Essential Genetics Terms for Board Exam Candidates

Precise vocabulary matters in genetics questions. Knowing that penetrance differs from expressivity, or understanding what haploinsufficiency means mechanistically, can change how you read a vignette. This glossary covers core terms for both genetic counseling and medical genetics preparation and flags common shortcuts that need qualification.

Definitions are introductory. For variant classification and clinical use, consult the current ACMG/AMP guidance, ClinGen PVS1 recommendations, and condition-specific GeneReviews chapters.

Core Genetics Vocabulary

Allele

A version of a DNA sequence at a particular locus. For a typical autosomal locus in a diploid cell, a person inherits two alleles, one from each parent. Alleles can differ in sequence, copy number, or regulation.

Use it precisely: dominance and recessiveness describe the relationship between alleles for a phenotype under a model; they are not complete intrinsic labels for every allele. A "dominant" allele is not universally dominant for every trait or in every context.

Why it matters: Many questions turn on whether a variant is present on one copy, both copies, or in trans with another variant.

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Locus

A locus is a genomic position or region. It may correspond to a gene, but it can also be an intergenic position, a regulatory element, or a chromosomal band.

Use it precisely: "locus" is not a synonym for "gene." A probe or variant can target a locus without describing a whole gene.

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Penetrance

The proportion of individuals with a given genotype who show the associated phenotype, under defined conditions. If a condition is 80% penetrant, about 20% of people with the pathogenic variant would not show the phenotype in the population and time frame studied.

Use it precisely: penetrance depends on the phenotype definition, age or time horizon, and population context. Penetrance estimates can inform risk counseling, but an individual's risk also depends on age, the phenotype being estimated, and other relevant factors. Penetrance is different from confidence in a variant's classification.

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Expressivity

The degree or range of severity of the phenotype among individuals who have the same genotype. Variable expressivity means the same variant can produce mild findings in one person and severe findings in another.

Why it matters: Distinguish whether a phenotype occurs (penetrance) from how it manifests (expressivity). Neurofibromatosis type 1 and Marfan syndrome are commonly used examples of variable expressivity.

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De Novo Variant

A variant present in an individual but not detected in either parent's tested sample, arising in a gamete or early embryo. Common in some severe autosomal dominant conditions, including achondroplasia and Dravet syndrome.

Use it precisely: a variant identified in a child and not detected in parental blood may still reflect parental germline mosaicism. Testing blood does not assess every parental tissue or gamete. An apparently de novo result should be interpreted with the laboratory's testing scope and the possibility of mosaicism in mind.

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Haploinsufficiency

A mechanism in which one functional copy of a gene is insufficient for normal function, producing a phenotype. It is one form of loss-of-function disease mechanism.

Example: PAX6-related aniridia illustrates how loss of one functional copy can cause disease through haploinsufficiency.

Use it precisely: loss of function and haploinsufficiency are related but not interchangeable terms. A variant can reduce function without producing disease through haploinsufficiency, and some loss-of-function variants act through other mechanisms.

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Imprinting (Genomic Imprinting)

An epigenetic phenomenon in which gene expression depends on the parent of origin. Imprinted genes are expressed from only the maternal or paternal copy, based on epigenetic marks such as DNA methylation.

Why it matters: Prader-Willi and Angelman syndromes both involve 15q11-q13 but have different phenotypes depending on the parent of origin. Beckwith-Wiedemann syndrome is another example of an imprinting disorder. A methylation result can establish an abnormal pattern without identifying whether the cause is a deletion, uniparental disomy, or an imprinting defect.

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Anticipation

A phenomenon in which a disorder has earlier onset or greater severity in successive generations, usually described for specific repeat-expansion disorders.

Why it matters: Myotonic dystrophy type 1 (CTG repeat), Huntington disease (CAG repeat), and fragile X syndrome (CGG repeat) are commonly used examples. Anticipation is condition-specific; it is not a general feature of all inherited disorders.

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Germline and Somatic Variants

A germline variant is present in germline cells and can be transmitted through a gamete. A variant confined to somatic tissues is not expected to be transmitted. An early postzygotic variant may involve both somatic and germline lineages.

Use it precisely: germline variants are not restricted to reproductive organs, and not every early embryonic variant is confined to somatic tissue. Mosaicism is a separate concept that can involve either or both lineages.

Why it matters: In cancer genetics, a germline BRCA1 variant has implications for family risk, while a somatic TP53 variant confined to a tumor does not carry the same inheritance implications.

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Heteroplasmy

The presence of more than one type of mitochondrial DNA (mtDNA) within a cell or organism — typically variant and wild-type mtDNA. Heteroplasmy level and tissue distribution can influence phenotype.

Use it precisely: higher levels of a pathogenic mtDNA variant do not provide a universal severity formula across people, tissues, variants, and disorders. Leigh syndrome can result from nuclear or mitochondrial gene variants; a syndrome name alone does not establish heteroplasmy or maternal inheritance.

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Variant of Uncertain Significance (VUS)

A variant with insufficient evidence to classify it as pathogenic or benign under the applicable framework. The ACMG/AMP framework uses five categories: pathogenic, likely pathogenic, uncertain significance, likely benign, and benign.

Use it precisely: a VUS may be reclassified, but resolution is not guaranteed. A VUS alone does not establish a diagnosis or justify variant-directed management. Care may still follow the person's clinical findings and family history, and additional evidence may support future reclassification.

Why it matters: VUS communication is a common counseling topic. The useful messages are uncertainty, what evidence would change the classification, and what the result does and does not mean for care.

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Pathogenic Variant

A variant causally associated with disease based on sufficient evidence under a recognized classification framework. The field increasingly uses "variant" rather than "mutation" for sequence changes.

Use it precisely: pathogenic, likely pathogenic, VUS, likely benign, and benign are classification categories. They are not the same as a patient's probability of disease, which also depends on penetrance, age, and context.

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Loss of Heterozygosity (LOH)

Loss of heterozygosity describes a region where the two alleles are no longer both represented as expected. It can result from deletion, mitotic recombination, or other mechanisms, including copy-neutral LOH.

Use it precisely: LOH does not always mean that a physical copy of an allele was deleted. In a tumor-suppressor model, LOH can provide a "second hit," but not every second hit is a deletion. In BRCA1/2 carriers, the inherited pathogenic variant can be the first hit and LOH in a tumor cell the second.

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Frameshift Variant

Within a protein-coding sequence, an insertion or deletion whose net length is not a multiple of three can shift the reading frame. A noncoding indel does not automatically cause a frameshift, although it may affect splicing or regulation. This can produce a different amino acid sequence and often a premature stop codon.

Use it precisely: a predicted frameshift is not automatically pathogenic. The ACMG/AMP PVS1 criterion applies in a gene where loss of function is an established disease mechanism, with transcript, exon, rescue, and other context considered. Evidence strength and final classification are separate decisions.

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Splicing Variant

A DNA change that affects splicing signals or creates or alters a splice site, potentially causing exon skipping, intron retention, or use of a cryptic splice site. Effects can involve canonical splice sites or deeper intronic regions.

Use it precisely: splice effects may require RNA-level or other functional evidence to classify.

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Copy Number Variant (CNV)

A structural variant that changes the number of copies of a DNA segment. CNVs can affect gene dosage and contribute to disease through deletion, duplication, or disruption.

Use it precisely: assay resolution and analysis determine what is detected. Not every CNV is pathogenic, and not every CNV is limited to a microarray finding.

Why it matters: Chromosomal microarray is a key test in developmental delay, autism, and congenital anomalies, but a normal dosage result does not exclude every mechanism.

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Single Nucleotide Variant (SNV) and Single Nucleotide Polymorphism (SNP)

An SNV is a single-nucleotide change in a DNA sequence. SNP is often used for a common single-nucleotide variation in a population, with terminology varying by context.

Use it precisely: frequency informs interpretation but does not independently establish benignity or pathogenicity. Most SNPs are common population variation; some are associated with disease risk. "SNP" is not simply the benign counterpart of "pathogenic variant."

Why it matters: SNVs underlie many genetic association studies and polygenic risk scores, but a variant's frequency and its clinical significance are different questions.

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Indel

An insertion or deletion of one or more nucleotides. Within a protein-coding sequence, an insertion or deletion whose net length is not a multiple of three can shift the reading frame. A noncoding indel does not automatically cause a frameshift, although it may affect splicing or regulation. Larger indels can overlap with copy-number changes.

Why it matters: Indels are commonly identified on sequencing panels and exome or genome sequencing. The classification still depends on gene context, predicted effect, and evidence.

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Aneuploidy

An abnormal chromosome number — an extra chromosome (for example, trisomy 21) or a missing chromosome (for example, monosomy X in Turner syndrome). Aneuploidy is a major cause of pregnancy loss and congenital anomalies.

Why it matters: Know the common trisomies (13, 18, 21), sex chromosome aneuploidies (45,X; 47,XXY; 47,XYY; 47,XXX), and their clinical associations, while recognizing that presentation varies.

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Balanced Reciprocal Translocation

A rearrangement in which segments from two chromosomes exchange positions without a net gain or loss of genetic material at the resolution evaluated. Carriers are often phenotypically normal but can have an increased risk of unbalanced offspring.

Use it precisely: "balanced" describes the copy-number result, not a guarantee of clinical neutrality. Apparently balanced rearrangements can disrupt genes or have other effects. See Robertsonian translocations for a different rearrangement mechanism.

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Robertsonian Translocation

A translocation in which the long arms of two acrocentric chromosomes (13, 14, 15, 21, 22) fuse, with loss of the short arms. The carrier usually has 45 chromosomes and can have a normal phenotype.

Why it matters: rob(14;21) and rob(21;21) are important for Down syndrome recurrence counseling. The parent of origin and the specific translocation affect the risk.

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Mosaicism

The presence of two or more genetically distinct cell populations in an individual, derived from one fertilized egg. Mosaicism can be somatic, germline, or combined.

Use it precisely: mosaicism does not guarantee a mild phenotype. A variant identified in a child and not detected in parental blood may still reflect parental germline mosaicism. Testing blood does not assess every parental tissue or gamete.

Why it matters: Germline mosaicism can explain parents with normal blood testing who have multiple affected children. Somatic mosaicism can explain variable or milder presentations of a condition.

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Proband

The person through whom a family first comes to clinical attention for a genetic concern. A proband may be affected or may be undergoing risk assessment.

Use it precisely: "index case" and "proband" are sometimes used interchangeably and are not distinguished universally in the way a simplified glossary may imply.

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Unexpected Biological Relationships (Misattributed Parentage)

A situation in which genetic testing reveals that an assumed biological relationship is not the biological relationship.

Use it precisely: prefer neutral language such as "unexpected biological relationship" or "misattributed parentage." Consent, confidentiality, and laboratory policy matter, and there is no single universal disclosure rule. The counseling task is to understand the policy, the family's context, and the person's preferences.

Penetrance and Expressivity: A Summary

For condition-specific risk figures, use a dated source and state the phenotype, age range, and population. A single lifetime number for a gene such as BRCA1 is not a complete risk statement; see BRCA1 and BRCA2 GeneReviews for the current discussion.

Using This Glossary for Board Preparation

These terms support both genetic counseling and medical genetics reasoning. Reading definitions is not enough — you need to apply them to unfamiliar vignettes. Use the current official ABGC or ABMGG outline to define your examination scope, then practice explaining why the closest alternative does not fit.

Continue with inheritance patterns, variant interpretation practice, or the medical genetics sample questions.

Selected sources: ClinGen PVS1 recommendations; GeneReviews mosaicism; MedlinePlus penetrance and expressivity; NHGRI frameshift definition; GeneReviews glossary. Definitions are introductory and do not replace clinical guidance.

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