ABMGG Clinical Genetics & Genomics key terms

The proportion of people who carry a disease-causing variant and actually show the associated phenotype. Penetrance may be age-dependent or reduced, which complicates counseling because carriers without features can still transmit the variant.

The range of severity and specific features produced by the same pathogenic variant in different people, from mild to severe. It differs from reduced penetrance, in which some carriers have no features at all.

One gene or variant causing several apparently unrelated clinical effects across organ systems. Pleiotropy explains why a single diagnosis may require surveillance of the heart, eyes, and skeleton at the same time.

A pattern in which a condition begins earlier or more severely in each succeeding generation, classically with unstable repeat expansions. Counseling requires knowing the family history and which parent transmitted the variant.

Two or more cell populations with different genetic content within one person, arising after fertilization through mutation, mitotic error, or trisomy rescue. The proportion and tissues involved shape the phenotype and the recurrence risk.

Both members of a chromosome pair inherited from one parent, with none contributed by the other. Clinical importance arises when imprinted genes are involved or when a recessive variant becomes homozygous.

Parent-of-origin-specific gene activity set by epigenetic marks laid down in the germline. Disruption causes disorders such as Prader-Willi and Angelman syndromes, which are often detected by methylation testing rather than sequencing alone.

A population principle holding that allele and genotype frequencies remain constant across generations when selection, migration, drift, mutation, and nonrandom mating are absent. Departures may indicate genotyping error or true association with disease.

The systematic study of structural variation in body form, including minor anomalies and measurements, to detect recognizable patterns. Findings are interpreted alongside growth, development, and family features rather than in isolation.

A standardized family tree recording ages, diagnoses, ancestry, consanguinity, and pregnancy outcomes across at least three generations. It guides inheritance assessment, testing strategy, and risk estimates.

A nongenetic condition that mimics an inherited disorder, caused by teratogens, infection, or another acquired process. Recognizing a phenocopy prevents unnecessary genetic testing and incorrect family risk estimates.

The relationship between a particular variant or class of variants and the resulting features, severity, or age of onset. Strong correlations support prognosis, surveillance planning, and interpretation of uncertain variants.

Loss of skills already acquired, such as speech, walking, or self-care. It suggests a progressive metabolic or neurodegenerative process and usually prompts urgent biochemical and genetic evaluation rather than watchful waiting.

A recognizable pattern of structural anomalies attributed to one cause, such as a chromosome abnormality, single-gene disorder, or teratogen. Naming the pattern directs confirmatory testing and expected natural history.

A genome-wide test comparing patient and reference DNA to detect copy-number gains and losses. It is first-tier for developmental delay, intellectual disability, and multiple anomalies but does not reliably detect balanced rearrangements.

Chromosomes from dividing cells arranged in numbered pairs and banded for inspection. It detects aneuploidy, large deletions and duplications, and balanced rearrangements that microarray misses, but at much lower resolution.

Sequencing of protein-coding regions, about one to two percent of the genome, to identify small variants underlying suspected Mendelian disease. It may miss intronic, structural, and some copy-number changes and often yields uncertain results.

Evidence that an assay measures what it claims, accurately and reproducibly, including its sensitivity, specificity, and failure rate. It is the first of the ACCE criteria, ahead of clinical validity and clinical utility.

The extent to which using a test improves health outcomes compared with not testing. A test can be accurate and predictive yet offer little utility if no effective intervention follows.

Analysis of placental DNA fragments circulating in maternal blood to estimate the chance of common aneuploidies. It is screening, not diagnosis, so high-risk results need confirmation by chorionic villus sampling or amniocentesis.

Population testing of dried blood spots soon after birth for conditions where early treatment prevents harm. Program quality depends on timely collection, rapid communication of positives, confirmatory testing, and tracking of lost follow-up.

A sequence change with too little evidence to classify as pathogenic or benign. Management rests on phenotype match, segregation, functional data, and reanalysis over time rather than on the variant report alone.

A structured scheme sorting variants into pathogenic, likely pathogenic, uncertain significance, likely benign, and benign, using population frequency, computational predictions, segregation, and functional evidence. Each category carries defined reporting and clinical implications.

The number of sequencing reads aligned to a given base or region, sometimes called read depth. Insufficient depth leaves blind spots where variants escape detection, so negative results should be qualified by coverage quality.

The share of sequencing reads at a locus that carry the alternate allele. It distinguishes heterozygous germline variants from mosaic or somatic ones and can reveal sample contamination or specimen mix-up.

A segment of DNA, from hundreds of bases to megabases, deleted or duplicated relative to the reference. Interpretation depends on the assay's resolution, the genes involved, and comparison with benign population variation.

Computational tools that estimate whether a sequence change, usually an amino acid substitution, disrupts protein function or splicing. Such predictions support, but never alone establish, a pathogenic classification.

The probability that a condition will occur again in a family, influenced by inheritance pattern, penetrance, consanguinity, and the number of affected relatives. It is best communicated as a range with stated assumptions.

A method for revising a prior probability using new information such as test results, carrier frequencies, or unaffected relatives. Counselors use it to update carrier and recurrence risks after negative or ambiguous testing.

Stepwise testing of relatives after a pathogenic variant is found in an index case, extending outward through the family. It enables early diagnosis and prevention in relatives who might otherwise remain unscreened.

A union between relatives, which increases the chance that offspring inherit two copies of the same ancestral variant. It raises recessive disease risk and may justify carrier testing or focused sequencing.

A communication method in which the patient explains the information back in their own words. It reveals gaps in understanding of risk figures and options, allowing the counselor to correct them immediately.

Regular infusion of a manufactured enzyme to substitute for deficient activity in lysosomal storage diseases. It can shrink organs and improve endurance but often does not cross into the brain or reverse skeletal damage.

The study of inherited variation affecting drug metabolism, transport, or targets, used to choose drugs and doses. Only variant-drug pairs with published prescribing guidance are routinely actionable.

A scheduled program of examinations, imaging, and laboratory tests designed to detect treatable complications early in a known genetic condition, such as tumor screening in hereditary cancer predisposition.

An ongoing process covering the purpose, limits, possible results including uncertain and secondary findings, privacy, cost, and alternatives before testing. It is documented and revisited when results or their interpretation change.

A United States law prohibiting health insurers and employers from using genetic information in coverage, premium, and employment decisions. It does not protect against discrimination in life, disability, or long-term care insurance.

A limited and jurisdiction-dependent professional obligation to inform former patients when new knowledge changes the meaning of their earlier results. Workable policies record consent and preferred contact methods in advance.

Pathogenic variants deliberately sought and reported although unrelated to the reason for testing, drawn from a curated gene list. Consent, opt-out, and disclosure practices differ among laboratories and programs.

The principle that people decide for themselves whether and how to reproduce, including use of carrier, prenatal, and preimplantation testing. Counseling presents options without steering toward a preferred choice.