Chromosome 22q11 2 Deletion Syndrome

Slide 1 · Chromosome 22q11.2

Deletion Syndrome

Genomic lesion • developmental mechanisms • multisystem phenotype

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Locate chromosome band 22q11.2 and explain an interstitial deletion.

Connect thymic, parathyroid, cardiac and palatal abnormalities to the syndrome.

Interpret the DiGeorge–velocardiofacial clinical spectrum.

Explain the TBX1/PAX9 developmental framework and FISH findings.

Slide 3 · A deletion syndrome—not a single clinical presentation

A small deletion on the long arm of chromosome 22 defines the disorder.

Clinical expression spans congenital structural and functional abnormalities.

A recognizable pattern may be incomplete in any one individual.

Slide 4 · One genomic locus, multiple organ systems

22q11.2 deletion

Heart / outflow tract

Palate / face

Thymus / T cells

Parathyroids / calcium

Neurodevelopment

Slide 5 · Decoding the cytogenetic name

22 identifies the affected autosome.

Q identifies the long chromosome arm; P denotes the short arm.

11.2 specifies region, band and sub-band along q.

The locus designation is not the same as the amount of deleted DNA.

Slide 6 · Numerical and structural chromosomal disorders

Numerical abnormality

Change in chromosome number

Example: Trisomy of a complete autosome

Overall chromosome dosage changes

Structural abnormality

Chromosome number may remain 46

Loss, gain or rearrangement of a segment

22q11.2 is a focal deletion

Slide 7 · The 22q11.2 band on chromosome 22

Intact chromosome 22

Q11.2

P arm

Q arm

Intact chromosome 22

Q11.2

P arm

Q arm

Two copies of the locus are present in this schematic normal cell.

Slide 8 · How an interstitial deletion can arise

Break 1

DNA break within one chromosome arm

Break 2

Second break farther along the arm

Segment loss

Intervening chromosomal DNA is lost

Rejoining

Remaining chromosomal ends are joined

A general structural-deletion mechanism; Not an asserted patient-specific mechanism.

Slide 9 · Interstitial loss on one homologue

Intact chromosome 22

Q11.2

P arm

Q arm

Chromosome 22 with 22q11.2 deletion

Deleted

P arm

Q arm

One chromosome 22 lacks the highlighted band: A copy-number loss, not a whole-chromosome loss.

Slide 10 · A deletion produces regional gene-copy loss

Two homologous copies of chromosome 22

22q11.2 locus retained

A

22q11.2 locus lost

B

Loss of one copy changes local gene dosage. The diagram does not specify expression levels.

Slide 11 · Why locus-level tests matter

Routine chromosome banding

Visible structural changes typically

Require ≈2–4 million bp

Fluorescence in situ hybridization

Higher locus-level resolution

Can detect kilobase-scale changes

Robbins structural cytogenetics background; Detection depends on assay/probe design.

Slide 12 · Size described for the deleted interval

≈1.5 Mb

A multigene chromosomal deletion.

The cited interval size is approximate; Deleted segments may differ.

Slide 13 · Why deletion size matters

Breakpoint position

Location of segment boundaries

Genes lost

Different combinations of affected loci

Tissue effects

Developmental disruptions vary

Phenotype

Relative prominence of findings differs

Variable deletion position/size as a probable contributor, not a complete explanation.

Slide 14 · How often is the syndrome encountered?

Up to 1:4,000

Birth frequency quoted

Variable clinical features contribute to missed recognition.

Slide 15 · From two historic labels to one spectrum

DiGeorge syndrome

Predominant thymic and parathyroid problems

Cytogenetic overlap

Same chromosomal region implicated

Velocardiofacial syndrome

Prominent palatal, facial and cardiac findings

The shared molecular defect explains why older labels overlap clinically.

Slide 16 · DiGeorge and velocardiofacial patterns

DiGeorge emphasis

Thymic hypoplasia

T-cell immunodeficiency

Parathyroid hypoplasia; Hypocalcemia

Cardiac outflow tract malformations

Velocardiofacial emphasis

Facial dysmorphism

Cleft palate

Cardiovascular abnormalities

Learning disabilities

The labels describe predominant patterns within an overlapping syndrome.

Slide 17 · Shared features cross historic diagnoses

Clinical overlap

Congenital cardiac anomalies

Facial differences

Palatal findings

Developmental effects

Slide 18 · The DiGeorge phenotype: Linked developmental outcomes

DiGeorge pattern

Thymic hypoplasia

Parathyroid hypoplasia

Outflow tract defects

Mild facial anomalies

Slide 19 · Thymic hypoplasia explains T-cell immunodeficiency

Thymic hypoplasia

Underdevelopment of thymic tissue

T-cell compartment

Thymus supports T-cell development

Immune phenotype

Reduced T-cell immunity of variable degree

Mechanistic sequence is a concise interpretation of the Robbins organ-function relationship.

Slide 20 · Immune involvement is heterogeneous

The degree of T-cell immunodeficiency varies across affected patients.

Immunodeficiency is prominent in the DiGeorge presentation.

It is less frequent in the classic velocardiofacial description.

One apparently characteristic immune phenotype is not required in every case.

Slide 21 · Atopic disease belongs to the clinical spectrum

Atopic disorders may accompany the DiGeorge-pattern presentation.

Robbins specifically mentions allergic rhinitis.

Atopy and reduced T-cell immunity are not identical clinical phenomena.

Slide 22 · Autoimmunity can coexist with immunodeficiency

Autoimmune manifestations may occur in affected individuals.

The source names autoimmune thrombocytopenia as an example.

This reinforces that immune dysregulation is broader than infection susceptibility alone.

Slide 23 · Parathyroid hypoplasia explains hypocalcemia

Parathyroid hypoplasia

Underdeveloped parathyroid tissue

Calcium regulation

Impaired parathyroid contribution

Clinical consequence

Hypocalcemia may be present

The calcium-regulation intermediate is functional reasoning; No laboratory cutoff is supplied.

Slide 24 · Thymus and parathyroids: Two linked consequences

Thymus

Developmental hypoplasia

Functional correlate: T-cell immunity

Clinical category: Immunologic

Parathyroids

Developmental hypoplasia

Functional correlate: Calcium homeostasis

Clinical category: Endocrine

A shared embryologic region helps explain the co-occurrence; The organs have distinct functional outcomes.

Slide 25 · Embryologic context of the classic phenotype

Pharyngeal tissues

Mesenchyme and endodermal pouches

Developmental program

TBX1 expression in the region

Affected derivatives

Face, thymus, parathyroids

A schematic abstraction of the TBX1 expression/derivative relationship stated in the source.

Slide 26 · Cardiac malformations prominently affect the outflow tract

Outflow-tract defects are characteristic of the DiGeorge description.

Cardiovascular anomalies also occur in velocardiofacial presentations.

Congenital heart disease can be the dominant presenting feature.

Slide 27 · Heart disease may appear with or without other findings

Conotruncal defect

Palatal abnormality

Facial dysmorphism

Thymic deficiency

No other recognized feature

Slide 28 · Palatal defects are part of the syndrome

The source highlights abnormalities of the palate across the spectrum.

Cleft palate is a classic velocardiofacial feature.

The palatal phenotype connects structurally to the embryologic developmental network.

Slide 29 · Facial dysmorphism has a characteristic description

A prominent nose in velocardiofacial syndrome.

Retrognathia is another cited feature.

Facial abnormalities also occur, often mildly, with the DiGeorge phenotype.

Clinical appearance alone does not establish a specific deletion.

Slide 30 · Velocardiofacial features form a developmental constellation

Face

Prominent nose / retrognathia

Palate

Cleft palate

Cardiovascular system

Congenital anomaly

Function

Learning disability

Slide 31 · Neurodevelopmental effects extend beyond physical malformations

Developmental delay forms part of the broad syndrome definition.

Learning disabilities are stressed in the velocardiofacial description.

Structural and neurodevelopmental findings may coexist with different severity.

Slide 32 · Developmental delay is not a specific organ lesion

Structural domain

Palate and craniofacial malformations

Cardiac outflow tract defects

Thymic / parathyroid hypoplasia

Functional domain

Learning disability

Developmental delay

Behavioral or psychiatric vulnerability

The deletion affects multiple developmental and clinical domains.

Slide 33 · Psychiatric vulnerability is clinically important

Increased risk of psychotic disorders.

Schizophrenia and bipolar disorders are specifically mentioned.

Psychiatric morbidity broadens the relevant phenotype beyond congenital malformations.

Slide 34 · Schizophrenia risk reported in affected adults

≈25%

Adults with 22q11.2 deletion syndrome

Estimate quoted by Robbins; Not a current independently verified rate.

Slide 35 · Attention-deficit/hyperactivity disorder

30–35%

Affected children in the source description

Textbook estimate; Population and ascertainment may matter.

Slide 36 · Reverse association in childhood-onset schizophrenia

2–3%

Individuals reported to carry a deletion of this region

This is the reverse conditional association, not the individual risk of schizophrenia.

Slide 37 · Risk in carriers versus deletion among cases

Carrier-to-outcome direction

Start with a 22q11.2 deletion

Ask whether schizophrenia develops

About 25% of adults

Case-to-genotype direction

Start with childhood-onset schizophrenia

Ask whether 22q11.2 is deleted

2–3%

The denominators differ: These figures must never be interchanged.

Slide 38 · Not all components of the phenotype are explained

The deleted interval contains numerous genes.

TBX1 is closely linked to developmental malformations.

The source does not identify the responsible gene(s) for behavioral and psychiatric effects.

Avoid attributing all neuropsychiatric effects to TBX1 alone.

Slide 39 · Clinical suspicion arises from combinations of findings

Consider 22q11.2

Conotruncal heart defect

Cleft palate / dysmorphism

T-cell immune deficit

Hypocalcemia

Developmental difference

Slide 40 · A similar phenotype may have another genomic cause

Typical molecular association

Deletion involving chromosome 22q11.2

Common genomic finding in the named syndrome

Rare phenocopy described

Deletion involving chromosome 10p13–14

Small number of cases with a similar phenotype

Phenotypic resemblance does not prove the same molecular lesion.

Slide 41 · The deleted interval is a multigene region

DNA loss

Approximate interval: 1.5 Mb

Gene content

Approximately 30–40 genes

Complex phenotype

Multiple organ systems affected

All quantities are quoted. The source later mentions ≈30 candidate genes, not a contradictory fixed gene count.

Slide 42 · TBX1 is a central candidate gene

TBX1 encodes a T-box transcription factor.

It as most closely associated with phenotypic features.

Its normal developmental expression is relevant to face, thymus and parathyroid formation.

Slide 43 · Spatial expression of TBX1 helps explain tissue selectivity

TBX1 expression

Pharyngeal mesenchyme

Also expressed in

Endodermal pouch tissue

Developmental derivatives

Craniofacial structures, thymus, parathyroids

This schematic is not a histologic reconstruction of embryonic anatomy.

Slide 44 · TBX1 and PAX9: A developmental relationship

TBX1

T-box transcription factor

PAX9

Described as a TBX1 target

Organ development

Palate, thymus, parathyroids

Do not interpret this simplified model as the only pathway or a complete regulatory network.

Slide 45 · PAX9 expands the mechanistic explanation

PAX9 is described as a target gene of TBX1.

PAX9 to palatal, parathyroid and thymic development.

The relationship offers a mechanistic bridge between genotype and organ malformations.

Slide 46 · Why the phenotype varies even with a shared locus

Deleted position / size

May differ between affected individuals

Genes affected

Contributions can differ

Clinical dominance

Immune vs craniofacial / cardiac findings

Robbins says this probably contributes to heterogeneity; Not an established one-to-one genotype map.

Slide 47 · Causal interpretation has limits

The molecular basis is explicitly described as incompletely understood.

A multigene interval limits simple one-gene causal explanations.

Unidentified contributors may underlie behavioral and psychiatric features.

A phenotype–genotype association does not specify every intermediate mechanism.

Slide 48 · Clinical suspicion is followed by genomic testing

Clinical pattern

Cardiac, palatal, immune, endocrine findings

Suspect syndrome

Form a genetic diagnostic hypothesis

Demonstrate deletion

Use locus-specific laboratory detection

FISH to establish the deletion; Contemporary algorithms are not covered by this source-only lecture.

Slide 49 · FISH tests a chromosomal locus

Fluorescence in situ hybridization uses fluorescent DNA probes.

A probe targeted to 22q11.2 provides a locus-specific signal.

A separate chromosome-22 control probe demonstrates the chromosome region remains present.

Slide 50 · FISH signal schematic: A normal locus pattern

Chromosome 22: Homologue A

Chromosome 22: Homologue B

Red = 22q11.2 locus

Green = chromosome 22 control

Conceptual normal pattern: Both homologues retain the locus-specific and control signals.

Slide 51 · FISH signal schematic: One deleted locus

Chromosome 22: Homologue A

Chromosome 22: Homologue B

Red = 22q11.2 locus

Green = chromosome 22 control

Slide 52 · Interphase FISH: Interpretation of deletion signals

1 red + 2 green

22q11.2 loss

Schematic interphase nucleus

Slide 53 · Interphase FISH: Normal comparator

2 red + 2 green

No deletion

Schematic interphase nucleus

Slide 54 · FISH findings figure

Structure

Intact homologue

Deleted homologue

22q11.2 target probe

Target signal present

Target signal absent

Chromosome-22 control

Control signal present

Control signal present

Interpretation

Target region retained

Target region deleted

Editable reconstruction of the signal logic Fig. 5.23; Not copied microscopy.

Slide 55 · Historic phenotype labels and FISH yield

Older clinical diagnosis

Deletion detected by FISH

Interpretive caution

DiGeorge syndrome

≈90%

Not every clinical case

Velocardiofacial syndrome

≈80%

Overlapping phenotype

Isolated conotruncal defects

≈30%

No other features required

Approximate textbook values; Avoid extrapolating to all present-day referrals.

Slide 56 · Why ordinary banding can miss a small deletion

Conventional banding

Sees chromosome-scale band patterns

Needs large structural changes

A small loss may be unresolved

Targeted FISH

Interrogates selected DNA sequences

Can detect smaller structural changes

Depends on probe choice and tested locus

Robbins explains improved FISH resolution; This is not an exhaustive test comparison.

Slide 57 · A positive FISH result has a precise meaning

Loss of a 22q11.2 target signal supports deletion of the probed locus.

Retention of the chromosome-22 control distinguishes regional loss from total loss in the illustrated pattern.

The FISH signal pattern does not by itself predict symptom severity.

Slide 58 · Case discussion: Immune and endocrine phenotype

A newborn has a congenital outflow tract cardiac malformation, reduced thymic tissue, and low serum calcium.

Interpretation task

Which two underdeveloped organs explain the immune and endocrine findings?

Which contiguous chromosome locus should be considered?

Slide 59 · Case interpretation: A DiGeorge-pattern presentation

1. Thymic hypoplasia corresponds to reduced T-cell immunity.

2. Parathyroid hypoplasia corresponds to hypocalcemia.

3. The combined phenotype suggests a 22q11.2 deletion syndrome.

Hypothesis first; Demonstration of the deletion is needed for genetic confirmation.

Slide 60 · Case discussion: Palate, face and heart

A child has cleft palate, retrognathia, an identified congenital cardiovascular anomaly and learning difficulties.

Interpretation task

Which historic phenotype label best matches the presentation?

Why is that label not a distinct chromosomal diagnosis?

Slide 61 · Case interpretation: Velocardiofacial-pattern findings

1. Cleft palate and facial dysmorphism fit the classic phenotype.

2. Congenital cardiac and learning difficulties strengthen suspicion.

3. The historic label overlaps the same 22q11.2 deletion spectrum.

A molecular test addresses the chromosomal hypothesis.

Slide 62 · Case discussion: Count the FISH signals

An interphase nucleus has one 22q11.2 target signal but two chromosome-22 control signals.

Interpretation task

Does this pattern indicate deletion of the probed region?

Why does the control probe matter?

Slide 63 · Case interpretation: Target deletion with preserved control

1. Only one locus-specific signal is identified.

2. Two control signals support retention of the corresponding chromosome regions.

3. The signal arrangement matches deletion of one 22q11.2 locus.

Interpret only the tested locus; The drawing is schematic.

Slide 64 · Case discussion: Psychiatric presentations

A patient with a known 22q11.2 deletion develops psychiatric symptoms in adulthood.

Interpretation task

Which association makes psychiatric assessment relevant?

Can TBX1 alone be assigned responsibility for this clinical dimension?

Slide 65 · Case interpretation: Association without overattribution

1. Increased psychotic-illness vulnerability.

2. It estimates schizophrenia develops in approximately 25% of affected adults.

3. The source does not identify the responsible behavioral genes.

Reported risk does not make disease inevitable in an individual.

Slide 66 · Deletion versus trisomy: A useful cytogenetic contrast

22q11.2 deletion syndrome

Loss of a defined part of chromosome 22

Regional reduction of gene copies

Variable developmental phenotype

Trisomy 21 (parent context)

Extra complete chromosome 21 in usual form

Extra gene copies across that autosome

Different syndromic mechanism

This is a mechanism comparison, not a differential diagnosis based on clinical appearance.

Slide 67 · Integrated mechanistic synthesis

Chromosome 22q11.2

Interstitial deletion of a multigene region

Developmental regulation

TBX1 / PAX9-related organogenesis

Multisystem outcomes

Heart, palate, thymus, parathyroid

Clinical spectrum

Variable immune, endocrine, learning and psychiatric effects

Schematic synthesis with uncertainty: Many genotype-to-phenotype mechanisms remain unresolved.

Slide 68 · Textbook source and interpretive boundaries

Core reference

Robbins, Cotran & Kumar: Pathologic Basis of Disease, 11th ed. (2026). Chapter 5: Genes and Human Diseases. Chromosome 22q11.2 Deletion Syndrome, pp. 147–149.

Interpretive boundaries

Quantitative estimates and FISH-centered diagnostic wording follow the supplied textbook. No independent current-guideline verification or licensed histologic imagery was incorporated.