Gonadal Mosaicism

Slide 1 · Gonadal Mosaicism

Germ-cell lineage mutations, unexpected recurrence, and comparison with somatic mosaicism

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning outcomes

Explain why phenotypically normal parents may have more than one affected child.

Trace the postzygotic origin of gonadal mosaicism and its transmission through gametes.

Distinguish germ-lineage mosaicism from the regional overgrowth of somatic mosaicism.

Interpret the examples of osteogenesis imperfecta and paternal-age–associated mutations.

Slide 3 · The usual autosomal dominant pedigree

Affected parent

Possible transmission

Affected child

A pathogenic heterozygous variant often produces disease in the carrier.

Typically, an affected parent can transmit that variant to a child.

Slide 4 · Normal parents do not exclude dominant disease

Phenotype observed

One child may carry a new pathogenic variant despite unaffected parents.

Genotype transmitted

Unaffected parental phenotype is not a complete statement about germ cells.

Slide 5 · A new variant may begin in a single gamete

Normal parent

Mutant gamete

Affected offspring

The mutation originates in the egg or sperm contributing to conception.

The child may have a dominant disorder even though neither parent is clinically affected.

Slide 6 · A mutation may occur shortly after fertilization

Fertilization

Early cell division

New variant

Affected child

The textbook also describes very early embryonic mutation as an origin of apparently sporadic disease.

The affected child need not have inherited a pre-existing parental mutation.

Slide 7 · Why a single sporadic case can look straightforward

Single-child event

One de novo event may explain the first affected child.

Parental germ-lineage clone

The ordinary sporadic-case model does not itself require a parent with mutant germ cells.

Slide 8 · A second affected sibling poses a new question

Phenotypically normal parents

Two affected children

Conceptual pedigree — affected/unaffected symbols only

Two affected offspring born to phenotypically normal parents prompt reconsideration.

A single independent mutation in the first child does not explain recurrence.

Slide 9 · Osteogenesis imperfecta illustrates the exception

Osteogenesis imperfecta as an autosomal dominant example.

An apparently unaffected couple can have more than one affected child.

Gonadal mosaicism offers a mechanistic explanation for such a pedigree.

Slide 10 · Mendelian transmission is not abolished

Allele effect in child

A mutant allele can still act dominantly in an offspring.

Distribution in parent

The unusual feature is its nonuniform presence in the germ cells of an unaffected parent.

Slide 11 · Gonadal mosaicism: The defining feature

Mutant germ-cell lineage

A pathogenic mutation occupies some germ-cell precursors or gametes.

Clinically normal soma

The parent’s somatic tissues may be unaffected, leaving no overt phenotype.

Slide 12 · The initiating event is postzygotic

Zygote

Postzygotic mutation

Cell descendants

Gonadal lineage

The mutation occurs after fertilization during the parent’s early embryogenesis.

Its descendants form a lineage rather than replacing every cell of the parent.

Slide 13 · Developmental lineage determines the outcome

Embryonic precursor

Mutation-bearing germ precursors

Other somatic lineages

A postzygotic event is propagated only to descendants of the mutant cell.

If descendants enter germ-cell precursors, mutant gametes can be produced.

Schematic: Descendant-cell distribution

Slide 14 · The germ-cell precursor is the critical compartment

Mutant progenitor

Mutant gametes

More than one conception

Mutation in a progenitor can produce multiple genetically related gametes.

This is why the same pathogenic variant may recur in siblings.

Slide 15 · The somatic phenotype may remain normal

Somatic tissues: Normal

The parent’s clinically examined body tissues may lack the mutation.

Some germ cells: Mutant

Absence of a visible disorder therefore does not eliminate a germ-lineage mechanism.

Slide 16 · A mosaic gonad makes nonidentical gametes

Gamete population (illustrative, not quantitative)

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Both variant-bearing and variant-free gametes may arise.

The illustrated mixture is conceptual and does not encode a measured proportion.

Slide 17 · A mutant gamete can initiate an affected child

Variant-bearing gamete

Fertilization

Affected offspring

A variant-bearing sperm or egg participates in fertilization.

The resulting child can manifest the autosomal dominant phenotype.

Slide 18 · One parental lineage can yield repeated transmission

Phenotypically normal parents

Two affected children

Conceptual pedigree — affected/unaffected symbols only

Multiple offspring may receive variant-bearing gametes from the same parent.

This is recurrence through the parental germ-cell population, not transmission between siblings.

Slide 19 · The fraction of mutant gametes matters

Gamete population (illustrative, not quantitative)

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Recurrence likelihood to the proportion of germ cells carrying the mutation.

Without measuring or otherwise characterizing that proportion, a specific family risk cannot be inferred here.

Slide 20 · A standard 50% rule cannot simply be copied

Situation

Transmission interpretation

Constitutionally heterozygous parent

Classic dominant model: each conception can inherit one of two alleles.

Gonadal mosaic parent

Gametes arise from mixed mutant and nonmutant precursors; proportion is uncertain.

Slide 21 · The pedigree may hide the causal mosaicism

Phenotypically normal parents

Two affected children

Conceptual pedigree — affected/unaffected symbols only

The parent appears unaffected because phenotype tracks somatic distribution.

Siblings reveal a transmitted pathogenic variant, suggesting a parental germ-cell source.

Slide 22 · Which cells carry the variant is more informative than appearance

Observed phenotype

Phenotype describes what is observed in the person.

Cellular genotype distribution

Mosaic distribution describes which cell lineages carry the mutation.

Slide 23 · Mutation timing affects cellular distribution

Lineage-restricted mosaic event

Mutant germ-cell descendants

Other lineages without variant

A postzygotic mutation may populate only selected descendant lineages.

The text specifically identifies gonad-directed mutant lineages as the source of transmission.

Schematic: Descendant-cell distribution

Slide 24 · Germline-restricted and somatic mosaicism differ

Feature

Gonadal mosaicism

Somatic mosaicism

Cell population

Germ-cell lineage / gametes

A subset of body tissues

Immediate clue

Unexpected recurrence in siblings

Regional or asymmetric phenotype

Transmission emphasis

May transmit mutant gametes

Tissue growth or function in carrier

Slide 25 · An unaffected parent’s somatic test has limits

Sampled somatic cells

Testing a somatic specimen addresses variants present in that specimen.

Unsampled germ cells

A variant restricted to germ-cell precursors could be absent from that sample.

Slide 26 · An illustrative germ-cell model is not a risk estimate

Gamete population (illustrative, not quantitative)

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The relative numbers of circles are for mechanism teaching only.

Robbins provides no universal numeric recurrence percentage for gonadal mosaicism.

Slide 27 · Reproductive recurrence is a lineage property

Shared parental precursor

Repeated mutant gametes

Affected siblings

Embryonic mutant progenitor → mutant gametes → possible affected offspring.

A repeated event need not imply two independent, identical de novo mutations.

Slide 28 · Osteogenesis imperfecta: Interpreting family history

HYPOTHETICAL TEACHING CASE

Hypothetical: Two children show a clinically recognized dominant skeletal disorder; Both parents appear unaffected.

Question: Which biological compartment in a parent can explain repeated transmission?

Slide 29 · Case mechanism: Parental germ-cell mosaicism

Mechanistic interpretation

A postzygotic parental mutation can populate gamete precursors.

More than one mutant gamete can produce affected children despite a normal parental phenotype.

Slide 30 · Dominant collagen disorders add a mechanistic layer

Pathogenic collagen-chain variant

Impaired multimer assembly

Skeletal disease

Some osteogenesis imperfecta variants as dominant-negative collagen defects.

A variant inherited by the child can impair normal collagen multimer assembly.

Slide 31 · Mutation origin and molecular effect are distinct

Lineage-level question

Origin: When and in which parental cell lineage did the mutation arise?

Molecular-level question

Effect: What does the inherited variant do to the child’s protein or phenotype?

Slide 32 · Paternal age is relevant to a restricted subset

Increased paternal-age association for certain mutations.

This must not be generalized to all mosaic disorders or all autosomal dominant diseases.

The described mechanism involves positive selection in the male germline.

Slide 33 · Apert syndrome is an FGFR2 example

FGFR2 mutation

Selected male germline

Potential transmission

Apert syndrome is cited with pathogenic FGFR2 mutations.

It among disorders showing a paternal-age–associated increase.

Slide 34 · Costello syndrome is an HRAS example

HRAS mutation

Selected male germline

Potential transmission

Costello syndrome is cited with HRAS mutations.

Its inclusion illustrates a similar male-germline selection phenomenon.

Slide 35 · Positive selection changes clonal representation

Earlier germline

Selective advantage

More mutant sperm

Later germline

Some mutations favor expansion or persistence of mutant sperm-forming lineages.

Their relative representation can increase during a father’s reproductive lifespan.

Slide 36 · Representation and transmission risk are linked

Selection

Mutant sperm enrichment

Transmission likelihood

Mutant sperm representation can increase with age for these examples.

A greater relative presence among sperm can increase the likelihood of passing on that mutation.

Slide 37 · Aging and mosaicism are not interchangeable

Question

Ordinary gonadal mosaicism

Selected male germline

Why mutant gametes exist

Postzygotic mutant precursor lineage

Mutant lineage with positive selection

What determines transmission

Mutant germ-cell fraction

Representation may change with paternal age

Applies to

The germline mosaicism mechanism

Specified mutation classes only

Slide 38 · The paternal-age model is mutation-specific

The textbook examples are FGFR2-associated Apert and HRAS-associated Costello syndromes.

The selective advantage is a property of particular mutations and contexts.

Do not infer the same time course for osteogenesis imperfecta or every autosomal dominant variant.

Slide 39 · Somatic mosaicism concerns body-cell lineages

Somatic mutant clone

Mutation-bearing cells form a subset of the individual’s somatic tissues.

Tissue-restricted phenotype

Clinical consequences follow the distribution and activity of those cells.

Slide 40 · Somatic mutations arise during normal life

Development

Growth

Adult tissues

Aging

Somatic changes across tissue growth, development and aging.

A postzygotic mutation does not necessarily indicate inherited disease.

Slide 41 · Clonal expansion is one possible fate

Mutant somatic cell

Cell descendants

Mosaic tissue

A mutation in a cell may be propagated to numerous descendants.

Sequencing studies reveal recurrent expanded mutant populations in normal tissues.

Slide 42 · Potentially oncogenic does not mean cancer

Potential driver activity

Some recurrent somatic changes are potentially oncogenic.

Not sufficient alone for cancer

In isolation, they can be insufficient to cause malignancy.

Slide 43 · An important presentation is regional overgrowth

Somatic activation

Abnormal pro-growth signal

Asymmetric overgrowth

Activating somatic mutations can produce local excess growth.

The result can be asymmetry between affected and unaffected anatomical regions.

Slide 44 · Several named phenotypes belong to the spectrum

Proteus syndrome is listed among somatic overgrowth disorders.

CLOVES syndrome encompasses congenital lipomatous overgrowth and malformation features.

Robbins also names megalencephaly–polymicrogyria–polydactyly–hydrocephalus syndrome.

Slide 45 · CLOVES is a multisystem acronym

Congenital, lipomatous overgrowth

Vascular malformations

Epidermal nevi

Spinal/skeletal anomalies or scoliosis

Slide 46 · PIK3CA–AKT–mTOR regulates growth signals

Growth-factor receptor

PI3K / AKT

MTOR-directed growth

Activating mutations in components of this signaling system.

The pathway links extracellular growth-factor stimulation with intracellular pro-growth effects.

Slide 47 · Growth factors normally engage surface receptors

Growth factor

Receptor tyrosine kinase

PI3K activation

Receptor tyrosine kinase activation recruits intracellular PI3 kinases.

This creates a regulated link between outside signals and downstream growth pathways.

Slide 48 · PI3K acts on membrane phosphoinositides

Activated PI3K

Lipid phosphorylation

Downstream signaling

Activated PI3 kinases phosphorylate phosphatidylinositol and phosphoinositide lipid substrates.

These membrane events feed intracellular growth-signal transmission.

Slide 49 · AKT and mTOR are downstream components

Membrane signaling

AKT

MTOR / growth response

AKT and mTOR relay and regulate growth-related cellular signaling.

Their activation helps explain how a mutation alters tissue growth.

Slide 50 · Activating variants uncouple growth from stimuli

Regulated signaling

Ordinary signaling responds to external growth-factor activation.

Mutation-driven signaling

An activating missense mutation can sustain abnormal pro-growth signaling even without that input.

Slide 51 · Cell distribution predicts anatomical distribution

Embryonic tissue lineages

Mutation-bearing descendants

Other tissue lineages

Somatic daughter cells retain the mutation and occupy particular tissues.

The affected body regions depend on where the mutant lineage contributed during development.

Schematic: Descendant-cell distribution

Slide 52 · Asymmetry reflects unequal lineage contribution

Affected region

A mosaic clone can be concentrated in only part of the body.

Less affected region

Bone, skin or other affected structures may therefore grow at different rates.

Slide 53 · Different tissue types may share a growth phenotype

Bone: Regional overgrowth

Skin: Regional overgrowth

Other organs: Variable involvement

Final pattern: Anatomical asymmetry

Slide 54 · Distribution—not a single universal lesion—is central

Mosaic overgrowth can distort discrete central or distal anatomical regions.

Clinical appearance varies with the specific tissues and their mutant-cell distribution.

A general mechanism should not be mistaken for one fixed gross or histologic morphology.

Slide 55 · Targeted pathway inhibition: Textbook perspective

Aberrant pathway activity

Pathway inhibitor

Possible growth attenuation

The source describes trials of PI3K/AKT/mTOR pathway inhibition.

It reports that some interventions can attenuate progressive overgrowth in certain circumstances.

No specific regimen or current approval status is asserted.

Slide 56 · Gonadal versus somatic: The biological question

Dimension

Gonadal

Somatic

Mutation-bearing cells

Gamete progenitors / gametes

Selected body-cell clones

Key consequence

Potential transmission to offspring

Tissue-restricted phenotype

Typical clue in this lesson

Repeated affected siblings

Regionally asymmetric overgrowth

Important caution

Parent may be unaffected

Somatic mutation need not mean cancer

Slide 57 · Constitutional mutation versus mosaic mutation

Broad cellular distribution

A constitutional variant is broadly present because it is established at or near conception.

Restricted descendant lineage

A mosaic variant exists in a subset of descendants because it arose after fertilization.

Slide 58 · Recurrence and regional growth answer different questions

Family-level pattern

Recurrence asks whether a parent’s germ cells can transmit the variant repeatedly.

Tissue-level pattern

Regional growth asks which tissues of an individual contain an activating somatic mutation.

Slide 59 · Case: Normal examination, recurrent dominant disorder

HYPOTHETICAL TEACHING CASE

Hypothetical: Two siblings have an autosomal dominant condition. Neither parent has overt clinical manifestations.

Which two different genetic mechanisms can leave a parent phenotypically normal?

Slide 60 · Case answer: Mosaicism versus incomplete penetrance

Mechanistic interpretation

Gonadal mosaicism: A parent may carry the pathogenic variant in gamete precursors but not in examined somatic tissues.

Incomplete penetrance: A person with a disease-associated constitutional variant may show no clinical phenotype.

The two explanations should not be equated solely because the parent appears unaffected.

Slide 61 · Case: Asymmetric overgrowth in one child

HYPOTHETICAL TEACHING CASE

Hypothetical: A child has progressively disproportionate growth limited to selected anatomical regions.

What is the key cell-distribution mechanism?

Slide 62 · Case answer: Regionally restricted mutant cells

Mechanistic interpretation

A somatic activating variant within the PI3K/AKT/mTOR pathway can drive local growth.

Anatomical asymmetry follows where the mutant clone resides.

This vignette alone does not establish a named syndrome or a molecular diagnosis.

Slide 63 · An interpretation checklist for unusual pedigrees

Establish whether the condition is considered autosomal dominant in the cited context.

Determine whether the parents are clinically affected or apparently normal.

Ask whether more than one offspring has the same phenotype.

Distinguish a one-off de novo event from a possible parental germ-cell clone.

Slide 64 · Four concepts that must remain separate

De novo: A new mutation event

Gonadal: Mutant germ-cell lineage

Somatic: Mutant body-cell lineage

Positive selection: Mutant sperm enrichment in certain disorders

Slide 65 · Mechanism determines clinical interpretation

Mutation timing

Cell-lineage distribution

Clinical consequence

Timing determines descendant-cell distribution.

Cell distribution determines whether the dominant signal is familial recurrence, regional overgrowth, or both.

Phenotype alone may not disclose the genotype of every relevant lineage.

Slide 66 · Core synthesis

Gonadal mosaicism explains why a phenotypically normal parent can have more than one affected child.

The likelihood of recurrence depends on mutant germ-cell representation, not a universal fixed percentage.

Apert/FGFR2 and Costello/HRAS illustrate selected paternal-age associations.

Somatic mosaicism can cause asymmetric overgrowth through activating PI3K/AKT/mTOR signaling.

Slide 67 · Primary source

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

Chapter 5, Genes and Human Diseases: Autosomal Dominant Disorders (p. 125); Gonadal Mosaicism (pp. 158–159); Somatic Mosaicism (p. 159).

Teaching diagrams and cases are original conceptual representations of the cited textbook material; not patient or laboratory evidence.