STEPTRACKERGENETICS | INHERITANCE | HIGH-YIELD REVIEW

Inheritance Patterns & Pedigrees

Read a pedigree in four questions: every generation? sexes equal? father-to-son? only through mothers? — then do the risk math.

FOCUS ON

AD: every generation, both sexes, male-to-male transmission possible, 50% risk per child. AR: skips generations, consanguinity, 25% risk (2/3 of unaffected sibs are carriers). XLR: mostly males, through carrier mothers, never father-to-son. XLD: affected father → all daughters, no sons. Mitochondrial: only through mothers, all children may be affected (variable).

PATTERN

PEDIGREE SIGNS

RISK MATH

EXAMPLES

Autosomal dominant

Vertical (each generation), M = F, male-to-male transmission

Affected × normal → 50% each child

Often structural proteins; ADPKD, Huntington, Marfan, NF1

Autosomal recessive

Horizontal (siblings), skips generations, consanguinity

Carrier × carrier → 25% affected, 50% carrier; unaffected sib = 2/3 carrier

Often enzymes; CF, sickle cell, storage diseases

X-linked recessive

Mostly males; through unaffected carrier females; no father-to-son

Carrier mother → 50% sons affected, 50% daughters carriers · affected father → all daughters carriers, no sons affected

DMD, hemophilia A/B, G6PD, Lesch-Nyhan, Fabry, Hunter, OTC, Bruton

X-linked dominant

Affected father → all daughters, no sons; affected mother → 50% of all children

Females often milder (X inactivation)

Hypophosphatemic rickets, fragile X, Alport (most), Rett (lethal in males)

Mitochondrial

Only mothers transmit; all children at risk; variable severity (heteroplasmy)

Affected father → 0%

MELAS, MERRF, LHON; ragged red fibers

Y-linked

Father → all sons only

100% of sons

Rare (some infertility genes)

Multifactorial

Many genes + environment; recurrence ↑ with more affected relatives and severity

Usually 2–5%

Cleft lip, neural tube defects, pyloric stenosis, T2DM

Imprinting

Phenotype depends on which parent passes the deletion

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Prader-Willi vs Angelman (5.04)

De novo mutation

Affected child, unaffected parents, AD condition

Low recurrence unless gonadal mosaicism

Achondroplasia (often older father)

Pedigree symbols

Square = male, circle = female, filled = affected, half-filled/dot = carrier, double line = consanguinity

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Arrow marks the proband

Picture it — classic pedigrees (■ male · ● female · filled = affected · dot = carrier)

Autosomal dominantEvery generation, both sexes, father-to-son transmission.

Autosomal recessiveCarrier parents, affected siblings, often skips generations.

X-linked recessiveAffected males linked through carrier females; never father-to-son.

X-linked dominantAffected father → every daughter, no sons; affected mother → half of all children.

MitochondrialOnly affected mothers pass it on, to children of both sexes.

Schematic diagrams, not to scale.

Mechanism — four questions to read a pedigree

1. Every generation?Yes → dominant

→

2. Male-to-male?Yes → autosomal (not X)

→

3. Mostly males via mothers?→ XLR

→

4. Only from mothers?→ mitochondrial

Any father-to-son transmission rules out X-linked inheritance. An affected father with all daughters affected and no sons → XLD.

Common risk calculations

SITUATION

RISK

WHY

AR: sib of affected, unaffected

2/3 carrier

Excludes the aa outcome

AR: two carriers, next child

1/4 affected

Aa × Aa

XLR: carrier mom, son

1/2 affected

Gets either X

XLR: affected dad, daughter

Obligate carrier

Always gets his X

AD: one parent affected

1/2

Aa × aa

How it's tested

COMMON CONFUSIONXLD vs AD: look at an affected father — XLD gives all daughters and no sons; AD gives either sex 50%.

THE TRAPThe healthy sibling of a CF patient has a 2/3 (not 1/2) chance of being a carrier, because you already know they are not affected.

YOUR APPROACHRun the four questions, assign genotypes to the proband's parents, then multiply probabilities for the asked person.

If you see… think…

Affected father, affected son → not X-linked

Boys affected, related through healthy mothers → X-linked recessive

Affected father, every daughter affected, no sons → X-linked dominant

Passed only through mothers, all children may be affected → mitochondrial

Affected siblings, consanguineous parents → autosomal recessive

Healthy sib of CF patient, carrier chance → 2/3

Carrier mother, chance her son is affected → 1/2

Rickets that won't respond to vitamin D, father to daughters → X-linked hypophosphatemia

Achondroplasia in a child of average-height parents → de novo (paternal age)

Neural tube defect recurrence risk rises with each affected child → multifactorial