A
- allele
One version of a gene at a given location (locus) along a chromosome
Related terms: allele frequency;
benign variant; compound heterozygous;
heterozygote; homozygous;
likely benign; likely pathogenic;
locus; pathogenic variant; polymorphism;
variant of uncertain significance; wild type
- 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
Related term:
misattributed parentage
- alternate paternity
Synonym: non-paternity
The situation in which the presumed father of a particular individual is not the biological father
Related term:
misattributed parentage
- 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
- 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; gonadal mosaicism; heterozygote; 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;
heterozygote; 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;
likely pathogenic; pathogenic variant;
variant of uncertain significance
- biallelic
Referring to both alleles of a gene pair. 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;
may also refer to an individual with a balanced chromosome rearrangement. Note regarding autosomal dominant disorders: While the terms "heterozygote"
and "carrier" are often used synonymously in the literature, 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;
heterozygote; obligate heterozygote;
X-linked
- 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; heterozygote
- carrier testing
Synonym: carrier detection
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; heterozygote;
molecular genetic testing; pathogenic variant;
X-linked
- 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
- chimerism
Within a single individual or tissue, two or more genetically distinct cell lineages originating from different zygotes
Related terms: mosaicism
- 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 (also referred to as cytogenomic CMA), 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
- codominant
Referring to two phenotypes being expressed at the same time from the same gene; for example, the AB blood groups in humans
- 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;
heterozygote; 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
- consanguinity
See consanguineous.
Related terms: autosomal recessive;
pedigree
- constitutional variant
A variant that is present in all somatic and germline cells and thus has the potential to be passed to subsequent generations; may be used synonymously
with "germline variant"
Related term:
germline variant
- 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 genetic variant that is present for the first time in one family member
- 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
- 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).
- double heterozygosity
The presence in an individual of a heterozygous variant in two different genomic regions of interest (typically, a heterozygous variant
in each of two different genes). The clinical consequences of double heterozygosity depend on the related disorder(s) and the mode(s)
of inheritance of the disorder(s).
Related term:
heterozygote
- 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
- epigenetic
Referring to chemical alterations to DNA nucleotides or proteins that control gene expression but do not alter the DNA sequence
- epimutation
A heritable change in gene activity that is not associated with a DNA variant but rather with gain or loss of DNA methylation or other heritable modifications of chromatin
(Reprinted from Trends in Genetics, 30:519-20. Oey H, Whitelaw E. On the meaning of the word "epimutation." Copyright 2014, with permission from Elsevier.)
- 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 array
A microarray designed to determine exon-level copy number for as many genes associated with disease as possible regardless of phenotype or
clinical features associated with the genes
Related term:
gene-targeted array
- 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 nonstandardized,
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 noncoding 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
F
- familial
Referring to a condition or 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
- FISH
Fluorescent in situ hybridization; a technique used to identify the presence of specific chromosomes or chromosomal 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 gene variant associated with one of the following abnormalities: an increase in one or more functions of the gene product;
a novel function of the gene product; a change in timing of gene expression
Related terms: loss-of-function;
pathogenic variant
- 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 noncoding RNA.
Related terms: allele;
genomic; genotype
- 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
- gene-targeted array
A microarray designed to determine exon-level copy number for a gene or set of genes associated with a phenotype or specific clinical feature
Related term:
exome array
- 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 noncoding regions typically performed
by next-generation sequencing (NGS) of sheared genomic DNA; genome sequencing techniques have nonstandardized, 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 terms:
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 correlations
Associations 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
See gonadal mosaicism.
- germline variant
A variant that is presumed to be present in all germ (egg and sperm) cells and somatic cells. Unlike a somatic variant (i.e., a
variant that arises spontaneously in a somatic cell), a germline variant can be transmitted to offspring.
Related terms: constitutional variant;
de novo; germline; gonadal mosaicism
- gonadal mosaicism
Synonym: germline mosaicism
Mosaicism confined to or involving gonadal cells
Related term:
somatic 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: heterozygote;
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. The risk that an individual who is heterozygous
for a pathogenic variant will have manifestations of the related phenotype depends on the specific disorder and the mode of inheritance of the disorder.
Related terms: carrier;
homozygous; obligate heterozygote
- heterozygous
See heterozygote.
- histone
A member of the family of proteins (referred to as histones) around which nuclear DNA is wrapped to facilitate condensation into chromosomes
and access for transcription. Eight histone proteins form a single histone core.
Related terms:
chromosome;
epigenetic; nucleosome
- 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; heterozygote
- 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 a variant characterized by partial loss of gene activity (including reduction in protein production or function)
I
- idiopathic
Relating to or denoting a disease or condition for which the cause is unknown
- 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
Noncoding sequence of DNA removed from mature messenger RNA prior to translation
Related terms: coding region;
exon; intronic; splicing
- 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
L
- likely benign
Referring to 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; pathogenic variant;
variant of uncertain significance
- likely pathogenic
Referring to 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. A likely pathogenic
variant is considered diagnostic and can be used for clinical decision making (see Related terms).
Related terms: benign variant;
likely benign; 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; heterozygote;
homozygous
M
- manifesting heterozygote
An individual who has at a particular locus a pathogenic variant on one chromosome 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; heterozygote; 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 noncoding regions between genes or within genes (i.e., in introns). Microsatellite DNA is inherently unstable and
susceptible to mutation.
- misattributed parentage
Refers to the situation in which a person reported to be the biological father or mother of a child is in fact not the biological parent. Factors that may
result in misattributed parentage include assisted reproduction (i.e., use of a donor sperm, donor egg, or donor embryo), undisclosed adoption, and alternate
paternity.
Related terms: alternate maternity;
alternate paternity
- 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; likely pathogenic;
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
- 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 combing
Technique in which fluorescent in situ hybridization (FISH) probes of known sequence are hybridized to uniformly stretched long fragments of DNA to determine content of and distance between targeted sequence with
high resolution. Used to assess repetitive regions of DNA not amenable to sequence analysis.
- molecular genetic testing
A term widely used in clinical genetics encompassing the diverse techniques used to identify the molecular basis of genetic
disease. 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.
- monoallelic
Referring to one allele of a gene pair, as opposed to biallelic, which refers to both alleles of a gene pair.
Related terms:
heterozygous; cis
- 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 postzygotic occurrence of two or more cell lines with a different genetic or chromosomal composition that are derived from a single fertilized egg. Mosaicism may involve somatic cells,
gonadal cells, and/or tumor cells.
Related terms: gonadal mosaicism; germline variant;
postzygotic; 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
- multigene 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
- 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 multigene 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 multiexon gene). Results from
NGS may require confirmation by an alternative sequencing method.
Related terms: copy number variant;
exome sequencing; genome sequencing;
multigene panel; sequence analysis;
single-nucleotide variant
- nonallelic 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
- noncoding RNA
Functional RNA (transcribed from a gene) that is not translated into protein
- 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.
- nucleosome
The functional unit of a chromosome, consisting of the length of DNA and the core of histone proteins around which DNA is wrapped.
The nucleosome is the building block of the chromosome.
Related terms:
chromosome; histone
- 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 nonfunctional protein
O
- obligate heterozygote
An individual who must be heterozygous for a variant based on analysis of the family history; applies to disorders inherited in an autosomal
recessive or X-linked manner. The term "obligate heterozygote" can also refer to individuals with an autosomal dominant disorder whose position in a
pedigree indicates that they must be heterozygous even though they do not manifest the phenotype.
Related terms: autosomal dominant;
autosomal recessive; carrier;
heterozygote; 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; likely pathogenic;
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
- 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 correlations; 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
- postzygotic
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: gonadal mosaicism;
mosaicism; somatic mosaicism; trisomy rescue
- preimplantation genetic diagnosis
See preimplantation genetic testing.
Related terms: molecular genetic testing;
polymerase chain reaction (PCR); prenatal testing;
targeted analysis for pathogenic variants
- preimplantation genetic testing
Synonyms: PGT, preimplantation testing
Genetic testing of one or more cells removed from early embryos conceived by in vitro fertilization and transferring to the mother's uterus 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 testing;
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
See prenatal testing.
- prenatal testing
Testing performed during pregnancy. Prenatal testing may be used 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:
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; heterozygote;
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
- 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 nonallelic homologous recombination (NAHR) - occurring multiple times in the general population
Related term:
nonallelic 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
- revertant mosaicism
Presence of two or more cell lines in one individual that have different genetic compositions - one or more cell lines having a germline pathogenic
variant and the other(s) derived from spontaneous somatic correction of the germline pathogenic variant to the normal (wild type) state
Related terms: germline variant;
mosaicism; somatic mosaicism
- 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
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 is shared (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; may be benign (may be referred to as a "polymorphism"), pathogenic, or of uncertain significance
Related terms: benign variant;
likely benign; likely pathogenic;
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)
Related term:
gonadal mosaicism
- 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 a variant or gene rearrangement
Related terms: 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 (noncoding 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
- 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 terms: 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; postzygotic; uniparental disomy
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; likely pathogenic;
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 nonallelic 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;
GBA1 [formerly GBA] and its pseudogene GBA1LP [formerly GBAP]) which result in de novo pathogenic variants.
See nonallelic homologous recombination.
Related terms: deletion; duplication;
gene conversion; recombination
- uniparental disomy
Synonym: UPD
The situation in which both copies of a chromosome pair (or chromosome pair segment) are from one parent (i.e., no copy is from the other parent). The individual may have two identical copies of one of the pair of parental chromosomes (termed uniparental isodisomy), or may have one copy of each of the parental chromosome pair (termed uniparental heterodisomy). Uniparental disomy can result in an abnormal phenotype in some instances.
Related terms: imprinting; trisomy rescue; uniparental heterodisomy; uniparental isodisomy
- uniparental heterodisomy
The situation in which an individual inherits both copies of a chromosome pair (or chromosome pair segment) from one parent; no copy is inherited from the other parent (compare uniparental isodisomy).
Related terms: imprinting; trisomy rescue; uniparental disomy; uniparental isodisomy
- uniparental isodisomy
The situation in which an individual inherits two identical copies of one of a chromosome pair (or chromosome pair segment) from one parent; no copy is inherited from the other parent (compare uniparental heterodisomy).
Related terms: imprinting; trisomy rescue; uniparental disomy; uniparental heterodisomy
- 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;
heterozygote; mode of inheritance; X-chromosome inactivation
- X-linked dominant
See X-linked.
- X-linked recessive
See X-linked.
