Microdeletion and Imprinting Syndromes
This review covers a microdeletion syndrome and the classic imprinting pair tested through pattern recognition: Williams syndrome (a 7q11.23 microdeletion) and Prader-Willi and Angelman (both mapping to 15q11-13 and governed by genomic imprinting). The framework is to link each syndrome's distinctive facies, behavioral phenotype, and signature association — and, for the imprinting pair, to know which parent's copy is lost.
Williams Syndrome
Williams results from a microdeletion at 7q11.23 that includes the elastin gene. The classic face is 'elfin' — wide mouth, upturned nose, and long philtrum. Behaviorally, children are overly friendly with a 'cocktail party personality' and have strong verbal skills (and musical ability) despite intellectual disability. The must-know associations are supravalvular aortic stenosis (from elastin loss) and hypercalcemia (in infancy).
Prader-Willi Syndrome
Prader-Willi arises from loss of the PATERNAL 15q11-13 — either paternal deletion or maternal uniparental disomy. Infants present with hypotonia and poor feeding, which switches around age 2–4 to hyperphagia and obesity. Additional features include short stature, small hands and feet, hypogonadism, and mild intellectual disability. The mnemonic hook: Prader-Willi = Paternal deletion.
Angelman Syndrome
Angelman is the maternal counterpart, from loss of the MATERNAL 15q11-13 — either maternal deletion or paternal uniparental disomy. Features include microcephaly, an ataxic gait, and severe intellectual disability with absent speech. The hallmark is a happy demeanor with frequent, inappropriate laughter (historically the 'happy puppet'), along with seizures. Angelman = loss of the mother's copy.
Genomic Imprinting at 15q11-13
Prader-Willi and Angelman are the board-favorite example of genomic imprinting: two entirely different phenotypes arising from the SAME chromosomal locus, depending on the parent of origin. Loss of the paternal copy (paternal deletion or maternal uniparental disomy) yields Prader-Willi; loss of the maternal copy (maternal deletion or paternal uniparental disomy) yields Angelman. Knowing which parent contributes which syndrome is the single most testable point.
Approach: Genetic Syndrome Pattern Recognition
On the exam, these syndromes are recognized by pattern. Anchor each to its signature feature: Williams to supravalvular aortic stenosis and an overly friendly personality (and check calcium), Prader-Willi to infantile hypotonia followed by hyperphagia/obesity, and Angelman to inappropriate laughter with ataxia and seizures. For the 15q pair, always look for the parent-of-origin clue distinguishing deletion from uniparental disomy.
High-yield
- Williams = 7q11.23 microdeletion (elastin gene) → supravalvular aortic stenosis + hypercalcemia.
- Williams personality: overly friendly 'cocktail party' with strong verbal/musical skills and elfin facies.
- Prader-Willi = PATERNAL 15q11-13 loss; infantile hypotonia → later hyperphagia, obesity, hypogonadism, short stature, small hands/feet.
- Angelman = MATERNAL 15q11-13 loss; happy demeanor with frequent laughter, ataxia, seizures, absent speech, microcephaly.
- Prader-Willi vs Angelman = the classic genomic imprinting pair at the same locus.
- Prader-Willi from maternal uniparental disomy; Angelman from paternal uniparental disomy.
Pitfalls
- Reversing parent-of-origin: Prader-Willi is loss of the PATERNAL copy; Angelman is loss of the MATERNAL copy.
- Confusing the uniparental disomy patterns — maternal UPD causes Prader-Willi, paternal UPD causes Angelman.
- Attributing supravalvular aortic stenosis or hypercalcemia to a syndrome other than Williams.
- Overlooking the biphasic feeding course of Prader-Willi (poor feeding in infancy, then hyperphagia at age 2–4).
Clinical pearls
- A friendly, verbally gifted child with a heart murmur (supravalvular AS) → think Williams and check calcium.
- A floppy infant who becomes an obese, constantly hungry toddler → Prader-Willi (paternal 15q loss).
- A child with ataxia, seizures, and inappropriate laughter → Angelman (maternal 15q loss).
- Same locus, opposite parent, opposite phenotype = genomic imprinting.
Frequently asked
How do I remember which parent's chromosome is lost in Prader-Willi versus Angelman?
Prader-Willi = Paternal loss (both start with P). Angelman is the opposite — loss of the maternal 15q11-13. Alternatively, maternal uniparental disomy causes Prader-Willi and paternal uniparental disomy causes Angelman.
What are the two signature associations of Williams syndrome?
Supravalvular aortic stenosis (from loss of the elastin gene) and hypercalcemia in infancy. Pair these with the elfin facies and overly friendly 'cocktail party' personality.
What is the classic behavioral clue for Angelman syndrome?
A happy demeanor with frequent, inappropriate laughter, combined with absent speech, ataxic gait, microcephaly, and seizures.
How does the clinical course of Prader-Willi change with age?
Infants present with hypotonia and poor feeding, but around age 2–4 this switches to hyperphagia and obesity. Other features include short stature, small hands and feet, and hypogonadism.
What makes Prader-Willi and Angelman the classic teaching example of genomic imprinting?
Both map to the same locus (15q11-13), yet produce completely different phenotypes depending on the parent of origin — demonstrating that gene expression can depend on whether a chromosome is inherited from the mother or father.
What is the genetic mechanism behind Williams syndrome?
A contiguous gene microdeletion at 7q11.23 that includes the elastin gene, explaining the connective tissue and cardiovascular findings such as supravalvular aortic stenosis.
How do deletion and uniparental disomy differ as causes of these imprinting syndromes?
Prader-Willi results from paternal deletion or maternal uniparental disomy (two maternal copies), while Angelman results from maternal deletion or paternal uniparental disomy (two paternal copies). Either way, the parentally imprinted contribution is missing.
Turn this into reasoning you can use on exam day — practice Microdeletion and Imprinting Syndromes on branching cases where your decisions shape the patient.