ABMGG Clinical Genetics & Genomics cheat sheet

Hardy–Weinberg: for a rare autosomal recessive allele with carrier frequency c, disease incidence ≈ c²/4.

Bayesian risk: posterior odds = prior odds × likelihood ratio; convert odds p/(1−p) to probability.

Penetrance = proportion of genotype-positive individuals with phenotype; age-dependent penetrance modifies risk estimates.

ISCN karyotype order: chromosome count, sex chromosomes, abnormalities; example 46,XX,del(5p).

Recurrent microdeletions often arise from non-allelic homologous recombination between low-copy repeats.

Mitochondrial DNA is maternally inherited; heteroplasmy and tissue threshold determine expression.

Imprinting disorders show parent-of-origin effects; 15q11-q13 deletion type distinguishes Prader-Willi from Angelman.

Repeat-expansion disorders can show anticipation; examples include CGG in FMR1, CAG in HTT, CTG in DMPK.

Consanguinity and founder effects increase autosomal recessive risk by raising homozygosity.

Pedigree standard: three generations with ages, ancestry, consanguinity, pregnancy losses, and affected relatives.

Growth assessment includes height, weight, and occipitofrontal circumference plotted on appropriate charts.

Dysmorphology examination covers facies, hands, feet, skin, hair, genitalia, and neurologic tone.

Red flags: multiple congenital anomalies, developmental delay, regression, dysmorphism, and unexplained growth failure.

Developmental regression is a red flag for metabolic or neurodegenerative disease.

Teratogen history includes timing, dose, prescription, alcohol, infections, and maternal chronic disease.

Consanguinity raises autosomal recessive risk; ask about ancestry and family structure.

Phenotype terms can be mapped to Human Phenotype Ontology to support differential diagnosis and testing.

Cardiac murmur, hepatosplenomegaly, and café-au-lait macules are exam findings that direct genetic testing.

Natural history describes onset, progression, complications, and variability for a defined genotype.

Variable expressivity = same genotype, different severity; incomplete penetrance = genotype without phenotype.

Anticipation = earlier or more severe presentation in later generations, typical of repeat expansions.

Pleiotropy = one gene affects multiple organ systems, requiring multisystem surveillance.

Newborn screening identifies presymptomatic disease; positive screens require confirmatory diagnostic testing.

Adult-onset conditions may be absent in childhood; age-specific surveillance and counseling apply.

Diagnostic criteria exist for conditions such as NF1 and Marfan syndrome; criteria guide clinical diagnosis.

Genotype–phenotype correlations inform prognosis but are rarely absolute.

Early developmental intervention is associated with improved outcomes in many neurodevelopmental disorders.

Test choice: karyotype for aneuploidy or balanced rearrangement; CMA for copy-number variants; sequencing for SNVs/indels.

Repeat-expansion disorders require targeted repeat-sizing assays; exome sequencing may miss them.

Trio exome or genome sequencing improves de novo and phasing interpretation compared with proband-only testing.

Targeted familial variant testing is appropriate when the family variant is known.

Biochemical testing measures metabolites or enzyme activity for suspected metabolic disorders.

Methylation testing is used for imprinting disorders such as Beckwith-Wiedemann and Prader-Willi.

CVS is performed at 10–13 weeks; amniocentesis is performed at 15 weeks or later.

Cell-free DNA screening is a risk estimate, not a diagnosis; invasive testing is required for confirmation.

Assay limitations include mosaicism, low-level variants, technical artifacts, and variants of uncertain significance.

ACMG/AMP classes: pathogenic, likely pathogenic, VUS, likely benign, benign.

Population frequency from gnomAD helps classify variants; high frequency for a rare disease argues against pathogenicity.

In silico predictors are supporting evidence and cannot alone classify a variant as pathogenic.

De novo status, segregation, and functional data strengthen variant classification.

VUS results do not establish diagnosis and should not guide irreversible clinical decisions.

CNV interpretation considers size, gene content, inheritance, and curated databases.

Mosaicism detection depends on tissue sampled and assay sensitivity.

Reverse phenotyping uses a genotype-first approach to match variants to clinical features.

Secondary findings are medically actionable variants unrelated to the primary indication; reporting follows policy.

Autosomal dominant recurrence from an affected parent is 50% per pregnancy.

Autosomal recessive carrier parents: 25% affected, 50% carrier, 25% noncarrier per pregnancy.

X-linked carrier mother: 50% of sons affected and 50% of daughters carriers per pregnancy.

Age-dependent risk = carrier probability × penetrance by that age.

Bayesian analysis combines pedigree prior and test likelihood to update carrier risk.

Informed consent covers purpose, benefits, limitations, incidental findings, and privacy.

Teach-back and plain language improve recall and comprehension of genetic risk.

Psychosocial assessment addresses grief, guilt, family dynamics, and insurance concerns.

Carrier testing in minors is generally deferred until reproductive decision-making age.

Management is condition-specific and may include surveillance, prophylaxis, enzyme replacement, substrate reduction, or diet.

Multidisciplinary care coordinates cardiology, neurology, ophthalmology, and developmental services as indicated.

Avoiding known triggers prevents crises in disorders such as fatty acid oxidation defects or porphyria.

Reproductive options include prenatal diagnosis, preimplantation genetic testing, donor gametes, and adoption.

Newborn screening follow-up requires confirmatory testing and early treatment initiation.

Gene therapy eligibility depends on age, genotype, organ involvement, and monitoring requirements.

Surgical management addresses structural anomalies and complications such as cardiac defects.

Transition planning from pediatric to adult care prevents loss of surveillance and treatment.

Palliative care addresses symptom burden and quality of life in progressive genetic conditions.

Informed consent requires capacity, disclosure, understanding, voluntariness, and authorization.

Confidentiality can be limited by duty-to-warn statutes when relatives face serious actionable risk.

GINA protects health insurance and employment in the U.S.; it does not cover life, disability, or long-term care insurance.

Genetic testing of minors is generally limited to conditions with childhood actionability; carrier testing is deferred.

Secondary findings policies specify which actionable genes are reported and allow patient opt-out.

Direct-to-consumer genetic results require clinical confirmation before management changes.

Biobanking requires consent for storage, future use, and data-sharing limits.

Equitable access includes language services, financial counseling, and awareness of discrimination risk.

Professional scope requires referral for services outside the clinician's expertise.