (NGS). Exome sequencing techniques have non-standardized, highly variable coverage; of particular note are regions of the exome refractory to accurate sequencing by this method (including genes with a pseudogene, highly repetitive coding regions, and large deletions and duplications). Laboratories may also include sequence analysis of some non-coding regions of the genome (e.g., promoters, highly conserved regulatory sequences). Note that the term "exome sequencing" is preferred over the formerly used term "whole-exome sequencing" because coverage of the exome is less than 100%, and thus the "whole" exome is not sequenced.

Related terms: coding region; exome; exon; genome sequencing; next-generation sequencing

exon

Coding sequence of DNA present in mature messenger RNA

Related terms: coding region; exome sequencing; intron

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F

familial

Referring to a condition or allelic variant that occurs in more than one family member

first-degree relative

A parent, full sib, or child of an individual

Related terms: pedigree; second-degree relative

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FISH

Fluorescent in situ hybridization; a technique used to identify the presence of specific chromosomes or chromosome regions through hybridization (attachment) of fluorescently labeled DNA probes to denatured chromosomal DNA. Examination under fluorescent lighting detects the presence of the hybridized fluorescent signal (and hence presence of the chromosome material) or absence of the hybridized fluorescent signal (and hence absence of the chromosome material).

With interphase FISH, probes are introduced directly to the interphase cell. Interphase FISH is often used for rapid detection of specific types of aneuploidy in fetal cells and for the detection of certain deletions, duplications, and other abnormalities in tumor cells. In contrast to metaphase FISH, interphase FISH does not permit visualization of the actual chromosomes; therefore, certain structural rearrangements or aneuploidy will not be detected.

With metaphase FISH, cells progress through the division process until metaphase, when chromosomes are condensed and can be individually distinguished. In contrast to interphase FISH, metaphase FISH permits visualization of the actual chromosomes as well as the general location of the abnormality on the chromosome.

Related term: aneuploidy

fluorescent in situ hybridization

See FISH.

founder effect

The higher-than-average frequency of a rare allele in a population isolated over time by geography, language, and/or culture, resulting from the presence of the allele in an early member or members ("founders") of that group. For example, a founder effect accounts for the high incidence of Huntington disease in the Lake Maracaibo region of Venezuela.

Related term: founder variant

founder variant

A pathogenic variant observed in high frequency in a specific population due to the presence of the variant in a single ancestor or small number of ancestors

Related terms: allele frequency; founder effect

frameshift variant

Synonyms: out-of-frame variant, out-of-frame deletion

A deletion, duplication, or insertion within an exon involving a number of base pairs that is not a multiple of three, consequently disrupting the triplet reading frame and usually leading to the creation of a premature termination (stop) codon and subsequent loss of normal protein product

Related term: pathogenic variant

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

Related terms: anticipation; reduced-penetrance allele; trinucleotide repeat

G

gain-of-function

Referring to a variant associated with an increase in one or more functions of a gene product, a novel function of a gene product, or a change in timing of gene expression

gDNA

Genomic DNA. The DNA in a cell that is chromosomal DNA. Genomic DNA does not include mitochondrial DNA.

Related terms: cDNA; genomic; mRNA

gene

The basic unit of heredity, consisting of a segment of DNA arranged in a linear manner along a chromosome. A gene codes for a specific protein, a segment of protein, or non-coding RNA.

Related terms: allele; genomic; genotype

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gene conversion

The transfer of DNA sequences between two very similar genes, most often by unequal crossing over during meiosis; can be a mechanism for mutation if the transfer of material disrupts the coding sequence of the gene or if the transferred material itself contains one or more pathogenic variants

Related terms: pseudogene; recombination; unequal crossing over

gene product

Most genes are transcribed into segments of RNA (ribonucleic acid), which are translated into proteins. Both RNA and proteins are products expressed by the gene.

Related terms: gene; isoforms

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gene therapy

Treatment of a genetic disorder by replacing or manipulating an abnormal gene

genetic counseling

The process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. Genetic counseling deals with risk assessment and the use of family history and testing to clarify genetic status for family members.

genome sequencing

Sequence analysis of the genome including coding and non-coding regions typically performed by next-generation sequencing (NGS) of sheared genomic DNA; genome sequencing techniques have non-standardized, highly variable coverage. Note that "genome sequencing" is preferred over the formerly used term "whole-genome sequencing" because coverage of the genome is less than 100%, and thus the "whole" genome is not sequenced.

Related term: exome sequencing; genomic; next-generation sequencing

genomic

Referring to the human genome, which comprises the DNA in all chromosomes and in mitochondria

Related terms: gDNA; genome sequencing

genotype

Commonly, the allele or set of alleles at a single locus; less commonly, the set of alleles at multiple or all loci

genotype-phenotype correlation

The association between an individual's genotype and the resulting pattern of clinical findings, or phenotype

Related terms: genotype; phenotype

genotyping

Molecular assay designed to detect the presence or absence of a specific variant (or variants) in DNA; variants in DNA not targeted by the assay will not be detected.

germline

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

germline mosaicism

Synonym: gonadal mosaicism

Two or more cell lines with a different genetic composition confined to the precursor (germline) cells of the egg or sperm

Related term: somatic mosaicism

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germline variant

An allelic variant that is present in the egg or sperm (germ cell) and thus can be passed to subsequent generations

Related terms: de novo; germline; germline mosaicism

gonadal mosaicism

See germline mosaicism.

H

haploid

Half the diploid or normal number of chromosomes in a somatic cell; the number of chromosomes in a gamete (egg or sperm) cell, which in humans is 23 chromosomes, one chromosome from each chromosome pair

haploinsufficiency

A cause of disease in which the protein product from a single normal allele is insufficient -- given the presence of a loss-of-function pathogenic variant on the other allele -- to prevent the appearance of an abnormal phenotype

hemizygous

Referring to a gene normally present in only a single copy; usually an X-linked gene in a male

Related terms: heterozygous; homozygous; X-linked

heteroplasmic

See heteroplasmy.

heteroplasmy

The presence within a single cell of both normal and mutated mitochondrial DNA (mtDNA); the proportion of normal to mutated mtDNA (i.e., the mutant load) may vary in different tissues and is a critical factor in the expression and severity of disease caused by mutation of mtDNA.

Related terms: mitochondrial inheritance; variable expressivity

heterozygote

An individual with two different alleles at a particular locus (one on each chromosome of a pair), one of which is usually pathogenic.

Related terms: carrier; homozygous; obligate heterozygote

heterozygous

Denoting a variant (distinct from the reference sequence) that comprises one of two alleles of a given gene

Related terms: carrier; heterozygote; homozygous; obligate heterozygote

homoplasmic

Characterized by homoplasmy

homoplasmy

The presence of identical alleles at all mitochodondrial loci within a single cell or organism

homozygous

Denoting a variant (distinct from the reference sequence) that is present on both alleles of a given gene

Related terms: compound heterozygous; heterozygous

hot spot

A DNA sequence that is highly susceptible to mutation because of some inherent instability, a tendency toward unequal crossing over, or chemical predisposition to single-nucleotide substitutions; a region where pathogenic variants are observed with greater frequency

hypomorphic

Referring to an allelic variant characterized by partial loss of gene activity (including reduction in protein production or function)

I

imprinted

See imprinting.

imprinting

The process by which maternally and paternally derived chromosomes are uniquely chemically modified (usually by methylation), leading to different expression of a certain gene or genes on those chromosomes depending on their parental origin. Patterns of gene expression and repression vary between imprinted regions.

Related terms: methylation; trisomy rescue; uniparental disomy

inactivating

See loss-of-function.

indel

Abbreviation for an insertion (i.e., duplication) or a deletion of nucleotides, typically within a gene or coding region

Related terms: deletion; duplication; insertion

in-frame

Referring to a variant (usually a small deletion or insertion) that does not cause a shift in the triplet reading frame. Such variants can be pathogenic when they lead to the synthesis of an abnormal protein product (i.e., one with one or more missing or inserted amino acids).

insertion

Presence of extra DNA in a gene or other DNA region; may be as small as a single base or as large as one or more genes; if the insertion occurs in a coding region, it may potentially disrupt gene function. An insertion is considered a duplication when the inserted DNA is a perfect match to the adjacent DNA.

Related term: duplication

interfamilial variability

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

Related term: intrafamilial variability

intrafamilial variability

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

Related term: interfamilial variability

intron

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

Related terms: coding region; exon; intronic; splicing

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intronic

Referring to DNA or variants in DNA within an intron

Related term: intron

isoelectric focusing

Method by which proteins migrate in a matrix according to the pH; an amino acid substitution can change the isoelectric point of a protein.

isoforms

Similar forms of a protein produced by different versions of messenger RNA resulting from use of different promoters, skipping of exons, or differences in splicing; may be tissue specific.

isolated

Referring to a finding that occurs in the absence of other systemic involvement

K

karyotype

A photographic representation of the chromosomes of a single cell, cut and arranged in pairs based on their size and banding pattern according to a standard classification

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L

likely benign variant

An alteration in a gene (distinct from the reference sequence) that is very unlikely to be associated with an abnormal phenotype or increased disease risk. A likely benign variant meets most, but not all, criteria to be classified as benign according to the five-tier system for describing the clinical significance of genetic variants (see Related terms).

Related terms: benign variant; likely pathogenic variant; pathogenic variant; variant of uncertain significance

likely pathogenic variant

An alteration in a gene (distinct from the reference sequence) that is likely to be associated with an abnormal phenotype or increased disease risk. A likely pathogenic variant meets most but not all criteria to be classified as pathogenic according to the five-tier system for describing the clinical significance of genetic events (see Related terms).

Related terms: benign variant; likely benign variant; pathogenic variant; variant of uncertain significance

locus

The physical site or location of a specific gene on a chromosome. OMIM (http://omim.org) is the standard reference used for locus information included in GeneReviews.

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-function

Referring to a variant associated with partial or total loss of the function of a gene product

Related terms: gain-of-function; pathogenic variant

loss of heterozygosity

Synonym: LOH

Loss of one of the two alleles at a locus or at multiple loci leading to a homozygous or hemizygous state. LOH can be caused by a variety of genetic mechanisms including deletion, chromosome loss, and mitotic crossing over.

Related terms: deletion; hemizygous; heterozygous; homozygous

M

manifesting heterozygote

An individual who has at a particular locus a pathogenic variant on one chromosome (usually expressed in a recessive manner) and a wild-type allele on the other chromosome, and who has findings of the disorder; generally refers to a clinically affected female with a heterozygous pathogenic variant in an X-linked gene. The phenotype is usually less severe than in a hemizygous male with the same pathogenic variant.

Related terms: carrier; heterozygous; X-chromosome inactivation; X-linked

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

Related terms: imprinting; X-chromosome inactivation

methylation analysis

Testing that evaluates the methylation status of a gene (attachment of methyl groups to DNA cytosine bases). Genes that are methylated are not expressed.

Related terms: imprinting; methylation; sequence analysis; X-chromosome inactivation

microdeletion syndrome

See deletion syndrome.

microsatellite

Synonyms: satellite DNA, short tandem repeats

A segment of DNA two to five nucleotides in length (di-, tri-, tetra-, or pentanucleotide repeats) typically repeated five to 50 times or more. Microsatellite DNA is dispersed throughout the genome in non-coding regions between genes or within genes (i.e., in introns). Microsatellite DNA is inherently unstable and susceptible to mutation.

mismatch repair

The DNA 'proofreading' system that identifies, excises, and corrects errors in the pairing of the bases during DNA replication. Mutation of the genes encoding mismatch repair proteins can result in susceptibility to some cancers.

missense

Referring to a single base-pair substitution that results in the translation of a different amino acid at that position; can be pathogenic or benign

Related terms: benign variant; likely benign variant; likely pathogenic variant; pathogenic variant; variant of uncertain significance

mitochondrial inheritance

Synonym: maternal inheritance

Mitochondria -- cytoplasmic organelles that produce the energy source ATP for most chemical reactions in the body -- contain their own distinct genome; pathogenic variants in mitochondrial genes are responsible for several recognized syndromes and are always maternally inherited because mitochondria are transmitted by the ova, not the sperm.

Related terms: heteroplasmy; homoplasmy; mode of inheritance; variable expressivity

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mode of inheritance

Synonyms: inheritance pattern, pattern of inheritance

The manner in which a particular genetic condition is passed from one generation to the next. Autosomal dominant, autosomal recessive, X-linked, multifactorial, and mitochondrial inheritance are examples.

molecular genetic testing

A term widely used in clinical genetics encompassing the diverse testing methods that use molecular biology techniques to identify disease-causing genetic alterations. Examples of molecular genetic tests include: genotyping to detect specific pathogenic variants; sequencing of a gene to detect pathogenic variants; amplification or hybridization methods (e.g., qPCR, array CGH, MLPA) to detect copy number variants involving one or more genes; methylation-specific techniques to detect epigenetic changes that influence gene expression; and exome and genome sequencing.

monosomy

The presence of only one chromosome from a pair; partial monosomy refers to the presence of only one copy of a segment of a chromosome

mosaicism

Within a single individual or tissue, the occurrence of two or more cell lines with a different genetic or chromosomal composition. Mosaicism may involve somatic cells, germline cells, and/or tumor cells.

Related terms: germline mosaicism; germline variant; post-zygotic; somatic mosaicism

mRNA

Messenger RNA

multifactorial

Referring to the combined contribution of one or more often unspecified genes and environmental factors, often unknown, in the causation of a particular finding

multi-gene panel

Simultaneous molecular testing of multiple genes associated with the same or similar clinical phenotypes. The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and over time. Methods used may include sequence analysis, deletion/duplication analysis, or other non-sequencing based tests.

N

newborn screening

Testing done within days of birth to identify infants at increased risk for a specific condition so that treatment and/or preventive measures 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.

Related terms: sensitivity

next-generation sequencing (NGS)

Synonyms: massively parallel sequencing (MPS), high-throughput sequencing

Referring to several different technologies, all of which allow simultaneous sequence analysis of millions of DNA fragments. NGS can detect variations as small as a single-base substitution; depending on the methods used, NGS may detect copy number variants (CNVs). NGS is used primarily for multi-gene panels and genome, exome, and transcriptome sequencing. NGS may also be used for single-gene testing (e.g., targeting of a single gene on a mult-gene panel or sequencing of a large multi-exon gene). Results from NGS may require confirmation by an alternative sequencing method.

Related terms: copy number variant; exome sequencing; genome sequencing; multi-gene panel; sequence analysis; single-nucleotide variant

non-allelic homologous recombination

Synonym: NAHR

The result of a process in which segmental duplications (low copy repeats) flanking a region misalign during meiosis, followed by unequal crossing over between the segmental duplications. The process can produce gametes with the recurrent deletion or the reciprocal recurrent duplication.

Related term: unequal crossing over

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nonsense

Referring to a variant in which a codon is changed from one that specifies an amino acid to one that specifies a termination (stop)

normal variant

See benign variant.

nucleotide repeat

Sequence of n nucleotides repeated a number of times in tandem; can occur within or near a gene. The size of nucleotide repeats varies: smaller numbers of repeats are common and not associated with phenotypic abnormalities; abnormally large numbers of repeats may be associated with phenotypic abnormalities and are classified as (in increasing order): mutable normal alleles, premutations, reduced-penetrance alleles, and full-penetrance alleles.

Related terms: premutation; trinucleotide repeat

null

Referring to a pathogenic variant that results in either no mRNA, no protein, or a non-functional protein

O

obligate carrier

See obligate heterozygote.

obligate heterozygote

Synonym: obligate carrier

An individual who must be heterozygous for an allelic variant based on analysis of the family history; applies to disorders inherited in an autosomal recessive or X-linked manner

Related terms: autosomal dominant; carrier; heterozygous; X-linked

oligogenic

Referring to a phenotype expressed only in the presence of pathogenic variants in more than one gene; may be referred to (with less precision) as multigenic or polygenic

Related terms: digenic; trigenic

open reading frame

See coding region.

P

pathogenic variant

An alteration in a gene (distinct from the reference sequence) that is associated with an abnormal phenotype or increased disease risk. A pathogenic variant meets criteria to be classified as pathogenic according to the five-tier system for describing the clinical significance of genetic variants (see Related terms).

Related terms: benign variant; likely benign variant; likely pathogenic variant; variant of uncertain significance

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 commonly used either: (a) to generate a sufficient quantity of DNA to perform a test (e.g., sequence analysis); or (b) as a test in and of itself (e.g., allele-specific amplification, trinucleotide repeat quantification).

Related terms: quantitative PCR; sequence analysis; targeted analysis for pathogenic variants; X-chromosome inactivation

pedigree

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

Related terms: consanguineous; obligate heterozygote; proband

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penetrance

The proportion of individuals with a pathogenic variant causing a particular disorder who exhibit clinical findings of that disorder; most often refers to autosomal dominant conditions.

Related terms: autosomal dominant; intrafamilial variability; variable expressivity

phenotype

The observable characteristics of the expression of a gene; the clinical presentation of an individual with a particular genotype

Related terms: allelic heterogeneity; dysmorphic; genotype; genotype-phenotype correlation; variable expressivity

polygenic

Referring to a condition caused by the additive contributions of variants in multiple genes at different loci

polymerase chain reaction

See PCR.

polymorphism

A natural variation in a gene, DNA sequence, protein, or chromosome that has no adverse effect on the individual

Related terms: allele; benign variant; variant of uncertain significance

post-zygotic

Referring to a pathogenic variant or abnormality in chromosome replication/segregation/methylation that occurs after fertilization of the ovum by the sperm, often leading to mosaicism (two or more genetically distinct cell lines within the same organism)

Related terms: germline mosaicism; mosaicism; somatic mosaicism; trisomy rescue

preimplantation genetic diagnosis

Synonyms: PGD, preimplantation testing

Genetic testing of one or more cells removed from early embryos conceived by in vitro fertilization and transfer to the mother's uterus of only those embryos determined not to have the pathogenic variant(s) / chromosome anomaly(ies) of concern

Related terms: molecular genetic testing; polymerase chain reaction (PCR); prenatal diagnosis; targeted analysis for pathogenic variants

premutation

An allele in which a tandemly repeated nucleotide sequence within or near a gene contains more repeats than a normal allele. A premutation allele can expand into a full-penetrance allele (repeat size associated with disease) when passed through the germline. Although premutation alleles are not typically associated with disease, in rare instances they are; the best example is premutation FMR1 alleles, which are associated with disease phenotypes distinct from fragile X syndrome (which is caused by full-penetrance FMR1 alleles).

prenatal diagnosis

Synonym: prenatal testing

Testing performed during pregnancy to determine if a fetus is affected with a particular disorder. Invasive procedures such as chorionic villus sampling (CVS), amniocentesis, or periumbilical blood sampling (PUBS) are used to obtain a sample for testing; imaging (e.g., ultrasound, MRI) is used to evaluate fetal anatomy.

private

Referring to a variant that does not have appreciable allele frequency in the general population; a private variant may be benign or pathogenic; historically used to describe a variant thought to occur in a single family

proband

Synonyms: propositus, index case

The affected individual through whom a family with a genetic disorder is ascertained; may or may not be the individual presenting for genetic counseling

Related terms: affected; pedigree

promoter region

A region of DNA (just upstream of a gene) that acts as a binding site for transcription factors and RNA polymerase to initiate transcription

pseudodominant inheritance

An autosomal recessive condition present in individuals in two or more generations of a family, thereby appearing to follow a dominant inheritance pattern; occurs as a result of reproduction between an affected individual and a carrier partner

pseudogene

A copy of a gene that is transcriptionally or translationally inactive due to accumulation of inactivating variants. Pseudogenes are classified as either non-processed (includes introns) or processed (does not include introns).

Related terms: deletion; duplication; unequal crossing over

Q

quantitative PCR

Synonyms: kinetic quantitative PCR, real time quantitative PCR

A form of PCR used to determine the relative amount of DNA or RNA in a sample; commonly used to detect heterozygous deletions and duplications

Related terms: deletion; duplication; heterozygous; PCR; targeted analysis for pathogenic variants

R

recombination

The exchange of a segment of DNA between two homologous chromosomes during meiosis leading to a novel combination of genetic material in the gamete

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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

recurrent deletion

Deletion of a specific size -- usually mediated by non-allelic homologous recombination (NAHR) -- occurring multiple times in the general population

Related term: non-allelic homologous recombination

reduced-penetrance allele

An alteration in a gene (distinct from the reference sequence) that is associated with an abnormal phenotype or increased disease risk in some (not all) individuals who have the alteration

Robertsonian translocation

The joining of two acrocentric chromosomes at the centromeres with loss of their short arms to form a single abnormal chromosome; in acrocentric chromosomes the centromere is located near the end of the chromosome. Acrocentric chromosomes are 13, 14, 15, 21, and 22.

Related terms: chromosome; deletion; duplication

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S

Sanger sequencing

A method of DNA sequencing that uses DNA polymerase to copy single-stranded DNA templates by adding nucleotides to form a complementary strand. Its use is limited to sequence analysis of a single region of DNA (maximum ~1000 bp) -- in contrast to massively parallel sequencing, in which millions of fragments of DNA can be sequenced simultaneously.

Related terms: deletion/duplication analysis; molecular genetic testing; PCR; targeted analysis for pathogenic variants

second-degree relative

A relative who shares one quarter of an individual's genes (i.e., grandparent, grandchild, uncle, aunt, nephew, niece, half-sib)

segregation

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

sensitivity

The frequency with which testing yields a positive result when the individual being tested either (a) is actually affected (clinical sensitivity) or (b) has a pathogenic variant detected by molecular genetic testing (analytic sensitivity)

sequence alteration

Synonym: variant

Any alteration in a gene from its natural state; can be benign (may be referred to as a polymorphism), pathogenic, or of uncertain significance

Related terms: benign variant; likely benign variant; likely pathogenic variant; pathogenic variant; variant of uncertain significance; wild-type

sequence analysis

Synonym: sequencing

Process by which the nucleotide sequence for a segment of DNA is determined

Related terms: molecular genetic testing; next-generation sequencing; PCR; Sanger sequencing; targeted analysis for pathogenic variants

simplex

Referring to a single occurrence of a disorder in a family

single-nucleotide variant

Synonyms: SNV, point mutation

An alteration in DNA sequence caused by a single-nucleotide base change, insertion, or deletion; can be benign, pathogenic, or of uncertain significance

sister chromatid exchange

Synonym: SCE

Exchange of genetic material between the two chromatids of a single chromosome during the cell division process; similar to crossing over (recombination), except that the exchange involves the two sister chromatids of a single chromosome, whereas crossing over refers to exchange of genetic material between the two homologous chromosomes of a chromosome pair

SNP array

Method used in a given individual to genotype single-nucleotide polymorphisms (SNPs) across the genome to identify: (1) copy number variants; (2) regions of uniparental disomy; (3) evidence of parental consanguinity

Related terms: chromosomal microarray; comparative genomic hybridization; copy number variant; single-nucleotide variant; uniparental disomy

somatic mosaicism

Two or more cell lines with a different genetic composition within the cells of an individual (may or may not include the germline cells)

somatic pathogenic variant

Variant resulting from mutation that occurs during embryonic development (i.e., that is not inherited from a parent)

Southern blot

Synonyms: Southern analysis, Southern blot analysis

Technique used to detect differences in the lengths of DNA fragments occurring as a result of an allelic variant or gene rearrangement

Related term: molecular genetic testing; targeted analysis for pathogenic variants

splice site

The junction between an intron and an exon in a DNA sequence; the site of intron/exon splicing. A variant in the splice site can cause abnormal removal of introns and splicing together of exons such that one or more introns remaining in the mRNA can potentially disrupt generation of the protein product.

splicing

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

Referring to the chance occurrence of a disorder or abnormality that is not expected to recur in a family

Related terms: recurrence risk; simplex

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syndromic

In GeneReviews: referring to a disorder characterized by a constellation of phenotypic features that either: (1) specifically suggest the diagnosis (which can be confirmed by molecular genetic testing); or (2) allow diagnosis of the disorder in the absence of confirmatory molecular genetic findings

T

targeted analysis for pathogenic variants

Testing for specific variants known to cause disease. Examples include: (1) one or more specific pathogenic variants (e.g., Glu6Val for sickle cell anemia, a panel of pathogenic variants for cystic fibrosis); (2) a nucleotide repeat expansion (e.g., the trinucleotide repeat expansion associated with Huntington disease); and (3) common deletions (e.g., population-specific alpha globin gene deletions).

targeted mutation analysis

See targeted analysis for pathogenic variants.

trans

Synonym: trans configuration

Referring to two heterozygous variants on opposite homologous chromosomes (typically used to describe variants within the same gene)

Related term: cis

transcription factor

A protein that binds to DNA and either activates or represses transcription of one or more genes

translocation

Synonym: chromosome rearrangement

A chromosome alteration in which a whole chromosome or segment of a chromosome becomes attached to or interchanged with another whole chromosome or segment

Balanced translocations (in which there is no apparent net loss or gain of chromosome material) are usually not associated with phenotypic abnormalities, although gene disruptions at the breakpoints of the translocation can, in some cases, cause adverse effects, including some known genetic disorders.

Unbalanced translocations (in which there is loss or gain of chromosome material) are nearly always associated with an abnormal phenotype.

Balanced and unbalanced translocations can be visualized by karyotype analysis; chromosomal microarray (CMA) cannot detect balanced translocations.

trigenic

Referring to expression of a phenotype that requires the presence of pathogenic variants in three different genes

Related terms: digenic; oligogenic

trinucleotide repeat

Sequences of three nucleotides repeated a number of times in tandem within a gene

Related term: anticipation; nucleotide repeat; premutation; targeted analysis for pathogenic variants

trisomy rescue

The phenomenon in which a fertilized ovum initially contains 47 chromosomes (i.e., one chromosome is trisomic), but loses one of the trisomic chromosomes in the process of cell division such that the resulting daughter cells and their descendants contain 46 chromosomes, the normal number

Related terms: aneuploidy; imprinting; post-zygotic; uniparental disomy

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U

uncertain significance

A variant of uncertain significance (VOUS, VUS) is an alteration in a gene (distinct from the reference sequence) that may or may not be disease-causing or associated with increased risk of an abnormal phenotype; the identification of a variant of uncertain significance neither confirms nor rules out a diagnosis. A variant of uncertain significance does not meet criteria to be classified as pathogenic or benign according to the five-tier system for describing the clinical significance of genetic variants (see Related terms). Sequence analysis may identify multiple variants of uncertain significance in a given gene or hundreds to thousands in the human exome.

Related terms: benign variant; likely benign variant; likely pathogenic variant; pathogenic variant

unequal crossing over

Exchange of DNA during meiosis between improperly aligned segments of DNA that can result in a gain or loss of DNA. Circumstances that predispose to unequal crossing over are misalignment of: (1) highly homologous segment duplications (low copy repeats) referred to as non-allelic homologous recombination which result in recurrent deletions or duplications; and (2) a gene and its pseudogene in tandem on a chromosome (e.g., CYP21 and its pseudogene CYP21P; GBA and its pseudogene GBAP) which result in de novo pathogenic variants.

See non-allelic homologous recombination.

Related terms: deletion; duplication; gene conversion; recombination

uniparental disomy

Synonym: UPD

The situation in which both members of a chromosome pair or segments of a chromosome pair are inherited from one parent and neither is inherited from the other parent; uniparental disomy can result in an abnormal phenotype in some instances.

Related terms: imprinting; trisomy rescue

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unknown significance

See uncertain significance.

V

variable expressivity

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

Related terms: interfamilial variability; intrafamilial variability

W

whole-exome sequencing

See exome sequencing.

whole-genome sequencing

See genome sequencing.

wild-type

Referring to a normal, fully functional gene or allele

X

X-chromosome inactivation

Synonym: lyonization

In females, the phenomenon by which one X chromosome (either maternally or paternally derived) is randomly inactivated in early embryonic cells, with fixed inactivation in all descendant cells; first described by the geneticist Mary F Lyon, PhD

Related terms: manifesting heterozygote; X-linked

X-linked

Referring to a gene on the X chromosome or to the mode of inheritance in which the causative pathogenic variant is on the X chromosome; hemizygous males will be affected; heterozygous females may or may not be affected depending on the disorder and factors influencing X-chromosome inactivation.

Related terms: hemizygous; heterozygous; mode of inheritance; X-chromosome inactivation

X-linked dominant

See X-linked.

X-linked recessive

See X-linked.

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