1.12 Microdeletion Syndromes (22q11.2, Williams, and Related)
Key Takeaways
- 22q11.2 deletion syndrome (DiGeorge/VCFS spectrum) classically combines conotruncal cardiac defects, palatal anomalies, hypocalcemia/hypoparathyroidism, immune deficiency, and learning/psychiatric vulnerability
- Williams syndrome is caused by a contiguous gene deletion at 7q11.23 including ELN, producing supravalvular aortic stenosis, connective-tissue findings, hypercalcemia risk, and a characteristic social/cognitive profile
- Most classic 22q11.2 and Williams deletions are de novo, but parental testing still matters because inherited deletions change recurrence risk dramatically
- Chromosomal microarray (CMA) is the usual first-line genome-wide CNV test; FISH can confirm a known targeted deletion but will miss deletions outside the probe’s target
- Microdeletion counseling requires systems-based surveillance (cardiac, calcium/immune, development) rather than a single-organ narrative
1.12 Microdeletion Syndromes (22q11.2, Williams, and Related)
Quick Answer: Contiguous-gene microdeletions remove multiple neighboring genes. For CGC boards, master 22q11.2 deletion (cardiac–palate–calcium–immune–learning) and Williams syndrome (7q11.23, ELN) (supravalvular AS, hypercalcemia, cocktail-party personality). Most are de novo; diagnose with CMA (genome-wide) and use FISH when you need a targeted assay—not as a substitute for unknowing genome-wide CNV detection.
Standard karyotype resolution often misses these deletions. That historical gap is why “normal karyotype + suggestive phenotype” still triggers microarray thinking.
Contiguous Gene Logic
A microdeletion is a chromosomal deletion too small for reliable detection on routine banding but large enough to remove multiple genes. Phenotype reflects the sum of haploinsufficient genes in the interval (plus modifier effects). This is why features cluster into recognizable syndromes rather than single-gene Mendelian patterns.
| Concept | Exam application |
|---|---|
| Contiguous gene syndrome | Multi-system phenotype from one deletion event |
| Variable expressivity | Same deletion, different severity—counsel the range |
| Incomplete ascertainment | Mild cases diagnosed in adulthood (e.g., 22q psychiatric/learning presentations) |
| Recurrence | Usually de novo; parental carrier/deletion status changes risk |
22q11.2 Deletion Syndrome (DiGeorge / VCFS Spectrum)
Historical names—DiGeorge syndrome, velocardiofacial syndrome (VCFS), Shprintzen syndrome—largely describe the same 22q11.2 deletion continuum. Use the genomic name in counseling while recognizing older labels in records.
Key Clinical Features
| System | Findings |
|---|---|
| Cardiac | Conotruncal defects: tetralogy of Fallot, interrupted aortic arch type B, truncus arteriosus, VSD |
| Palate / ENT | Velopharyngeal insufficiency, cleft palate/submucous cleft, hypernasal speech |
| Endocrine | Hypoparathyroidism → hypocalcemia (neonatal seizures possible) |
| Immune | Thymic hypoplasia → T-cell immunodeficiency; infection risk; vaccine/live-vaccine considerations with immunology |
| Craniofacial | Hooded eyelids, squared nasal tip, ear anomalies (variable; avoid over-reliance on “looks”) |
| Development / neuro | Learning disabilities, ADHD, autism features; later psychiatric risk including schizophrenia-spectrum illness |
| Other | Renal anomalies, feeding issues, hearing loss, growth concerns |
A durable mnemonic still seen in teaching is CATCH-22 (Cardiac, Abnormal facies, Thymic, Cleft, Hypocalcemia)—useful as a checklist, not a requirement that every letter be present.
Inheritance and Recurrence
- ~90%+ of classic deletions are de novo.
- Autosomal dominant transmission occurs when a parent carries the deletion (often milder or differently ascertained).
- After a child is diagnosed, offer parental testing. If a parent is deleted, recurrence approaches 50% each pregnancy; if both parents test negative, residual risk is mainly rare germline mosaicism—counsel as low but not absolute zero.
Prenatal vs Postnatal Counseling
Prenatal: conotruncal cardiac defect ± cleft polyhydramnios/palate clues, or CMA/NIPT CNV findings → discuss multi-system involvement, surgical pathways, calcium/immune issues, and developmental supports. Postnatal: newborn hypocalcemia, feeding, cardiac surgery planning, immunology labs, early intervention. Adolescent/adult sessions often reopen psychiatric and reproductive counseling.
Williams Syndrome (7q11.23 Deletion)
Williams syndrome is a contiguous deletion at 7q11.23 that includes ELN (elastin). ELN haploinsufficiency drives much of the arteriopathy.
| Domain | Essentials |
|---|---|
| Cardiovascular | Supravalvular aortic stenosis (SVAS); pulmonary stenosis; risk of other arterial stenoses; hypertension surveillance |
| Calcium | Idiopathic infantile hypercalcemia possible; dietary/monitoring counseling |
| Facies / connective tissue | Periorbital fullness, stellate iris pattern in some, full lips/cheeks; soft skin, joint laxity |
| Growth | Failure to thrive in infancy; short adult stature common |
| Cognition / behavior | Strengths in verbal/social engagement (“cocktail party” personality); weakness in visuospatial construction; anxiety common |
| Endocrine / other | Hypothyroidism, diabetes risk later; hyperacusis |
Inheritance: usually de novo; rare parent-to-child transmission. Parental studies still indicated after diagnosis.
Related Microdeletion / Microduplication Context (Board Awareness)
Without turning this section into an encyclopedia, recognize that CMA commonly surfaces other recurrent CNVs counselors discuss:
| Region / condition | Why it appears on exams |
|---|---|
| 16p11.2 CNVs | Neurodevelopmental phenotypes; variable expressivity |
| 1p36 deletion | Distinctive craniofacial features, developmental disability, cardiac anomalies |
| 17p11.2 (Smith-Magenis) | Behavioral phenotype, sleep disturbance, RAI1-related mechanisms |
| Reciprocal duplications (e.g., 22q11.2 dup) | Often milder/variable vs deletion; still counsel carefully |
The principle is the same: dosage-sensitive genes + variable expressivity + usually de novo with parental testing exceptions.
CMA vs FISH: Diagnostic Strategy
| Test | What it does well | Limits |
|---|---|---|
| Chromosomal microarray (CMA) | Genome-wide detection of deletions/duplications at kilobase–megabase resolution; first-line for many congenital anomaly / developmental indications | Does not detect balanced rearrangements; may reveal VOUS; methylation/imprinting not assessed |
| FISH | Fast, targeted confirmation of a known locus (e.g., 22q11.2 probe) when phenotype is classic or for family studies of a known deletion | Will miss deletions outside the probe target; not a genome-wide screen |
| Karyotype | Large aneuploidy/rearrangements, mosaicism (to a point) | Misses most microdeletions |
CGC trap: Ordering FISH for “developmental delay, unknown cause” can falsely reassure if the probe set does not cover the causative CNV. Conversely, once CMA identifies a 22q11.2 deletion, FISH or another targeted method may be used for rapid parental testing or reflex confirmation depending on laboratory workflow.
NIPT may flag some large CNVs with lower positive predictive value than for common trisomies—abnormal CNV screens still need diagnostic confirmation (CMA/karyotype pathway as indicated).
Counseling Structure for Contiguous Gene Syndromes
- Explain deletion of multiple genes in accessible language (a missing segment, not “one broken gene” only).
- Map organ-system surveillance to the specific syndrome (echo, calcium, immunology for 22q; cardiology and calcium for Williams).
- Address developmental and psychiatric natural history without fatalism—supports change outcomes.
- Clarify inheritance: probable de novo, but test parents before quoting 50% vs near-population recurrence.
- Distinguish test capability: CMA finds unknown CNVs; FISH answers a targeted question.
Microdeletion fluency also prevents misclassifying these phenotypes as isolated single-gene disease or as full aneuploidy when the karyotype is normal—an essential Domain 1C discrimination skill.
A neonate has tetralogy of Fallot, cleft palate, and hypocalcemic seizures. Which genomic finding best fits this constellation?
Why is chromosomal microarray generally preferred over a single-locus FISH study as the first genetic test for nonspecific developmental delay with congenital anomalies?
Parents of a child newly diagnosed with a typical de novo-appearing 22q11.2 deletion ask about recurrence. What is the most appropriate immediate counseling action?
Which cardiovascular finding is most characteristically linked to Williams syndrome among the options below?