You’re cruising through your genetics Q-bank and hit a vignette that looks like imprinting… but the twist is uniparental disomy (UPD). These questions are deceptively high-yield because they force you to integrate meiotic nondisjunction, trisomy rescue, and genomic imprinting—and then separate UPD from similar-sounding answer choices (like balanced translocations or mitochondrial inheritance). Let’s break it down the way test writers build it: one correct mechanism, plus distractors designed to catch specific misconceptions.
The Clinical Vignette (Q-Bank Style)
A 6-year-old child is evaluated for developmental delay and hyperphagia. The parents report that the child has had insatiable appetite since early childhood and has gained weight rapidly. Physical exam shows obesity, hypotonia, and mild intellectual disability. Karyotype is normal. Methylation analysis demonstrates absence of paternally expressed genes on chromosome 15.
Which of the following best explains this patient’s condition?
A. Deletion of the maternal allele on chromosome 15
B. Uniparental disomy of chromosome 15 due to trisomy rescue
C. Robertsonian translocation involving chromosome 15
D. Trinucleotide repeat expansion with anticipation
E. Mitochondrial inheritance due to heteroplasmy
Step 1: Identify the Syndrome, Then the Mechanism
This is Prader-Willi syndrome (PWS):
- Hyperphagia + obesity
- Hypotonia (classically “floppy baby”)
- Mild to moderate intellectual disability
- Often hypogonadism and behavioral issues
Key clue: absence of paternally expressed genes on chromosome 15 (specifically 15q11-q13).
That means the child is missing functional paternal contribution in that imprinted region.
✅ Correct Answer: B. Uniparental disomy of chromosome 15 due to trisomy rescue
Uniparental disomy (UPD) = both copies of a chromosome come from one parent.
In PWS due to UPD, the child typically has maternal UPD 15 (two maternal copies, no paternal copy). Since certain genes in 15q11-q13 are normally expressed only from the paternal allele, the child effectively has no expression of those genes.
High-Yield: How UPD Happens (The Board-Relevant Story)
The classic tested mechanism is trisomy rescue:
- Meiotic nondisjunction → conceptus starts as trisomy (e.g., three copies of chr 15)
- Early embryo “rescues” viability by randomly losing one chromosome
- If the lost chromosome is the only paternal chromosome → two maternal remain → maternal UPD
Why karyotype can be normal
After trisomy rescue, the cell line that survives may end up with a “normal” chromosome number (46), so routine karyotype may look normal—yet imprinting is still disrupted.
UPD: The Two Flavors You Should Know
| Type | What it means | Why it matters |
|---|---|---|
| Heterodisomy | Two different homologs from one parent | Suggests meiosis I nondisjunction |
| Isodisomy | Two identical copies of one homolog from one parent | Suggests meiosis II nondisjunction or postzygotic duplication; can unmask recessive disease |
USMLE pearl: UPD can cause disease via:
- Imprinting disorders (most classic)
- Unmasking autosomal recessive mutations (especially with isodisomy)
The Imprinting Classic Pair: PWS vs Angelman
Both involve chromosome 15q11-q13, but which parent’s allele is missing determines the syndrome.
| Syndrome | Missing functional allele | Typical mechanism | Key findings |
|---|---|---|---|
| Prader-Willi | Paternal | Paternal deletion or maternal UPD | Hyperphagia, obesity, hypotonia, hypogonadism |
| Angelman | Maternal | Maternal deletion or paternal UPD | Seizures, ataxia, inappropriate laughter (“happy puppet”) |
Now, Why Each Answer Choice Matters (Systematic Distractor Breakdown)
A. Deletion of the maternal allele on chromosome 15 ❌
This would remove maternally expressed genes—pushing you toward Angelman syndrome, not Prader-Willi.
- If the question had said: absence of maternally expressed genes, plus seizures + ataxia + inappropriate laughter, then maternal deletion would be perfect.
- Here, the lab specifically indicates missing paternally expressed genes → think PWS.
Test-writer trap: swapping which parent matters in imprinting.
B. Uniparental disomy of chromosome 15 due to trisomy rescue ✅
This directly explains:
- Normal karyotype (post-rescue)
- Absent paternal expression (if maternal UPD)
- Clinical PWS phenotype
Extra-high-yield: UPD is disproportionately tested in imprinting syndromes because it’s the “weird” mechanism people forget.
C. Robertsonian translocation involving chromosome 15 ❌
A Robertsonian translocation usually involves acrocentric chromosomes: 13, 14, 15, 21, 22. So chromosome 15 being mentioned is a deliberate lure.
Why it doesn’t fit:
- Robertsonian translocations classically lead to aneuploidy syndromes in offspring (e.g., translocation Down syndrome with 21)
- They do not explain methylation/imprinting-specific loss of paternal gene expression in 15q11-q13
- PWS/Angelman are not classic Robertsonian translocation outcomes
Test-writer trap: “15 is acrocentric → must be Robertsonian.” Not here.
D. Trinucleotide repeat expansion with anticipation ❌
Trinucleotide repeat disorders have a different signature:
- Anticipation (worse/earlier in successive generations)
- Often neurodegeneration or characteristic systemic signs
Examples you should know:
- Huntington (CAG, AD, paternal anticipation)
- Myotonic dystrophy (CTG, AD)
- Fragile X (CGG, X-linked, maternal anticipation)
Why it doesn’t fit:
- This vignette is anchored by imprinting/methylation testing and chromosome 15 imprinting patterns.
- PWS is not a trinucleotide repeat disorder.
Test-writer trap: seeing neurodevelopmental delay and reflexively choosing Fragile X.
E. Mitochondrial inheritance due to heteroplasmy ❌
Mitochondrial disease clues include:
- Maternal inheritance pattern (all children of affected mother potentially affected)
- High-energy tissues: brain, muscle, heart
- Lactic acidosis, seizures, myopathy, ophthalmoplegia
- Variable expressivity due to heteroplasmy
Why it doesn’t fit:
- Mitochondrial inheritance doesn’t map to a specific autosome imprinting region (like 15q11-q13)
- The key lab result is methylation/imprinting, not mitochondrial genome dysfunction
Test-writer trap: “developmental delay = mitochondria.” But the phenotype and testing point elsewhere.
How to Recognize UPD on Test Day (Pattern Recognition)
Think UPD when you see:
- A classic imprinting disorder phenotype (PWS/Angelman, sometimes Beckwith-Wiedemann)
- Normal karyotype but abnormal methylation/imprinting studies
- A story involving trisomy rescue or a pregnancy initially flagged for aneuploidy that “resolved”
A quick diagnostic logic chain
- Imprinting phenotype + methylation abnormality → imprinting problem
- No deletion on microarray / normal karyotype → consider UPD
- Parent-of-origin effect specifies which UPD (maternal vs paternal)
Rapid-Fire High-Yield Facts (USMLE-Style)
- UPD definition: both homologs of a chromosome from one parent
- Mechanism: usually trisomy rescue (post-zygotic loss of one chromosome)
- UPD consequences:
- Imprinting disorders (most classic)
- Unmasking recessive disease (especially isodisomy)
- PWS: loss of paternal gene expression at 15q11-q13
- paternal deletion OR maternal UPD 15
- Angelman: loss of maternal gene expression at 15q11-q13
- maternal deletion OR paternal UPD 15
Takeaway
Uniparental disomy is a board-favorite because it’s a “normal chromosome count, abnormal gene expression” problem. If a vignette screams imprinting (especially chromosome 15), and the lab points to methylation abnormalities without a straightforward deletion—UPD due to trisomy rescue should jump to the top of your list. And if you can confidently eliminate the distractors, you’re not just memorizing syndromes—you’re reading the test writer’s mind.