ABPath Molecular Genetic Pathology key terms

The flow of genetic information from DNA to RNA to protein: DNA is replicated, transcribed into messenger RNA, and translated into polypeptide. Retroviruses and some assays reverse this flow using reverse transcriptase.

Synthesis of an RNA molecule from a DNA template by RNA polymerase, initiated at a promoter and terminated at defined signals. In eukaryotes the primary transcript is processed by capping, splicing, and polyadenylation.

Ribosome-mediated assembly of amino acids into protein according to the sequence of codons in mRNA, beginning at a start codon and ending at a stop codon, with tRNAs delivering matching amino acids.

A triplet of mRNA bases that specifies one amino acid or a stop signal. The code is degenerate, so several codons encode the same amino acid, and a single base change may or may not alter the protein.

Short conserved sequences at exon-intron boundaries where the spliceosome cuts and joins RNA. Variants at the canonical GT or AG dinucleotides commonly disrupt splicing and cause disease.

A DNA region upstream of a gene where RNA polymerase and transcription factors assemble to start transcription. Promoter variants can reduce or abolish gene expression without changing the encoded protein.

A noncoding segment of a gene that is removed from the primary transcript during RNA splicing, joining the flanking exons. Introns often contain regulatory elements and can harbor pathogenic variants.

A segment of a gene retained in the mature RNA after splicing. Exons contain the coding sequence and untranslated regions, and exon-level deletions are a common disease mechanism.

A single-base substitution that changes one codon so a different amino acid is incorporated. Effects range from benign to severe depending on the residue and protein function.

A base substitution that converts an amino acid codon into a premature stop codon, truncating the protein. The shortened product is usually unstable or nonfunctional.

Insertion or deletion of a number of bases not divisible by three, shifting the reading frame downstream. The result is a garbled amino acid sequence and typically an early stop codon.

A cellular quality-control pathway that degrades mRNA containing a premature termination codon, usually located more than about 50 nucleotides upstream of the last exon-exon junction, limiting truncated protein production.

Standardized rules for describing sequence variants at DNA, RNA, and protein levels, using prefixes such as c. for coding DNA, g. for genomic, and p. for protein, with numbered positions relative to defined reference points.

A defined, versioned DNA or RNA sequence against which variants are reported, such as a RefSeq transcript or genomic accession. Correct reporting requires specifying the exact accession and version used.

Assignment of a sequence change to categories such as pathogenic, likely pathogenic, variant of uncertain significance, likely benign, or benign, using evidence criteria on population frequency, functional data, segregation, and computational prediction.

A sequence change whose relationship to disease cannot be established with current evidence. Reporting it requires caution because clinical action based on it may be inappropriate.

Dideoxy chain-termination sequencing that reads one DNA fragment at a time with fluorescently labeled terminators. It remains the standard for confirming variants and for short targets.

Massively parallel methods that sequence millions of DNA fragments simultaneously, producing short reads aligned to a reference. Applications include gene panels, exomes, genomes, and RNA sequencing.

The average number of sequencing reads covering a given base or region. Adequate depth is needed to detect variants reliably, especially in heterogeneous tumor samples or low-level mosaicism.

The proportion of sequencing reads at a locus that carry a specific variant. It reflects tumor purity, clonality, mosaicism, or germline heterozygosity depending on the specimen.

Enzymatic amplification of a target DNA segment using specific primers and thermostable polymerase through repeated cycles of denaturation, annealing, and extension. It underpins most molecular assays.

PCR that monitors product accumulation each cycle using fluorescent reporters, allowing quantification of target copy number or transcript level and enabling melting-curve analysis for genotyping.

An enzyme that synthesizes complementary DNA from an RNA template. It enables analysis of RNA transcripts and detection of RNA viruses.

Separation of charged molecules such as DNA fragments through a narrow capillary under an electric field, with fluorescence detection. It is used for fragment sizing and Sanger sequencing reads.

A short single-stranded oligonucleotide that anneals to a complementary target and provides a starting point for DNA polymerase. Primer design determines assay specificity.

The principle that allele and genotype frequencies in a large, randomly mating population remain constant absent selection, mutation, migration, or drift. It allows calculation of carrier frequencies from disease incidence.

The proportion of individuals in a population who carry one copy of a recessive pathogenic variant without expressing disease. It is estimated from disease incidence using Hardy-Weinberg assumptions.

The proportion of individuals carrying a pathogenic genotype who show the associated phenotype. Reduced penetrance complicates risk prediction and counseling.

The range of clinical severity or features among individuals with the same pathogenic genotype. It reflects modifying genes, environment, and stochastic factors.

Inheritance requiring pathogenic variants on both alleles of a gene for disease to occur. Affected individuals typically have unaffected carrier parents, and recurrence risk for siblings is 25 percent.

An individual with two different pathogenic variants in the same autosomal recessive gene, one on each allele. Disease results from the combined loss of both functional copies.

Transmission of mitochondrial DNA variants exclusively through the maternal line, with affected mothers passing variants to all children and fathers passing none. Heteroplasmy causes variable severity.

Coexistence of normal and variant mitochondrial DNA within a cell or tissue. The proportion of variant genomes influences phenotype and can shift through mitotic segregation.

A genetic alteration acquired in a cell after conception and present only in its descendants. In cancer it drives clonal expansion and can serve as a marker of disease or resistance.

Testing of body fluids, usually plasma, for tumor-derived material such as circulating tumor DNA. It permits noninvasive detection of mutations, monitoring of response, and assessment of resistance.

Study of how inherited genetic variation affects drug response, including metabolism, transport, and target interactions. Results guide drug and dose selection to improve efficacy and reduce toxicity.

A named haplotype designation for a pharmacogene that combines variants defining enzyme activity, such as normal, decreased, or no function. Diplotype pairs of star alleles predict metabolic phenotype.

Conversion of detected diplotypes into predicted metabolic activity categories such as poor, intermediate, normal, or ultrarapid metabolizer, which are then linked to dosing recommendations.

Procedures that monitor assay performance within and across runs, such as positive and negative controls, to detect failures before results are reported. It is distinct from broader quality assurance activities.

External assessment in which a laboratory tests blinded samples and compares results with peer laboratories or a reference method. Unsatisfactory performance triggers corrective action.

The overall planned system of policies and activities, including quality control, proficiency testing, audits, and corrective actions, intended to ensure reliable and consistent laboratory results.

The computational workflow that converts raw sequencing data into interpretable results through base calling, alignment, variant calling, annotation, and filtering, with versioned software and databases.