Required core
Action pathway
Phenotype → recognize triggers → select testing → manage risk → interpret → counsel.
What mastery looks like
Six decisions residents must make reliably
This module deliberately de-emphasizes memorizing long gene lists. A resident should be able to initiate safe evaluation and management, then involve cardiovascular genetics for the parts that require subspecialty judgment.
- Phenotype every patient. Find extracardiac, developmental, and family-history clues that change pretest probability.
- Recognize trigger lesions. Know when the anatomy itself warrants targeted evaluation even without obvious dysmorphism.
- Match test to mechanism. Choose among karyotype, microarray, targeted testing, panel, and exome/genome sequencing.
- Protect the child now. Act on immune, calcium, airway, bleeding, splenic, vascular, and anesthesia risks before the report returns.
- Interpret without overclaiming. Distinguish pathogenic/likely pathogenic, VUS, and negative results; know what each does not prove.
- Counsel precisely. Separate screening from diagnosis and Mendelian risk from lesion-specific empiric recurrence.
Core correction: there is no single universal “genetic test for CHD,” no universal 2–4% recurrence number, and no permission to manage a family from a VUS. The phenotype, suspected variant class, acuity, family structure, and available laboratory determine the pathway.
Required core
Pattern recognition
Common lesion–syndrome pairings and the extracardiac action each should trigger.
Required core
Assessment
Pretest, five decision cases, and a scored posttest with domain feedback.
Diagnostic assessment
Pretest
Answer before opening the pathway. Feedback is immediate; the score is diagnostic and does not count toward completion.
The resident workflow
From CHD to a defensible genetics plan
Use this sequence for the newborn, inpatient consult, postoperative child, or outpatient referral. It is not a rigid test ladder.
1
Stabilize first; phenotype in parallel
Do not delay ductal support, shock treatment, respiratory support, arrhythmia care, or transfer for genetics. At the same time document pregnancy history, three-generation pedigree, growth/head circumference, development, dysmorphology, palate/airway, limbs, skin, neurologic findings, and renal/GI/hepatic anomalies.
Ask specifically: CHD, cardiomyopathy, arrhythmia/pacemaker, aortic disease, sudden death, recurrent pregnancy loss, consanguinity, infertility, and similarly affected relatives.
2
Identify high-yield triggers
- CHD plus dysmorphism, multiple congenital anomalies, abnormal growth, developmental delay/intellectual disability, or neurologic findings.
- Familial CHD, cardiomyopathy/conduction disease, laterality defects, consanguinity, or recurrent pregnancy loss.
- Conotruncal/arch disease—especially interrupted aortic arch type B, truncus arteriosus, tetralogy of Fallot, or arch anomaly—should prompt evaluation for 22q11.2 deletion. The 2025 AAP report specifically recommends chromosome microarray for any conotruncal defect or IAA-B. AAP 2025
- Supravalvar aortic stenosis or diffuse arteriopathy; left-sided disease with Turner features; AVSD with trisomy 21 features; pulmonary stenosis/HCM with a RASopathy phenotype.
- Critically ill infant with complex CHD plus extracardiac anomalies: discuss rapid trio ES/GS early. Evolving implementation
3
Choose a test that can see the suspected change
| Clinical question | Useful test | Key limitation |
|---|---|---|
| Aneuploidy, Turner syndrome, large rearrangement, mosaicism | Karyotype; rapid aneuploidy testing may be paired with definitive cytogenetics | Low resolution for submicroscopic CNVs |
| Genome-wide deletions/duplications; 22q11.2 or 7q11.23 deletion | Chromosomal microarray (CMA) | Usually misses balanced rearrangements, most sequence variants, and low-level mosaicism |
| Highly specific phenotype with known mechanism | Targeted assay or focused panel selected with genetics | A negative narrow test can miss phenocopies and locus heterogeneity |
| Nonspecific syndromic CHD or CHD plus GDD/ID | CMA and trio exome/genome sequencing, concurrent or sequential based on phenotype, access, and laboratory capabilities | ES may miss noncoding, repeat, methylation, some CNV/structural and mitochondrial changes; capabilities vary |
| Familial apparently isolated CHD | Cardiovascular genetics evaluation; phenotype-driven panel or ES/GS | Yield is variable; a negative result does not erase familial risk |
ACMG recommends ES/GS as a first- or second-tier test for children with congenital anomalies, DD, or ID. The 2025 AAP GDD/ID report retains CMA and ES in first-tier agnostic evaluation, performed sequentially or concurrently. ACMG/AAP
4
Manage syndrome-specific danger before confirmation when suspicion is high
- Suspected 22q11.2 deletion: calcium, CBC, lymphocyte subsets/T-cell function, renal/palate/feeding assessment; coordinate blood-product and live-vaccine decisions with immunology/transfusion medicine.
- Suspected Williams syndrome: four-extremity blood pressure, full arterial/coronary assessment, renal/calcium evaluation, and anesthesia planning at an experienced center.
- Suspected RASopathy: ECG/echo, bleeding history and hemostatic evaluation before procedures, feeding/growth and developmental assessment.
- Heterotaxy with absent/poor splenic function: infection prevention plan and urgent fever instructions; evaluate airway/ciliary and GI concerns.
- Turner syndrome: congenital cardiology evaluation, blood pressure in all limbs, complete arch/aortic imaging; cross-sectional imaging when age/condition permits.
5
Order with counseling and the right family samples
Explain possible positive, negative, uncertain, secondary/incidental, and family-relevant results; document consent/assent as appropriate. Trio testing often improves interpretation. Collect the most informative affected relative first when possible. Involve genetics/genetic counseling rather than treating a commercial panel as the diagnostic strategy.
6
Close the loop
Link a molecular result to phenotype and management, communicate it to the family and care team, arrange indicated targeted testing or clinical screening of relatives, and create a plan for reinterpretation after a negative or uncertain result.
Pattern → test → action
High-yield clinical patterns
These are recognition prompts, not one-to-one rules. The same lesion occurs in multiple syndromes, and many affected children lack a classic facial gestalt.
| Pattern | Think about | Initial genetics move | Resident action beyond the heart |
|---|---|---|---|
| Conotruncal defect or IAA-B; hypocalcemia, palatal/feeding or immune clues | 22q11.2 deletion syndrome | CMA; genetics consultation | Calcium, immune status, palate/feeding, renal assessment; plan blood products and vaccines safely |
| AVSD with hypotonia and characteristic features | Trisomy 21 | Chromosome analysis; establish translocation status for recurrence counseling | Follow AAP health-supervision pathway; do not skip postnatal echo because prenatal imaging was reassuring |
| Coarctation/BAV/elongated arch in a girl; edema, short stature, webbed neck | Turner syndrome | Karyotype with attention to mosaicism/structural X; genetics/endocrinology | Complete aortic imaging, BP surveillance, renal/hearing/endocrine care |
| Supravalvar AS, branch PA stenosis, diffuse arteriopathy, characteristic cognitive/behavioral profile | Williams syndrome / 7q11.23 deletion | CMA or validated deletion assay | Assess coronary/arterial disease, hypertension, calcium/renal issues; high-risk anesthesia planning |
| Dysplastic pulmonary valve stenosis or HCM with short stature, pectus, hypertelorism/webbed neck | Noonan spectrum disorder / RASopathy | RASopathy multigene testing, usually with genetics | ECG/echo, bleeding risk, feeding/growth/development; refer severe progressive infantile RASopathy-HCM early to an expert center |
| Peripheral PA stenosis/TOF plus cholestasis, posterior embryotoxon, butterfly vertebrae, characteristic facies | Alagille syndrome | JAG1/NOTCH2 testing or broader testing if phenotype uncertain | Liver, renal, ocular, skeletal and vascular evaluation |
| ASD/VSD plus radial-ray or thumb abnormality; conduction disease | Holt–Oram syndrome (TBX5) | Targeted/panel testing with genetics | ECG/rhythm surveillance and evaluation of first-degree relatives |
| CHD plus coloboma, choanal atresia, cranial nerve/feeding, ear or hearing anomalies | CHD7 disorder / CHARGE | CHD7 testing or ES/GS if phenotype is incomplete | Airway, swallow, hearing, vision and endocrine assessment |
| Laterality defect, complex venous anatomy, asplenia/polysplenia | Heterotaxy; ZIC3 and multiple ciliary/laterality genes | Genetics; panel or ES/GS selected by phenotype/family history | Document splenic function, infection plan, airway/ciliary disease and GI warning signs |
| Familial BAV/coarctation/LVOTO | Familial left-sided CHD; occasionally monogenic | Clinical screening of first-degree relatives; genetics if syndromic, severe, or strongly familial | Do not promise a high-yield gene result; echocardiographic family screening can matter even when testing is negative |
Do not teach false exclusivity: AVSD is strongly associated with trisomy 21 but is not diagnostic of it; TOF is not synonymous with 22q11.2 deletion; and most isolated BAV does not yield a single actionable gene. Anatomy modifies probability—it does not replace phenotype or testing.
Optional depth
Syndrome deep dives
22q11.2 deletion: what changes today?
Cardiac: conotruncal and arch anomalies, including TOF, truncus, IAA-B and arch/branch PA abnormalities. Immediate: calcium and immune evaluation; feeding/palate, renal and airway assessment. Safety: do not use “absent thymic shadow” as an immune test; coordinate live vaccines and cellular blood products from actual immune data and local protocols. The 2025 AAP health-supervision report is the current pediatric anchor.
Williams syndrome: why anesthesia deserves its own warning
SVAS may coexist with coronary ostial disease, diffuse arterial stenosis, ventricular hypertrophy and hypertension. Sudden cardiovascular collapse under sedation/anesthesia is a recognized risk. Residents should escalate elective procedural planning to cardiology/anesthesia teams familiar with Williams syndrome rather than merely documenting “cleared by cardiology.”
RASopathies: genotype now can affect referral urgency
Pulmonary stenosis, HCM and ASD are the core patterns. RAF1 and RIT1 variants are strongly enriched for HCM; PTPN11 is common and often associated with pulmonary stenosis. The resident task remains ECG/echo, hemodynamic assessment, bleeding/procedure planning and multidisciplinary referral. A 2025 multicenter retrospective analysis compared 30 children offered standard care plus a MEK inhibitor with 31 offered standard care alone for severe RASopathy-associated HCM; PTPN11-associated disease was excluded. The MEK-inhibitor group had better cardiac-surgery, transplant and death outcomes. This is an important signal, but it was not a randomized trial and GeneReviews still lists trametinib under therapies under investigation. Resident action: recognize progressive infantile RASopathy-HCM and involve a center with RASopathy, heart-failure and clinical-trial expertise early; do not initiate MEK inhibition as routine therapy.
Familial CHD: what “negative genetics” does not mean
A negative panel or exome does not make a pedigree sporadic. Incomplete penetrance, variable expression, noncoding/structural variants, mosaicism, polygenic architecture and unrecognized phenotypes remain possible. Family members may need clinical screening even when no molecular diagnosis is found.
Optional advanced practice
Genomic workbench: from report to defensible interpretation
A database can supply evidence, context, or a hypothesis. None can independently convert a weak gene, discordant phenotype, or uncertain variant into a diagnosis.
Do not “look up the variant and vote.” First validate the gene–disease relationship and molecular mechanism; then assess the specific variant, inheritance, and phenotype. A pathogenic molecular consequence in a gene with no valid relationship to the child’s disease is not a molecular diagnosis.
| Resource | Best use at the point of care | Failure mode to avoid |
|---|---|---|
| GeneReviews | Expert disease chapters: diagnostic approach, mechanism, surveillance, management, counseling, and testing strategy. | It is not a variant classifier, and chapter update dates differ. Check the revision date and source studies. |
| OMIM | Gene–phenotype relationships, allelic series, molecular mechanism, phenotype history, and primary references. | An OMIM entry or phenotype number does not prove clinical validity, actionability, or that a panel gene belongs on the panel. |
| ClinGen gene validity / dosage | Strength of a gene–disease relationship; haploinsufficiency/triplosensitivity of genes and regions; expert actionability/variant curations where available. | “Limited,” “disputed,” “refuted,” or uncurated is not equivalent to a definitive relationship. Absence of a curation is not itself refutation. |
| ClinVar | Submitted variant assertions, condition specificity, review status, dates, evidence summaries, and conflicts. | ClinVar archives submissions; it does not adjudicate every conflict. Do not count submitters, ignore condition/transcript differences, or equate a zero/one-star assertion with expert review. |
| gnomAD | Population allele frequency, ancestry-stratified observations, constraint, coverage, and quality context. | Absence is not pathogenicity. Check allele number, coverage, quality flags, ancestry representation, disease prevalence, penetrance, and inheritance model. |
| HPO | Precise, computable phenotype terms for laboratory requisitions, phenotype-driven analysis, and later reanalysis. | A long copied problem list is not deep phenotyping. Include present and explicitly absent discriminating features, age of onset, and objective measurements. |
| DECIPHER | CNV/sequence-variant overlap, patient phenotypes, genomic content, constraint, and comparison with reported cases. | Overlapping cases are not matched controls; ascertainment, incomplete phenotyping, penetrance, inheritance, and genome build matter. |
| Orphanet | Rare-disease nomenclature, ORPHAcodes, classification, expert centers, registries, trials, and cross-border resources. | Disease summaries and service listings do not replace gene/variant curation or patient-specific guidance. |
| Face2Gene | Gestalt- and phenotype-assisted hypothesis generation when a syndrome is not obvious; can help structure an HPO differential. | It neither diagnoses nor excludes a syndrome. Use only through an approved clinical workflow with consent/privacy safeguards; performance can vary with age, ancestry, image quality, and training representation. |
A six-question interrogation
Before acting on any sequence or CNV result
- Is the identity correct? Confirm patient/sample, genome build, HGVS expression, transcript, zygosity, coordinates, and CNV boundaries.
- Is the gene or region valid? Check the exact gene–disease pair in ClinGen and the literature; for CNVs check dosage sensitivity and region content.
- Does the mechanism fit? Loss of function, gain of function, dominant-negative effect, dosage, variant location, and inheritance are not interchangeable.
- Does the phenotype fit? Use HPO terms, age-dependent findings, objective cardiac anatomy, extracardiac features, and informative negative findings.
- Does the variant evidence hold? Review laboratory evidence, ClinVar status/date/conflicts, gnomAD frequency/coverage, segregation, de novo status, and validated functional or splicing data.
- What action is justified? Use disease-specific guidance for surveillance and family testing. Separate a diagnostic finding from a risk allele, VUS, secondary finding, or research candidate.
Worked example
“Pathogenic” variant, weak gene
A predicted loss-of-function variant may be technically pathogenic for loss of that gene, yet still fail to explain CHD if haploinsufficiency is not an established disease mechanism or the gene–CHD relationship is limited/disputed. Escalate interpretation; do not label the child.
Worked example
CNV near a famous gene
Interpret the actual coordinates and build, inheritance, dosage-sensitive genes/regions, size, phenotype, and overlapping cases. Proximity to a familiar CHD gene is not sufficient.
Worked example
Negative genome
Confirm CNV/SV, mitochondrial, repeat, mosaic, coverage, and reanalysis capabilities. Re-phenotype after the child evolves and plan laboratory-based reanalysis when new clinical or scientific information could change interpretation.
State of the art, with epistemic labels
What is ready now—and what remains frontier
| Capability | Current position | Resident-level action |
|---|---|---|
| Rapid trio genome sequencing in critically ill infants | Rapidly entering practice Recent CHD cohorts show clinically useful diagnoses and management impact, but eligibility, turnaround, CNV/SV performance, coverage, and access vary by center. | Discuss early when complex CHD coexists with extracardiac anomalies, neurologic findings, severe unexplained physiology, or time-sensitive decisions; obtain parental samples and genetics input. |
| Genome-first analysis with CNV/SV calling | Laboratory-dependent A single assay may detect sequence and copy-number findings, but “genome” is not a uniform product and does not guarantee CMA-equivalent performance for every variant class. | Read the laboratory’s validated reportable range rather than assuming the assay sees everything. |
| Phenotype-driven reanalysis | Current best practice New phenotype, segregation, gene–disease discoveries, and variant reclassification can convert a nondiagnostic study. | Keep HPO-quality phenotyping current and give the family a named recontact/reanalysis plan; no universal calendar interval fits every laboratory. |
| Long-read sequencing, RNA/splicing assays, methylation and other functional omics | Specialized / emerging These can solve selected structural, repeat, phasing, splicing, imprinting, or otherwise unresolved cases but are not a universal clinical CHD tier. | Escalate a compelling unsolved phenotype to a genomic center; do not order a technology without a mechanism-level question. |
| AI-assisted facial/phenotype matching | Hypothesis generator Useful for prioritization, vulnerable to representation, image, age, and privacy limitations. | Use to widen a differential—not to rule in, rule out, or bypass consent and clinical genetics. |
| MEK inhibition for severe RASopathy-HCM | Promising, off-label Positive multicenter retrospective data exist in a selected non-PTPN11 cohort; prospective trial evaluation is ongoing. | Recognize the referral phenotype and contact an expert RASopathy/HCM program early. Treatment selection and monitoring are subspecialty decisions. |
Interpretation discipline
What the report permits you to say
Classification is not the whole interpretation. A result must fit the gene–disease relationship, inheritance, phenotype, and assay limitations.
Pathogenic / likely pathogenic
Potentially diagnostic
- Confirm phenotype and inheritance.
- Change surveillance/management only when the gene–disease relationship and variant fit.
- Offer targeted familial testing or clinical screening as indicated.
Variant of uncertain significance
Not a diagnosis
- Do not use alone for surgery, medications, reproductive prediction, or predictive testing of unaffected relatives.
- Segregation studies may help classification when genetics recommends them.
- Track for reinterpretation.
Negative / nondiagnostic
Not “not genetic”
- Review what the assay could not detect.
- Continue phenotype-driven care and family screening when clinically indicated.
- Revisit after phenotype evolution, new family data, or laboratory reanalysis.
Counseling without false precision
Four distinctions families need
Screening ≠ diagnosis
Cell-free DNA/NIPT estimates risk for selected chromosomal conditions; a positive screen requires diagnostic confirmation with CVS or amniocentesis. A negative screen does not exclude most causes of CHD.
Mendelian risk ≠ empiric lesion risk
A parent with an autosomal dominant pathogenic variant may have a 50% transmission risk. Without a molecular diagnosis, recurrence depends on lesion, number/relationship/sex of affected relatives, and family structure; use genetics and lesion-specific data rather than a universal percentage.
Variant transmission ≠ phenotype prediction
Variable expression and reduced penetrance mean an inherited pathogenic variant may produce a different cardiac or extracardiac phenotype—or no recognized phenotype—in another relative.
Fetal imaging ≠ genomic testing
Detailed fetal cardiac screening is optimally performed at 18–22 weeks; some lesions evolve or remain difficult to detect. Imaging defines anatomy; genetic testing addresses etiology and recurrence. They answer different questions.
Deliberate practice
Five branching clinical cases
Choose the next best action. The case unfolds after each decision, and explanations address why the distractors are unsafe or incomplete.
Summative assessment
Mastery posttest
Eighteen new questions. Answer all, then submit. Passing requires ≥80% (15/18). Unlimited retries reshuffle question and option order.
Print-ready
Genetic CHD: resident quick reference
Use at the bedside as a prompt. It does not replace genetics consultation or institution-specific laboratory and transfusion protocols.
1. Phenotype every child with CHD
Pregnancy/exposure history · three-generation pedigree · growth/head circumference · development · face/palate/airway · limbs · skin · neurologic exam · renal/GI/hepatic anomalies · hearing/vision.
2. Escalate when
Syndromic or extracardiac features · developmental difference · family history/consanguinity/recurrent loss · cardiomyopathy/conduction/aortic disease · laterality defect · conotruncal/arch trigger · critically ill infant with unexplained complex disease.
3. Match test to suspected mechanism
Karyotype: aneuploidy/Turner/large or balanced rearrangement/mosaicism. CMA: deletions/duplications such as 22q11.2 and 7q11.23. Panel/targeted: recognizable monogenic phenotype. Trio ES/GS: heterogeneous/nonspecific syndromic CHD; rapid testing early in selected critically ill infants.
4. Protect before proof
22q11.2: calcium + immune + palate/feeding/renal/blood-product planning. Williams: arterial/coronary + BP + anesthesia risk. RASopathy: ECG/echo + bleeding/procedure planning. Heterotaxy: splenic infection + airway/ciliary + GI plan. Turner: complete arch/aortic imaging + BP.
5. Interpret safely
P/LP may be actionable if phenotype and gene–disease relationship fit. VUS is not diagnostic. Negative does not exclude a genetic cause. Plan reanalysis and clinical family screening when indicated.
6. Counsel precisely
Screening ≠ diagnosis. Transmission ≠ phenotype. Molecular risk ≠ empiric lesion recurrence. Prenatal imaging ≠ etiologic testing.
7. Interrogate the report
Identity/build/transcript → gene or region validity → molecular mechanism → phenotype/inheritance → variant evidence → justified action. ClinVar is submitted assertions; gnomAD absence is not pathogenicity; Face2Gene generates hypotheses, not diagnoses.
Evidence and provenance
Primary sources
Clinical statements and practice guidance take priority; the 2026 review is included to mark the current sequencing transition. Links are direct and were checked August 12, 2026.
- Pierpont et al. Genetic Basis for Congenital Heart Disease: Revisited. AHA Scientific Statement. Circulation. 2018.
- Landstrom et al. Genetic Testing for Heritable Cardiovascular Diseases in Pediatric Patients. AHA Scientific Statement. 2021.
- Manickam et al. Exome and genome sequencing for pediatric patients with congenital anomalies or ID. ACMG evidence-based guideline. 2021.
- Scheuerle et al. Health Supervision for Children With 22q11.2 Deletion Syndrome. AAP Clinical Report. 2025.
- Rodan et al. Genetic Evaluation of the Child With Intellectual Disability or Global Developmental Delay. AAP Clinical Report. 2025.
- Sandmann & Morton. Genetic Testing in Congenital Heart Disease: From Microarray to Genome Sequencing. Circ Genom Precis Med. 2026.
- Richards et al. ACMG/AMP standards for interpretation of sequence variants. 2015.
- Riggs et al. ACMG/ClinGen technical standards for constitutional copy-number variant interpretation. 2020.
- Deignan et al. ACMG points to consider in reevaluation and reanalysis of genomic test results. 2019.
- Bull et al. Health Supervision for Children and Adolescents With Down Syndrome. AAP Clinical Report. 2022.
- Morris et al. Health Care Supervision for Children With Williams Syndrome. AAP Clinical Report. 2020.
- Gravholt et al. Clinical practice guidelines for the care of girls and women with Turner syndrome. 2024.
- Roberts et al. Noonan Syndrome. GeneReviews. Updated 2025.
- Carvalho et al. ISUOG Practice Guidelines: fetal cardiac screening. 2023.
- Landstrom et al. Genetic and Genomic Testing in Cardiovascular Disease. AHA Policy Statement. 2025.
- Wolf et al. Impact of MEK Inhibition on Childhood RASopathy-Associated Hypertrophic Cardiomyopathy. JACC: Basic to Translational Science. 2025.
- Durbin et al. Rapid Genome Sequencing Shows Diagnostic Utility in Infants With Congenital Heart Disease. Circ Genom Precis Med. 2026.
Point-of-care genomics resources
- GeneReviews · OMIM · ClinGen · ClinVar
- gnomAD · Human Phenotype Ontology · DECIPHER
- Orphanet · Face2Gene (commercial hypothesis-support tool; institutional privacy/consent requirements apply)
Evidence labels: “Guideline” marks a formal guideline/clinical report recommendation; “consensus” marks an expert scientific statement; “evolving” marks implementation supported by newer evidence but not a universal resident-level mandate. Local genetics, laboratory, transfusion, and immunology protocols can legitimately differ.