Genetics-Genes-Heredity All About You Need To Knows Genetics is the scientific study of genes and heredity—of how certain qualities or traits are passed from parents to offspring as a result of changes in DNA sequence. A gene is a segment of DNA that contains instructions for building one or more molecules that help the bodywork. DNA is shaped like a corkscrew-twisted ladder, called a double helix. The two ladder rails are called backbones, and the rungs are pairs of four building blocks (adenine, thymine, guanine, and cytosine) called bases. The sequences of these bases provide the instructions for building molecules, most of which are proteins. Researchers estimate that humans have about 20,000 genes. All of an organism’s genetic material, including its genes and other elements that control the activity of those genes, is its genome. An organism’s entire genome is found in nearly all of its cells. In human, plant, and animal cells, the genome is housed in a structure called the nucleus. The human genome is mostly the same in all people with just small variations Division of Genetics and Molecular, Cellular, and Developmental Biology The division supports research to understand the structure and function of cells and cellular components and the cellular and molecular mechanisms that underlie inheritance, gene expression, and development. In most cases, research whose overall goal is to gain knowledge about a specific organ or organ system or the pathophysiology, treatment, or cure of a specific disease or condition is not supported by GMCDB. The division consists of three branches: Cell Biology Branch This branch supports studies on the molecular basis of cellular function in a wide range of cell types and research organisms. Research topics include: plasma and intracellular membrane systems and functions protein processing, membrane trafficking, and intracellular transport cellular aspects of protein folding organelle biogenesis, inheritance, and dynamics cell division cytoskeletal structure and function cellular organization, motility, and mechanics cell adhesion and signaling cell-cell junctions and interactions mechanisms of cell death cellular signaling in growth Developmental and Cellular Processes Branch This branch supports studies on the genetic and biochemical pathways that cells utilize in development and in normal physiological processes. Research topics include: stem cell biology developmental genetics developmental signaling genetics of behavior and circadian biology chromosome structure and epigenetic regulation of gene expression population genetics and evolution adaptive responses to stress and nutrients microbiome, biofilms, and quorum sensing organismal response to the environment Genetic Mechanisms Branch This branch supports studies on the mechanism and regulation of basic molecular processes and the interactions among these processes. Research topics include: DNA and RNA metabolism (i.e., replication, modification, processing, and repair) transcription and gene regulatory networks coding and noncoding RNA mechanisms of action and function protein synthesis the genetic basis of human biology chromosomal and genome stability Genetics-Genes-Heredity All About You Need To Know 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 causes 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 biological 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; is 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 was 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 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; 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 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; is often discussed in the genetic counseling process as a comparison to the proband‘s risk given his/her family history or other circumstances Related terms: allele frequency; carrier rate base pair Synonym: bp Two nitrogenous bases are paired together in double-stranded DNA by weak bonds; the 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 the 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. 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 frequency 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 is 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; is 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 A 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 cytogenetic 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 A physical structure consists 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 The 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 is 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 is 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 The 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. You Might Also Read Neural Tube DefectsRelated 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 is 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 the expression of a phenotype that requires the presence of pathogenic variants in two different genes Related terms: oligogenic; transgenic 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 that 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 model(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 the 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 is 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 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 The 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; is 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 the presence of the chromosome material) or the absence of the hybridized fluorescent signal (and hence the 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 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’s disease in the Lake Maracaibo region of Venezuela. Related term: founder variant founder variant A pathogenic variant is observed in high frequency in a specific population due to the presence of the variant in a single ancestor or a 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 several base pairs that are 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 is chromosomal DNA. Genomic DNA does not include mitochondrial DNA. Related terms: cDNA; genomic; mRNA gene The basic unit of heredity, consists of a segment of DNA arranged linearly 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 the 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 the 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 the genetic status of 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 terms: exome sequencing; genomic; next-generation sequencing genomic Referring to the human genome, which comprises the DNA in all chromosomes and 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 A molecular assay is 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 are confined to the precursor (germline) cells of the egg or sperm Related term: somatic 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; 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: 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), 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 mitochondrial 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 a 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 expressions 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). You Might Also Read Binder-Type Nasomaxillary Dysplasiainsertion The 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 the clinical presentation of a particular disorder among affected individuals from different families Related term: intrafamilial variability intrafamilial variability Variability in the clinical presentation of a particular disorder among affected individuals within the same immediate or extended family Related term: interfamilial variability intron The noncoding sequence of DNA removed from mature messenger RNA before translation Related terms: coding region; exon; intronic; splicing intronic Referring to DNA or variants in DNA within an intron Related term: intron isoelectric focusing The 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 the 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 Refers 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 Refers 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 is used in the process of mapping to designate a putative gene before 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 multiple loci leads 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; is correlated with reduced transcription of the gene and is 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) is 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 not the biological parent. Factors that may result in misattributed parentage include assisted reproduction (i.e., use of donor sperm, donor egg, or donor embryo), undisclosed adoption, and alternate paternity. Related terms: alternate maternity; alternate paternity mismatch repair The DNA “proofreading” system 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 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, the pattern of inheritance How 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 the 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 encompasses 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. 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 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 multi-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 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 consists 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 The sequence of n nucleotides repeated several 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, permutations, 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; transgenic 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 the 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 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 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 transferred to the mother’s uterus only those embryos determined not to have the pathogenic variant(s)/chromosome anomaly(ies) of concern You Might Also Read Shaky Legs Syndrome - Causes, Symptoms, TreatmentRelated 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 was performed during pregnancy. Prenatal testing may be used to determine if a fetus is affected by 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, the 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 the 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 leads 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) – occurs 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 has 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 the loss of their short arms 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 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 The 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; is similar to crossing over (recombination), except that the exchange involves the two sister chromatids of a single chromosome, whereas crossing over refers to the exchange of genetic material between the two homologous chromosomes of a chromosome pair SNP array The 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: germline mosaicism somatic pathogenic variant Variant resulting from a mutation that occurs during embryonic development (i.e., that is not inherited from a parent) Southern blot Synonyms: Southern analysis, Southern blot analysis The 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; is the site of intron/exon splicing. A variant in the splice site can cause abnormal removal of introns and splice together of exons such that one or more introns remaining in the mRNA can potentially disrupt the 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 syndromic In GeneReviews: refers 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. transgenic Referring to the 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 several 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; post-zygotic; 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 the 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 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 results 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 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; was first described by the geneticist Mary F Lyon, Ph.D. 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