ABMGG General Examination: Inheritance, Testing and Interpretation Study Guide

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A diagram shows both members of a homologous pair moving into the same daughter cell while each chromosome retains its sister chromatids. Identify a meiosis I segregation error, rather than premature sister chromatid separation.

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A laboratory image shows a normal human metaphase cell with 46 centromeric units, each containing two chromatids. Report 46 replicated chromosomes and 92 chromatids; do not interpret replication itself as whole-genome aneuploidy or chromosome gain.

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A variant lies in an exon included in a brain-expressed transcript but skipped in a blood-expressed transcript. A normal blood transcript does not establish normal processing in the clinically relevant brain transcript or tissue.

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A child has a phenotype suggesting an imprinting disorder, but copy-number testing detects no deletion. Consider abnormal parental origin or an imprinting defect; unchanged dosage does not establish that the necessary parental expression pattern is intact.

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Two variants remove two bases and six bases from the same coding exon. Predict a frameshift for the two-base deletion and an in-frame deletion for the six-base change, then assess their functional and disease context separately.

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A patient has a plausible intronic variant and a matching phenotype. An RNA study demonstrates abnormal exon skipping. This provides a mechanistic connection that mere proximity to the disease-associated gene would not establish by itself.

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In a hypothetical equilibrium population, a fully penetrant recessive disorder affects 1 in 10,000 people. Calculate q = 0.01, p = 0.99 and carrier frequency 2pq = 0.0198, approximately 1 in 51.

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A recessive disorder is frequent in an isolated community descended from a few founders. Explain the frequency through population sampling and drift before proposing that carriers necessarily gained a survival advantage from the variant.

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An unaffected parent carries a reciprocal translocation, and a child has a deletion of one exchanged segment with duplication of another. Connect the child's imbalance to segregation of the parental rearrangement rather than assuming an unrelated event.

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Two children have deletions of different sizes. The smaller deletion disrupts a gene with an established dosage-related disorder. Prioritize the affected genomic content and phenotype match rather than assuming the larger deletion must explain more severe disease.

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A chromosome segment appears in reverse order on structural analysis, while copy-number testing shows no gain or loss. Interpret this as compatible with a balanced inversion rather than excluding a rearrangement because dosage is normal.

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Genetically distinct skin patches arise after a documented postzygotic chromosome error in a single embryo. Classify the pattern as mosaicism. A normal blood sample would not exclude the abnormal population being restricted to affected skin.

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A family has a known balanced reciprocal translocation. Select chromosome analysis to evaluate the familial arrangement. A copy-number-only microarray would address gains and losses but would not reliably answer whether the balanced rearrangement is present.

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Two confirmed carriers have three unaffected children and ask about a fourth pregnancy. Assuming the same recessive model and complete penetrance, the affected probability remains 25%; previous unaffected births do not reduce or increase it.

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An adult is unaffected by a fully penetrant childhood-onset recessive disorder affecting a sibling. Both parents are confirmed carriers. Before molecular testing, calculate the adult's carrier probability as (1/2) divided by (3/4), or two thirds.

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A heterozygous parent has a dominant pathogenic variant with 80% penetrance by a specified age. Assuming no other disease mechanism, the child's probability of showing the phenotype by that age is 0.5 × 0.8 = 40%.

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A grandparent and grandchild share a dominant disorder, and the intervening parent carries the familial variant without recognized signs. Reduced or age-dependent penetrance can explain the pedigree without changing its underlying dominant transmission pattern.

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A parent and child carry the same pathogenic variant. The parent has mild skeletal findings, while the child has several organ manifestations. This illustrates variable expressivity; both individuals express the condition despite their different severity.

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A carrier mother and unaffected father ask about a fetus known to be male. Under the stated fully penetrant model, the affected probability is 50%; the additional one-half probability of male sex has already been resolved.

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An affected father has an X-linked dominant pathogenic variant, and the mother lacks it. Under a fully penetrant model, all daughters inherit the variant and sons do not inherit that paternal variant through the X chromosome.

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Two sisters carry the same X-linked pathogenic variant but differ in clinical severity. Consider differences in expression and X-inactivation patterns as possible contributors; do not reject the molecular diagnosis solely because one sister is more affected.

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Affected individuals include a mother, her son and her daughter, while the affected son's children lack the familial mtDNA variant. Recognize a maternal mtDNA transmission pattern, then assess variable expression separately from transmission direction.

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A mother and two children carry the same mtDNA variant but have different clinical involvement. Variable heteroplasmy and tissue distribution provide a mechanism for these differences without requiring a different pathogenic variant in each person.

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A child has two chromosome 15 copies but both are maternal. Explain how Prader-Willi syndrome can occur despite normal chromosome count: the child lacks the normally active paternal contribution in the relevant imprinted region.

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A child with cystic fibrosis is homozygous for the mother's pathogenic CFTR allele, while the father lacks that allele and chromosome 7 dosage is normal. Two identical maternal chromosome 7 copies explain recessive-variant unmasking; informative parental markers establish the abnormal origin.

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A woman has an FMR1 allele with 90 CGG repeats. Classify it as a premutation, then discuss premutation-associated health and transmission implications rather than labeling the result a full mutation causing classic fragile X syndrome.

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An adult with an FMR1 premutation seeks counseling after a child's evaluation. Include the carrier's own reproductive and later-life neurological implications in the discussion, while distinguishing these risks from a diagnosis of classic fragile X syndrome.

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A mother carries an FMR1 premutation, and her child has a full mutation. Explain the change through repeat expansion during transmission rather than assuming that ordinary Mendelian segregation always preserves the transmitted repeat length exactly.

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A patient has a sharply localized skin abnormality, while blood sequencing is negative. Testing affected tissue may address a postzygotic mosaic mechanism more directly because the relevant cell population may be absent or uncommon in blood.

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Two siblings share the same dominant pathogenic variant, but neither parent has the variant detected in blood. Consider parental germline mosaicism rather than concluding that the molecular findings necessarily contradict the reported family relationships.

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A child has a genetically heterogeneous hearing-loss phenotype and negative testing for one common familial variant. Distinguish that limited negative result from comprehensive exclusion of other pathogenic variants in the same gene or different relevant genes.

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A tall adolescent has arachnodactyly, ectopia lentis and aortic root enlargement. A single pleiotropic connective tissue disorder can unify the findings. Document the aortic measurement and ocular examination, assess the Ghent criteria and pursue FBN1 testing rather than diagnosing from body habitus alone.

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A child has two pathogenic variants in a recessive gene. One is inherited from the mother and the other from the father. This establishes trans configuration and supports biallelic disease when the phenotype and gene mechanism agree.

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An infant has persistent elevation of phenylalanine and two pathogenic PAH variants in trans. Link the biochemical abnormality to impaired conversion of phenylalanine to tyrosine, then explain recessive recurrence risk to the confirmed carrier parents.

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An infant has disproportionate proximal limb shortening, frontal bossing and compatible radiographs. Test for the recurrent FGFR3 variants causing p.Gly380Arg. A different FGFR3 variant predicted to truncate the protein cannot be assumed to cause achondroplasia merely because it appears disruptive.

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A prepubertal child has seven bilateral café-au-lait macules larger than 5 mm and a plexiform neurofibroma. These represent two distinct NF1 criteria. A child with only macules and freckling needs consideration of Legius syndrome and age-dependent emergence of additional features.

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An adolescent has exertional syncope, repeatedly prolonged QTc and a relative with unexplained sudden death. This pattern warrants inherited channelopathy evaluation even with a normal echocardiogram. A pathogenic KCNQ1 variant supports the diagnosis; a VUS alone does not confirm it.

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A hypothetical medication requires enzyme X for activation, and a patient has markedly reduced enzyme X activity. Predict reduced active-product formation, while checking interacting medications and clinical context before attributing the entire response to genotype.

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Several relatives have a common complex disorder, but no single-gene diagnosis is established. Avoid assigning an automatic 50% recurrence risk; explain that shared genes and exposures can raise familial risk without producing simple Mendelian transmission.

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A woman with PKU has a partner who is not a PAH carrier. Explain that the absence of an expected affected fetal genotype does not eliminate fetal risk from elevated maternal phenylalanine during pregnancy.

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A positive prenatal cell-free DNA result is followed by normal fetal diagnostic findings. Confined placental mosaicism is one possible explanation because the placental DNA contributing to screening need not exactly match the fetal cell population.

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A patient receives a high-risk cell-free DNA result and asks whether it establishes fetal trisomy. Explain the difference between screening and diagnosis, then discuss diagnostic testing and how placental biology can affect interpretation.

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One partner carries a pathogenic variant for a recessive condition. The other has a hypothetical residual carrier probability of 1 in 100 after screening. Under the standard model, affected pregnancy risk is 1/100 × 1/4 = 1/400.

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In a hypothetical screened group, 80 positive results are true positives and 20 are false positives. The positive predictive value is 80/100, or 80%; it cannot be calculated from the true-positive count alone.

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A child with bilateral retinoblastoma has one pathogenic RB1 variant in blood and loss of the normal allele in tumor tissue. The constitutional finding establishes predisposition, and the tumor finding supplies the second hit. Negative family history does not exclude a newly arising constitutional variant.

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A child develops thrombocytopenia and neutropenia and has a hypoplastic thumb. Order crosslinker-induced chromosome breakage testing and molecular evaluation for Fanconi anemia. Identifying two pathogenic FANCA variants in trans establishes a recessive mechanism, rather than a dominant single-allele cancer predisposition.

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One tumor contains an activating signaling variant; another has inactivation of both RB1 copies. Distinguish excessive growth-promoting activity in the first tumor from loss of growth restraint in the second, despite both supporting tumor development.

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A well-appearing newborn has an out-of-range blood spot result. Arrange the specified follow-up promptly and explain that additional testing is needed; visible wellness does not resolve the biochemical screening signal or establish that it is false.

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An infant develops poor feeding and lethargy after a reported normal newborn screen. Investigate the current illness rather than excluding metabolic disease solely from the screening result; the relevant condition may be missed or outside the screening panel.

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A patient expects sequencing to provide a certain diagnosis. Before testing, explain possible negative and uncertain findings, unexpected results and family implications, then check understanding and allow the patient to decide without pressure from relatives.

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For an asymptomatic child, first determine whether knowing the familial variant changes care during childhood. Offer testing when it does; generally defer adult-onset prediction without childhood benefit. Explore a mature adolescent's wishes and any substantial psychosocial burden rather than treating parental curiosity as sufficient justification.

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A patient has a broad, unexplained multisystem phenotype after focused evaluation. Exome or genome sequencing may widen the search, but compare coverage and detectable variant classes rather than assuming that broader scope guarantees a diagnosis.

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A strong imprinting phenotype remains unexplained after negative exome sequencing. Consider testing the relevant methylation mechanism instead of concluding that a genetic disorder is excluded because no coding sequence explanation was reported in the exome analysis.

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A report calls a variant likely pathogenic for a recessive disorder, but the patient has only one identified allele. Separate classification of that allele from establishing a biallelic diagnosis; the inheritance requirement still needs evaluation.

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A VUS appears in a cancer predisposition gene. Do not use that result alone to justify irreversible preventive surgery. Evaluate the person's established clinical and family risks, and identify evidence that could clarify the variant's classification.

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A variant is proposed to cause a very rare, fully penetrant dominant childhood disorder, yet it is common among unaffected adults. This frequency is difficult to reconcile with the proposed mechanism and should challenge the pathogenic interpretation.

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During exome testing for developmental delay, deliberate analysis of an agreed actionable-gene list identifies an unrelated predisposition. This is a secondary finding. An unrelated result encountered unexpectedly during the primary analysis is incidental. Explain the deliberate search and opportunity to decline before testing.

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A child has findings consistent with Prader-Willi syndrome and an abnormal methylation result. Further mechanism-directed studies can distinguish deletion, maternal uniparental disomy and imprinting defects, which are not interchangeable explanations for family counseling and recurrence assessment.

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A splice-region VUS is evaluated in cells that express the relevant transcript. The assay shows reproducible abnormal splicing. Use this as functional evidence in the full classification process rather than treating the experimental observation alone as a complete diagnosis.

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A candidate dominant variant is found in an unaffected young relative. Before using this as strong benign evidence, ask whether the condition normally develops later or has reduced penetrance; the relative may not yet be informative.