2.1 Family History, Pedigree Construction & Analysis
Key Takeaways
- Standard pedigree symbols encode sex, status (affected/unaffected/carrier/deceased), relationship lines, consanguinity, adoption, twins, and unknown information so inheritance patterns can be read at a glance
- Autosomal dominant pedigrees show vertical transmission and male-to-male transmission; autosomal recessive pedigrees often show horizontal sibship clustering, especially with consanguinity
- X-linked patterns lack male-to-male transmission; mitochondrial pedigrees transmit only through females to all children, with males not transmitting further
- A three-generation pedigree with ethnicity, ages/ages at diagnosis, and negative findings is the minimum intake product for CGC risk assessment
- Pattern recognition drives differential diagnosis and testing strategy; incomplete penetrance and phenocopies can mimic or mask classic Mendelian patterns
2.1 Family History, Pedigree Construction & Analysis
Quick Answer: Construct a three-generation (or more) pedigree using standardized symbols for sex, affection status, relationships, consanguinity, adoption, twins, and unknowns. Read the pedigree for AD, AR, XL, and mitochondrial patterns, then reconcile incomplete penetrance, variable expressivity, and phenocopies before assigning risk.
Domain 2A items test whether you can turn a messy family story into a usable pedigree and recognize inheritance patterns that change carrier risk, testing strategy, and residual risk counseling.
Why Pedigree Skills Matter on the CGC Exam
Nearly every risk vignette starts with family history. Exam stems may give a drawn pedigree, a verbal history, or both. Your tasks are to (1) encode the history correctly, (2) identify the most likely inheritance pattern, (3) spot red flags that weaken a classic pattern (non-paternity assumptions, adoption, limited family size, early deaths without diagnoses), and (4) use the pedigree to choose who to test first and how to counsel relatives.
A pedigree is not decorative. It is the primary risk-assessment worksheet for Mendelian and Bayesian calculations in later sections of this chapter.
Intake → Pedigree Workflow
Collect at least three generations centered on the consultand (the person seeking counseling). Include:
- Ages or year of birth; ages at diagnosis and death when relevant
- Specific diagnoses (not only "cancer" or "heart problem")
- Negative findings ("no one else with hearing loss") — negatives change Bayesian calculations
- Ancestry/ethnicity for carrier-frequency priors
- Consanguinity, donor gametes, adoption, half-sibs, multiple partners
- Pregnancy losses, terminations, and infertility when relevant to the indication
Document who provided the history and flag unverified diagnoses. When a relative's diagnosis drives risk (for example, pathologically confirmed colon cancer at 35), note verification status.
Standard Symbols and Relationship Lines
Use conventional genetic counseling pedigree nomenclature (NSGC-style / Bennett et al. conventions commonly taught for board exams):
| Element | Standard representation | Counseling note |
|---|---|---|
| Male / female / unknown sex | Square / circle / diamond | Prefer sex recorded at birth or self-identified sex per clinic policy; exam stems usually use binary symbols |
| Consultand | Arrow pointing to the individual | The consultand is not always the proband |
| Proband | Arrow (often with "P") identifying the affected person who brought the family to medical attention | May differ from the person in session |
| Affected | Filled symbol | Shade by phenotype key when multiple traits |
| Carrier (autosomal / X-linked) | Dot in center (or half-shaded per legend) | Distinguish obligate vs. possible carrier in the key |
| Deceased | Diagonal slash through symbol | Record age and cause when known |
| Pregnancy | "P" or diamond/triangle conventions per key | Annotate gestational age and outcome |
| No offspring by choice / infertility | Hash mark or annotated "no issue" | Do not confuse with unknown |
| Relationship line | Horizontal line between partners | Multiple partners = multiple lines or numbered unions |
| Sibship line | Vertical drop to a horizontal sibship bar | Order left-to-right by birth when known |
| Consanguinity | Double relationship line | Critical for AR risk elevation |
| Adoption | Brackets around adoptee; dashed line to adoptive parents; solid to biologic when known | Clarify biologic vs. social risk |
| Twins | Converging lines from sibship bar; monozygotic often with a bar between twins | Ask zygosity; unknown zygosity affects some risks |
| Unknown / limited information | "?" annotation or open symbol with note | Do not invent affection status |
Relationship pitfalls: half-siblings share one parent; step-relatives without shared biology do not contribute Mendelian risk; donor-conceived children require a separate biologic pedigree when the indication is heritable disease.
Pattern Recognition: AD, AR, XL, Mitochondrial
| Pattern | Classic pedigree clues | High-yield exceptions |
|---|---|---|
| Autosomal dominant (AD) | Vertical transmission; both sexes affected; male-to-male transmission present | Incomplete penetrance creates "skipped" generations; de novo variants in the proband; mosaicism |
| Autosomal recessive (AR) | Horizontal clustering in sibs; parents usually unaffected; consanguinity raises suspicion | Small families may show only one affected child; pseudodominance in high-carrier populations |
| X-linked (XL) | No male-to-male transmission; more severe/affected males; carrier females may be mildly affected | Skewed X-inactivation; germline mosaicism; de novo variants in mothers of isolated cases |
| Mitochondrial | Transmission only through females to sons and daughters; males do not transmit the mtDNA variant | Heteroplasmy causes variable severity; nuclear gene mimics exist |
Worked Pattern Reads
AD example: A grandfather, father, and son all have neurofibromas and café-au-lait macules. Male-to-male transmission rules out XL and mitochondrial inheritance for that phenotype and strongly supports AD (for example, NF1).
AR example: Two sisters with cystic fibrosis; parents healthy; parents are first cousins. Horizontal sibship plus consanguinity supports AR. Each parent is an obligate carrier if the children's diagnoses are confirmed and truly AR.
XL example: Multiple males related through females have Duchenne muscular dystrophy; no father-to-son transmission. An unaffected sister of an affected boy has a prior carrier risk that Bayesian analysis will refine (Section 2.3).
Mitochondrial example: A mother and all of her children show sensorineural hearing loss and maternal relatives are similarly affected; the father's lineage is clear. Mitochondrial inheritance is on the differential, but confirm that a nuclear AD mimic is not equally plausible.
Analytic Traps That Change Risk
- Incomplete penetrance: An unaffected parent with an affected child and affected grandparent does not automatically exclude AD.
- Variable expressivity: Mild findings in "unaffected" relatives may reclassify the pedigree.
- Phenocopies: Sporadic disease in a relative can falsely suggest transmission.
- Misattributed parentage: Silent assumption of biologic relationships can break an XL or AD narrative.
- Limited family structure: Few males in an XL pedigree underpowers pattern recognition.
- Assisted reproduction / adoption: Social pedigree ≠ biologic risk pedigree.
Exam Scenario Mindset
When a stem shows a pedigree and asks "most likely inheritance," eliminate patterns that violate hard rules first (male-to-male transmission eliminates XL and mtDNA). Then weigh penetrance, sex distribution, and consanguinity. When asked what information is missing, prioritize ethnicity, ages at onset, pathologic confirmation, and relationship biology.
Connecting Pedigree to Downstream Risk Work
Once the pattern is proposed:
- Identify obligate carriers and consultand position in the pedigree.
- Assign simple Mendelian priors (Section 2.2).
- Incorporate negative tests, normal exams, or age-related unaffected status via Bayes (Section 2.3).
- Translate residual probability into follow-up testing and medical plans (Section 2.5).
Pedigree construction quality determines whether those later calculations are even pointed at the right person.
A pedigree shows an affected father transmitting a trait to his son, and both sexes are affected across three generations. Which inheritance pattern is effectively excluded by the male-to-male transmission?
On a standard pedigree, how should a child who was adopted into the consultand's family be drawn when biologic parents are unknown?
Two unaffected first-cousin parents have two children with the same rare metabolic disease and no other affected relatives. Which pedigree interpretation is most appropriate?
Why must negative family-history findings (for example, "no other relatives with hearing loss") be recorded on or with the pedigree?