Autosomal Dominant Disorders

Slide 1 · Autosomal Dominant Disorders

Inheritance • penetrance • molecular pathogenesis • clinicopathologic examples

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Interpret pedigrees and Mendelian recurrence risk for dominant alleles.

Distinguish de novo mutation, penetrance, expressivity, and delayed onset.

Explain haploinsufficiency, dominant-negative effects, and gain of function.

Connect molecular lesions to familial hypercholesterolemia, Marfan syndrome, and EDS.

Slide 3 · Single-gene disorders: Transmission patterns

Autosomal dominant

Autosomal recessive

X-linked

These are distinct Mendelian transmission patterns, not sequential stages.

Slide 4 · Dominant phenotype in a heterozygote

Normal allele (A)

Disease-associated allele (a*)

A / a* heterozygote

A single altered autosomal allele can be sufficient to produce disease.

Slide 5 · Both sexes can inherit and transmit

Affected father

Unaffected mother

Affected son

Affected daughter

Schematic pedigree: Illustrates sex-independent transmission, not an observed family.

Slide 6 · The canonical 1-in-2 transmission risk

Affected heterozygous parent (A / a*)

A

A*

A

A/A

A/a*

A

A/A

A/a*

Each pregnancy has a 50% chance of inheriting the disease-associated allele.

Slide 7 · Recurrence risk applies to each pregnancy

Pregnancy 1

50% allele inherited

50% allele not inherited

Pregnancy 2

50% allele inherited

50% allele not inherited

Pregnancy 3

50% allele inherited

50% allele not inherited

The outcome of one pregnancy does not alter the Mendelian allele risk of the next.

Slide 8 · Pedigree clue: Vertical transmission

Generation I

Generation II

Generation III

Affected individuals in successive generations support, but do not prove, dominance.

Slide 9 · A negative family history does not exclude dominance

A pathogenic variant may arise de novo in the proband.

An affected parent may appear healthy because penetrance is incomplete.

An inherited disorder may present after the parent’s current age.

The degree of disease expression may be subtle in relatives.

Slide 10 · De novo mutation: A new germline event

New mutation arising in a parental germ cell

A sporadic presentation can still have an autosomal dominant molecular cause.

Slide 11 · Reproductive fitness shapes observed pedigrees

Disease impairs reproductive fitness

Fewer affected individuals transmit an allele

Greater relative contribution of de novo cases

This relationship describes case origins, not a fixed mutation rate.

Slide 12 · Paternal-age association in selected syndromes

Paternal germline mutation

FGFR2 or FGFR3 alteration

Apert syndrome or achondroplasia

Some RTK–RAS–MAPK pathway mutations with increased paternal age.

Slide 13 · Penetrance: Whether the phenotype appears

Variant carriers

Clinically manifest

Clinically nonmanifest

Incomplete penetrance: Some genotype-positive individuals lack the defined trait.

Slide 14 · Penetrance is a population proportion

Penetrance

=

Carriers expressing the phenotype

All carriers of the variant

50% penetrance to mean expression in half of variant carriers.

Slide 15 · Expressivity: How severe or extensive disease becomes

Same disease-associated allele

Phenotype is expressed

Mild → moderate → severe manifestations

Variable expressivity concerns phenotype intensity, not the presence of a variant.

Slide 16 · Penetrance and expressivity are different

Dimension

Incomplete penetrance

Variable expressivity

Question

Is the trait present?

How strongly is it expressed?

Carrier status

Variant present

Variant present

Phenotype

May be absent

Present, but variable

Clinical implication

Apparently unaffected relative

Relatives differ in manifestations

Slide 17 · Neurofibromatosis type 1: Phenotype spectrum

Pigmented skin macules

Multiple cutaneous tumors

Skeletal abnormalities

Examples across an expressivity spectrum; This is not a temporal sequence.

Slide 18 · Why can relatives express one allele differently?

Other inherited loci may modify the phenotypic effect.

Environmental exposures may amplify or attenuate consequences.

Different tissues can show different clinical manifestations.

The full basis of incomplete penetrance and expressivity is not settled.

Slide 19 · Environmental modifier: LDL burden in FH

Familial hypercholesterolemia genotype

Elevated LDL cholesterol

Diet modifies atherosclerotic expression

The allele contributes susceptibility; Exposures modify clinical outcome.

Slide 20 · Age-dependent onset: Huntington disease

Inherited mutant HTT allele

Long presymptomatic interval

Neurologic manifestations in adulthood

A young carrier may have no clinical manifestations despite the genotype.

Slide 21 · Family-history interpretation requires three questions

Is the mutation de novo?

Could an inherited allele have incomplete penetrance?

Is onset delayed?

Is expression subtle or heterogeneous?

Slide 22 · Three molecular routes to autosomal dominance

Haploinsufficiency

Too little functional protein

Dominant-negative action

Mutant product impairs normal product

Gain of function

Excess or new pathological activity

Slide 23 · Loss of function does not always mean dominance

Adequate compensation

Inadequate compensation

One normal allele produces enough active product.

The heterozygote can be phenotypically normal.

One normal allele cannot meet functional demand.

A heterozygote manifests disease.

Slide 24 · Haploinsufficiency: One normal allele is insufficient

One allele loses function

Functional product decreases

Normal copy cannot compensate

Dominant phenotype

Disease follows insufficient total functional gene product.

Slide 25 · LDLR loss of function: Pathophysiologic chain

Reduced LDL receptor abundance

Defective LDL clearance

Plasma LDL rises

Premature atherosclerosis

Familial hypercholesterolemia illustrates haploinsufficiency in heterozygotes.

Slide 26 · Gene dosage matters, but mechanism matters more

Molecular observation

Functional consequence

An allele can yield less normal protein.

A mutant polypeptide may still be synthesized.

Too little total functional protein: Haploinsufficiency.

Disruption of normal complexes: Dominant-negative effect.

Slide 27 · Dominant-negative action: Protein interference

Mutant subunit is synthesized

Subunit enters a shared assembly

Assembly loses normal function

The mutant protein affects products from the normal allele.

Slide 28 · Collagen trimer assembly illustrates interference

Normal chain

Normal chain

Mutant chain

Composite collagen trimer

Abnormal subunit compromises the complex

Slide 29 · Osteogenesis imperfecta: A structural-protein model

Some variants involve defective collagen chains in multimeric assemblies.

A mutant chain can destabilize otherwise normal collagen molecules.

The resulting collagen deficiency or dysfunction produces skeletal fragility.

The same clinical grouping can encompass distinct molecular mechanisms.

Slide 30 · Gain of function: An altered protein acquires activity

Increased normal activity

Novel pathological activity

A pre-existing function becomes overactive.

Signaling or enzymatic output can be excessive.

A mutation may impart a new protein behavior.

The new activity can be toxic to cells.

Slide 31 · Neomorphic alleles create a new functional effect

Variant protein is produced

Activity differs qualitatively from normal

New activity injures tissue

A neomorphic effect differs from simple loss of the wild-type activity.

Slide 32 · Huntington disease: Pathogenic protein toxicity

Trinucleotide-repeat mutation

Altered huntingtin protein

Neuronal toxicity

Neurologic dysfunction

Huntington disease as a dominant gain-of-function example.

Slide 33 · Mechanism comparison: Three distinct lesions

Mechanism

Core defect

Illustrative condition

Haploinsufficiency

Insufficient normal product

Familial hypercholesterolemia

Dominant negative

Mutant product impairs an assembly

Some osteogenesis imperfecta

Gain of function

Increased/new harmful activity

Huntington disease

Slide 34 · Predict the mechanism from the molecular lesion

Half of receptor supply cannot clear sufficient ligand

Mutant collagen chain destabilizes an assembled trimer

A toxic mutant protein injures neurons

The clinical dominance alone does not define the mechanism

Slide 35 · Autosomal dominant disorders affect many systems

System

Textbook examples

Nervous

Huntington disease; neurofibromatosis; myotonic dystrophy; tuberous sclerosis

Urinary

Polycystic kidney disease

Gastrointestinal

Familial polyposis coli

Hematopoietic

Hereditary spherocytosis; von Willebrand disease

Skeletal

Marfan; some EDS; osteogenesis imperfecta; achondroplasia

Metabolic

Familial hypercholesterolemia; acute intermittent porphyria

Slide 36 · Disorder names alone do not identify inheritance

Some disease groups contain both dominant and recessive genetic subtypes.

Ehlers–Danlos syndromes illustrate molecular and inheritance heterogeneity.

A pedigree must be interpreted together with phenotype and genotype.

Do not assume every patient bearing a syndrome label has the same molecular lesion.

Slide 37 · Familial hypercholesterolemia: Clearance failure

LDL clearance pathway defect

Cholesterol-rich LDL accumulates

Xanthomas and premature vascular disease

The dominant phenotype is expressed through impaired hepatic LDL removal.

Slide 38 · Normal LDL uptake: Receptor-mediated endocytosis

LDL binds its receptor

Complex enters coated vesicle

LDL is degraded in lysosome

Receptor normally recycles

This trafficking pathway controls LDL residence time in plasma.

Slide 39 · PCSK9 controls LDL receptor recycling

Without excess PCSK9 action

With activating PCSK9 mutation

LDL receptor is retrieved after internalization.

Recycling sustains cell-surface receptor supply.

More internalized receptors are degraded.

Cell-surface LDL receptors decline.

Slide 40 · Three molecular entry points to FH

Gene

Affected step

Consequence

LDLR

Receptor synthesis, binding, trafficking

Less hepatic LDL clearance

APOB

LDL ligand binds receptor poorly

Reduced receptor-mediated uptake

PCSK9

Enhanced receptor degradation (activating variants)

Reduced surface LDL receptors

Slide 41 · Heterozygous LDLR loss shows gene dosage

Two functioning alleles

Normal LDL receptor supply

One functioning allele

Reduced receptor supply → LDL accumulation

Slide 42 · Why LDL accumulation damages arteries

Persistently high circulating LDL

Increased lipid delivery to vascular wall

Macrophage foam-cell accumulation

Premature atherosclerosis

The vascular phenotype arises downstream of a defective clearance receptor.

Slide 43 · Heterozygous and biallelic FH are not equivalent

Finding

Heterozygous LDLR variant

Biallelic severe LDLR variants

Receptor function

Reduced

Much more severely reduced

Plasma cholesterol

Increased from birth

Markedly increased

Manifestations

Xanthomas; premature atherosclerosis

Potential very early vascular disease

Interpretation

Classic dominant expression

More severe gene-dosage phenotype

Slide 44 · Familial hypercholesterolemia: Clinical reasoning

A family history of premature coronary disease strengthens suspicion.

Tendon xanthomas can reflect chronically elevated circulating LDL.

Recognize that multiple gene products can converge on the same pathway.

A phenotype alone does not resolve LDLR, APOB, and PCSK9 mechanisms.

Slide 45 · Marfan syndrome: A connective-tissue disorder

Skeleton: Disproportionate growth and skeletal features

Eye: Lens-support abnormality

Cardiovascular: Aortic and valvular disease

Core molecular defect: Fibrillin-1

Slide 46 · Fibrillin-1 provides structural support

FBN1 encodes fibrillin-1

Fibrillin microfibrils form ECM scaffolds

Elastic-fiber organization is supported

Tissue stretch/recoil is maintained

Aorta, ciliary zonules, and ligamentous tissue are especially dependent on support.

Slide 47 · Marfan syndrome: Excess TGF-β signaling

Fibrillin microfibrils altered

TGF-β sequestration reduced

TGF-β signaling increases

Adverse matrix remodeling

Dysregulated signaling adds to the mechanical consequences of ECM failure.

Slide 48 · Two pathogenic pathways converge in Marfan

FBN1 variant

Weak microfibril support

Increased TGF-β bioavailability

Multisystem pathology

Slide 49 · Marfan skeletal features reflect connective-tissue weakness

Tall habitus and long extremities may be prominent.

Long, tapering digits and ligamentous laxity affect the hands and feet.

Spinal curvature and chest-wall deformities can accompany the phenotype.

Skeletal findings vary; They are not required to be equally prominent.

Slide 50 · Ectopia lentis localizes a structural defect

Fibrillin-rich ciliary zonules weakened

Lens support becomes unstable

Lens subluxation or dislocation

Bilateral ectopia lentis is a characteristic ocular clue in Marfan syndrome.

Slide 51 · Aortic medial degeneration is the life-threatening lesion

Medial structural support fails

Ascending aortic root dilates

Intimal tear and dissection may develop

Rupture can be fatal

Aortic pathology is more consequential than the visible skeletal phenotype.

Slide 52 · Marfan syndrome varies across and within families

Predominantly skeletal presentation

Cardiovascular/ocular presentation

Tall habitus and ligamentous changes.

Little clinically evident eye disease may coexist.

Aortic pathology or ectopia lentis may dominate.

Skeletal abnormalities may be subtle.

Slide 53 · EDS: A heterogeneous set of collagen disorders

EDS encompasses defects in collagen chains, collagen-processing enzymes, and ECM-associated proteins.

Affected subtypes may be autosomal dominant or autosomal recessive.

Clinical variability reflects differences in the protein and pathway affected.

Skin, joints, vessels, and hollow viscera are variably vulnerable.

Slide 54 · EDS skin and joint findings follow reduced tensile strength

Collagen synthesis or assembly altered

Connective tissue tensile strength falls

Hyperextensible skin and joint hypermobility

Dislocation, easy bruising, poor wound repair

Clinical manifestations follow the tissue distribution of the affected collagen system.

Slide 55 · Vascular EDS: Type III collagen fragility

COL3A1-associated type III collagen defect

Arterial and intestinal walls become fragile

Spontaneous vessel or bowel rupture

Skin hyperextensibility may be less prominent than in other EDS subtypes.

Slide 56 · EDS inheritance depends on the affected pathway

Illustrative subtype

Genetic lesion (textbook example)

Inheritance

Classical EDS

Type V collagen genes

Autosomal dominant

Vascular EDS

COL3A1, type III collagen

Autosomal dominant

Kyphoscoliotic EDS

PLOD1, lysyl hydroxylase

Autosomal recessive

Slide 57 · Dominant and recessive pedigrees differ

Clue

Autosomal dominant

Autosomal recessive

Typical family history

Multiple generations may be affected

Parents often clinically unaffected

Affected × unaffected

50% mutant-allele transmission if heterozygous

Risk depends on partner carrier status

Heterozygote

May have phenotype

Usually clinically unaffected for classic loss of function

Exceptions

De novo, incomplete penetrance, late onset

Consanguinity, compound heterozygosity

Slide 58 · Case 1: The apparently sporadic disorder

A child has achondroplasia. Both parents have no clinical skeletal abnormality.

Question: Does an unaffected parental phenotype rule out autosomal dominant disease?

Slide 59 · Case 1: Interpret the genetic event

No: A de novo pathogenic germline mutation can cause a dominant disorder.

Some FGFR3-associated achondroplasia cases to paternal-age-related mutation occurrence.

A sporadic presentation and a dominantly acting variant are compatible.

Slide 60 · Case 2: Opposite clinical severity in one pedigree

A parent has a few pigmented skin macules; Their affected child has multiple neurofibromas and skeletal changes.

Question: Which concept best explains the different intensity of manifestations?

Slide 61 · Case 2: Variable expressivity, not penetrance

Both relatives express a recognizable disease phenotype.

The clinical spectrum differs in extent and severity.

Variable expressivity describes this pattern; Incomplete penetrance would refer to a carrier with no phenotype.

Slide 62 · Case 3: Match the lesion to the mechanism

A heterozygous variant yields an abnormal protein that enters a multimeric ECM complex and disrupts its organization.

Question: Haploinsufficiency, dominant-negative interference, or gain of function?

Slide 63 · Case 3: Dominant-negative interference

The mutant polypeptide enters a complex with other protein subunits.

The abnormal component impairs assembly or stability of the shared structure.

This is a dominant-negative mechanism, distinct from merely producing less protein.

Slide 64 · Integrating inheritance with molecular pathology

50% allele transmission per pregnancy (heterozygous affected × unaffected)

Penetrance = whether; Expressivity = how much

Haploinsufficiency / dominant negative / gain of function

Mechanism explains phenotype and guides family interpretation

Slide 65 · Source and scope of this lecture

Robbins, Cotran & Kumar: Pathologic Basis of Disease. 11th edition (2026).

Chapter 5: Genes and Human Diseases — section Autosomal Dominant Disorders.

Related source sections: transmission patterns; structural and receptor protein disorders; Marfan syndrome; EDS; familial hypercholesterolemia.

All schematics and teaching cases are original educational compositions based on those sections.