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Block 5 · Heme · HEM17 · Rev 1.0 · Updated Oct 8, 2026
HEM17 · Genetics · Study Guide

Mendelian Inheritance & Pedigrees

Updated Oct 9, 2026 Revision 1.0 5 learning objectives

Learning objectives

  1. LO 1Read and draw a pedigree using standard symbols.
  2. LO 2Recognize autosomal dominant and recessive patterns and calculate recurrence and carrier risks.
  3. LO 3Recognize X-linked recessive, X-linked dominant and Y-linked patterns, and explain how X-inactivation lets females be affected.
  4. LO 4Adjust a pedigree reading for new mutations, age of onset, penetrance and expressivity.
  5. LO 5Weigh the benefits and risks of presymptomatic and predisposition testing.
◆ In-house exam ★ Step 1 ▲ High yield Memory tool Analogy Trap

MAPPattern finder: three questions

1 · Male → male transmission?father passes to son YES → not X-linkedautosomal (or Y-linked) 2 · Every generation?vertical vs horizontal Verticaldominant Skipsrecessive 3 · Sex pattern?who is affected, who transmits Mostly males via carrier mothers → XLR Affected dad → all daughters → XLD Dad → all sons only → Y-linked Mom → all children → mitochondrial Then adjust for complicating factors new mutation · late onset · reduced penetrance · variable expressivity a "skipped" generation in a dominant disorder = non-penetrance

LO 1Pedigree symbols and basics

Q1. What are the basic rules of transmission?
  • 46 chromosomes in 23 pairs; pairs 1–22 (autosomes) same in both sexes; pair 23 = sex chromosomes (XX, XY)
  • Genes come in pairs (alleles); one from each parent; each gamete gets one
  • Any given allele has a 50% chance of passing to a child
Q2. What do the pedigree symbols mean?
malefemaleaffectedcarriersex unknown
SymbolMeaning
Square / circle / diamondMale / female / sex unknown
FilledAffected
Dot in the center (or half-filled)Carrier
Number insideMultiple individuals (n)
Slash throughDeceased
"P" insidePregnancy
Small triangleMiscarriage
Horizontal line between partnersMating (double line = consanguinity)
ArrowProband
Step 1

A double mating line marks consanguinity → think autosomal recessive.

LO 2Autosomal dominant and recessive

Q1. What does autosomal dominant look like?
Autosomal dominantevery generation · male→male · ½ affected
  • Gene on an autosome; ½ of offspring of an affected person are affected
  • No skipped generations (vertical); males and females equally affected
  • Male-to-male transmission occurs (rules out X-linked)
  • To have an affected child, the patient or partner must be affected (barring new mutation); each child then has a 50% risk
Memory tool

Dominant = "Down every generation." Recessive = "Runs sideways" (siblings).

Q2. What does autosomal recessive look like?
Autosomal recessiveparents unaffected carriers · ¼ affectedhorizontal · skips generations · consanguinity
  • Gene on an autosome; disease only in homozygous or compound heterozygous state
  • Parents are carriers; ¼ of offspring affected; males = females
  • Usually one generation (horizontal); can mimic AD with consanguinity or high carrier frequency (sickle cell, hemochromatosis)
  • Both partners must carry the same disorder; carrier risk comes from family history or, without one, population frequency
Trap — pseudodominance

A common AR disease (sickle cell, hemochromatosis) can appear in several generations when an affected person marries a carrier. Don't call it dominant without male-to-male transmission and 50% ratios.

Q3. How do I calculate AR risks?
PersonRisk
Child of two carriers¼ affected · ½ carrier · ¼ non-carrier
Sibling of an affected person¼ affected
Unaffected sibling of an affected person⅔ carrier
Child of an affected person × carrier partner½ affected
Child of an affected person × non-carrier partner0 affected; all carriers
Carrier × carrier (Aa × Aa) AA Aa aA aa ✕ (affected) Sibling is unaffected → remove aa Carriers: 2 of 3 = ⅔
High yield

Classic chain: the unaffected sister of a child with CF (⅔ carrier) marries a man with population risk 1/25. Risk their child is affected = ⅔ × 1/25 × ¼ = 1/150.

Trap

"Sibling of an affected" (unknown status) → ¼ affected, ½ carrier. "Unaffected sibling" → ⅔ carrier. Read the stem carefully.

ApplyLO 2 application questions

A1A man affected with an AR disease marries a woman with no family history (carrier risk 1/50). Risk their child is affected?
1/50 × ½ = 1/100.
A2Both parents are unaffected; two of their four children have the same disease; the parents are first cousins. Pattern?
Autosomal recessive (consanguinity, horizontal).

LO 3X-linked and Y-linked inheritance

Q1. What is the Lyon hypothesis?
  • Females have two copies of X-linked genes, males one, yet gene product levels are similar: dosage compensation
  • One X in each female somatic cell is inactivated, early in embryonic life and at random (≈50% maternal, 50% paternal)
  • Once inactivated, an X stays inactive in all descendant cells → females are mosaics
Analogy — the patchwork quilt

A carrier female is a quilt of patches: some running mom's X, some dad's X. If most patches happen to run the mutant X (skewed), she shows the disease.

Q2. What does X-linked recessive look like?
X-linked recessive½ sons affected · ½ daughters carriersno male→male · affected dad → all daughters carriers
  • No father-to-son transmission
  • All daughters of affected males are carriers
  • ½ of sons of carrier females are affected; ½ of daughters are carriers
  • Skipped generations (through carrier females); unaffected males don't transmit
  • Heterozygous females usually unaffected, but may express with variable severity
High yield — affected females
  • Skewed X-inactivation (normal X preferentially silenced)
  • Turner syndrome (45,X with the mutant X)
  • Other X-chromosome abnormality (also: affected father × carrier mother)
Q3. What do X-linked dominant and Y-linked look like?
X-linked dominantaffected father → ALL daughters, NO sonsaffected mother → ½ of either sex
Y-linkedall sons, no daughtersspermatogenesis, male differentiation genes

X-linked dominant

  • No father-to-son transmission
  • Affected mother → ½ of children of either sex
  • Affected father → all daughters, no sons
  • Skipped generations uncommon; many are lethal in males

Y-linked

  • Gene on Y
  • Father → all sons
  • Mostly male differentiation and spermatogenesis genes
Step 1

XLD examples: hypophosphatemic (vitamin D–resistant) rickets, fragile X, Alport (most), Rett and incontinentia pigmenti (male-lethal).

Memory tool

Affected dad in XLD: "Daddy's girls": every daughter gets his X; every son gets his Y.

ApplyLO 3 application question

A1A man with an X-linked recessive disease and a non-carrier wife ask about their children.
Sons: unaffected (get his Y). Daughters: all carriers.

LO 4Complicating factors

Q1. How do new mutations change the risks?
  • New mutation = arises during gametogenesis; the parent carries it in no other cell; the child has it in every cell and passes it on with 50% risk
  • AD: risk to the offspring of an affected person is 50% regardless; risk to the affected person's siblings depends on whether it was new (low) or inherited (50%)
  • Example: achondroplasia, >80% new; ↑ with paternal age
X-linked recessive rule
Overall≈⅓ new mutation; ≈⅔ carrier mother
Obligate carrierWoman with an affected father; woman with an affected brother AND an affected child
Single affected male, no family history⅓ chance he's a new mutation
Trap

A woman with only an affected son (no other history) is not an obligate carrier: the son could be a new mutation (or gonadal mosaicism).

Q2. Why does age of onset matter?
  • Disorders can start in the newborn period, childhood or adulthood; ignoring late onset makes risk assessment misleading
  • Huntington disease: mean onset 35–44; survival after symptoms 15–18 years. A healthy 25-year-old at 50% risk may simply not be symptomatic yet
Q3. What is the difference between penetrance and expressivity?

Penetrance

  • Probability of any phenotype at all ("all or none")
  • % of people with the genotype who are affected
  • Non-penetrance → apparent skipped generation; an unaffected "at-risk" person can still have affected children
  • Example: split-hand deformity (≈70% penetrant)

Expressivity

  • Extent of expression
  • Variable: mild to severe, but never completely absent
  • Example: NF1 (≈1/3,000): café-au-lait spots, neurofibromas, Lisch nodules, malignant tumors; ½ new mutations
Memory tool

Penetrance = does the light turn on? Expressivity = how bright is it?

In-house exam

A dominant disorder that seems to skip a generation → reduced penetrance (not recessive). Different severity within one family → variable expressivity.

ApplyLO 4 application question

A1A boy has Duchenne; there is no other family history. What is the chance he has a new mutation?
≈⅓ (⅔ chance his mother is a carrier).

LO 5Presymptomatic and predisposition testing

Q1. How do presymptomatic and predisposition testing differ?
PresymptomaticPredisposition
GoalDiagnose a disorder that will occur, before symptomsMeasure susceptibility
PenetranceNearly 100%Reduced: a variant doesn't guarantee disease
ExampleHuntington diseaseHereditary cancer genes (BRCA)
RiskPositive = certain disease, timing unknown; job/insurance lossJob/insurance discrimination
Q2. Why would someone test for Huntington disease, and what are the concerns?

Reasons

  • Relieve intense daily anxiety
  • Adjust choice of employment
  • Financial arrangements for family
  • Family planning

Concerns

  • Depression (waiting; no treatment or cure; test can't say when)
  • Suicide
  • Discrimination: social, employment, insurance
  • Decide individually, in the context of the person's life; patient must understand risks and benefits
  • Test at a center with extensive psychological counseling
High yield

Minors are generally not tested for adult-onset, untreatable conditions like HD; they can choose at 18.

Step 1

HD: CAG repeat in HTT (chr 4), AD with anticipation (expands through the father); caudate atrophy, chorea, depression. GINA bars genetic discrimination in health insurance and employment, but not life, disability or long-term-care insurance.

IDPedigree ID

Pedigree 1
Autosomal dominantevery generation · male→male · ½ affected
Autosomal dominant: every generation, male-to-male.
Pedigree 2
X-linked recessive½ sons affected · ½ daughters carriersno male→male · affected dad → all daughters carriers
X-linked recessive: carrier mother, affected sons.
Pedigree 3
X-linked dominantaffected father → ALL daughters, NO sonsaffected mother → ½ of either sex
X-linked dominant: affected father → all daughters.
Pedigree 4
Autosomal recessiveparents unaffected carriers · ¼ affectedhorizontal · skips generations · consanguinity
Autosomal recessive: carrier parents, affected child.

MCQExam-style questions

Score: 0 / 0

1A disorder appears in every generation, affects males and females equally, and an affected father has an affected son. Pattern?

2A healthy woman's brother has cystic fibrosis; her parents are healthy. What is the chance she is a carrier?

3That same woman marries a man with no family history (carrier risk 1/25). Risk their child has CF?

4A man with an autosomal recessive disease has children with a non-carrier woman. Their children will be:

5Which finding rules out X-linked inheritance?

6A father has an X-linked dominant disorder; the mother is unaffected. Expected children?

7A girl has hemophilia A. Her karyotype is 45,X. Best explanation?

8Which woman is an obligate carrier of an X-linked recessive disorder?

9A dominant hand malformation is seen in a grandfather and his grandson, but the boy's father is normal. Best explanation?

10In one family with NF1, the mother has only café-au-lait spots while her son has plexiform neurofibromas. This illustrates:

11A child has achondroplasia; both parents are of average stature. Risk to the child's future offspring?

12A 25-year-old whose father has Huntington disease asks about testing. Which is most appropriate?

!Source notes

ItemLectureStep 1 / standard references
Presymptomatic testing"A positive result is a death sentence"Framed as near-certain disease with unknown timing; counsel neutrally
Insurance / jobsPositive test risks job and insurance lossGINA (2008) protects health insurance and employment; not life, disability or long-term-care insurance
XLR new mutations≈⅓ of casesHaldane's ⅓ applies to lethal/non-reproducing XLR disorders (e.g., DMD)

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