Clinical GeneticsMarch 21, 20265 min read

Q-Bank Breakdown: Uniparental disomy — Why Every Answer Choice Matters

Clinical vignette on Uniparental disomy. Explain correct answer, then systematically address each distractor. Tag: Genetics > Clinical Genetics.

Q-Bank Breakdown: Uniparental disomy — Why Every Answer Choice Matters

System: Genetics
Topic: Clinical Genetics
Tag: Genetics > Clinical Genetics

Uniparental disomy (UPD) is a classic “sounds rare, tests often” concept because it links meiotic nondisjunction, trisomy rescue, and genomic imprinting—and it creates answer choices that are almost right. This post walks through a USMLE-style vignette, explains the correct answer, and then dissects each distractor so you can spot UPD under exam pressure.

Clinical Vignette (USMLE-Style)

A 6-year-old child is evaluated for poor feeding in infancy, hypotonia, developmental delay, and hyperphagia with obesity beginning at age 3. Physical exam shows short stature and small hands/feet. Karyotype is 46,XX. Fluorescence in situ hybridization (FISH) for 15q11–q13 deletion is negative. Methylation testing at 15q11–q13 shows an imprinting pattern consistent with two maternal copies of the region and no paternal contribution.

Which genetic mechanism best explains these findings?

A. Uniparental disomy due to trisomy rescue
B. De novo deletion of 15q11–q13
C. Balanced Robertsonian translocation
D. Trinucleotide repeat expansion with anticipation
E. Germline mosaicism for a pathogenic variant
F. Incomplete penetrance of an autosomal dominant allele

Stepwise Reasoning: What’s the Diagnosis?

This vignette is classic for Prader–Willi syndrome (PWS):

  • Hypotonia + poor feeding in infancy
  • Later hyperphagia → obesity
  • Developmental delay, short stature, small hands/feet, hypogonadism often present

Key lab clue:

  • FISH for deletion is negative, but methylation testing suggests absence of the paternal allele at 15q11–q13.

That pattern strongly points to maternal uniparental disomy (UPD) of chromosome 15 (i.e., child inherited two maternal copies, no paternal contribution), which is a common cause of PWS.

✅ Correct answer: A. Uniparental disomy due to trisomy rescue

The Correct Answer Explained: UPD + Imprinting (High Yield)

What is Uniparental Disomy (UPD)?

UPD = both homologs of a chromosome come from one parent.

  • Maternal UPD: two maternal copies, no paternal copy
  • Paternal UPD: two paternal copies, no maternal copy

Why does UPD cause disease?

UPD can cause disease via:

  1. Imprinting effects (most tested)
    • Some genes are silenced depending on parent of origin.
  2. Unmasking autosomal recessive disease
    • If you inherit two copies of a recessive pathogenic variant from one parent.

How does “trisomy rescue” create UPD?

Most commonly:

  1. Nondisjunction → trisomic conceptus (e.g., trisomy 15)
  2. Early embryo “rescues” viability by losing one chromosome
  3. If the lost chromosome is the only paternal chromosome, the result is maternal UPD.

Boards clue: Normal total chromosome number (46) but abnormal imprinting/methylation pattern.

Why Every Answer Choice Matters (Distractor Breakdown)

B. De novo deletion of 15q11–q13

Why it’s tempting:
Deletion of paternal 15q11–q13 is the most common cause of PWS.

Why it’s wrong here:

  • The vignette explicitly says FISH for deletion is negative.
  • While FISH can miss small deletions depending on probe/technique, the stem then gives you methylation evidence of two maternal copies, which is more consistent with UPD than a simple deletion.

USMLE pearl:

  • PWS = loss of paternal expression at 15q11–q13
    • Causes: paternal deletion, maternal UPD, or imprinting center defect
  • Angelman = loss of maternal expression (classically maternal deletion; can also be paternal UPD)

C. Balanced Robertsonian translocation

Why it’s tempting:
Translocations are a common genetics distractor whenever karyotypes appear.

Why it’s wrong here:

  • A balanced translocation usually causes no phenotype in the carrier.
  • Robertsonian translocations involve acrocentric chromosomes (13, 14, 15, 21, 22) and primarily raise risk of aneuploid offspring (e.g., Down syndrome via t(14;21)).
  • PWS/Angelman are imprinting disorders, not classic translocation syndromes.

Board nuance:
Translocations can predispose to unbalanced gametes, but the stem’s key abnormality is parent-of-origin methylation, not altered chromosome structure.

D. Trinucleotide repeat expansion with anticipation

Why it’s tempting:
Many neurodevelopmental vignettes bring this to mind (Fragile X, myotonic dystrophy, Huntington).

Why it’s wrong here:

  • PWS is not caused by repeat expansion.
  • Anticipation = worsening or earlier onset in successive generations, often with a known repeat disorder.
  • This vignette is centered on imprinting at 15q11–q13 and methylation testing.

USMLE anchor list:

  • Fragile X: CGG in FMR1 (X-linked, macroorchidism, autism features)
  • Myotonic dystrophy: CTG (myotonia, distal weakness, cataracts)
  • Huntington: CAG (chorea, dementia)
  • Friedreich ataxia: GAA (ataxia, cardiomyopathy)

E. Germline mosaicism for a pathogenic variant

Why it’s tempting:
Often used to explain recurrence in “de novo” disorders.

Why it’s wrong here:

  • Germline mosaicism explains inheritance patterns (e.g., recurrence risk) rather than producing a parent-of-origin methylation signature.
  • PWS UPD is a chromosomal segregation/imprinting mechanism, not a single-gene variant scenario.

High yield:
Germline mosaicism is classically tested in conditions like osteogenesis imperfecta type II (parents unaffected but multiple affected children possible).

F. Incomplete penetrance of an autosomal dominant allele

Why it’s tempting:
Another common explanation for “skipping generations.”

Why it’s wrong here:

  • PWS is not primarily an autosomal dominant condition with variable penetrance.
  • The stem provides molecular evidence: methylation indicates two maternal copies → points directly to UPD/imprinting, not a penetrance issue.

High-Yield UPD + Imprinting: What USMLE Loves

1) Prader–Willi vs Angelman (Same Locus, Different Parent)

Both involve 15q11–q13, but parent-of-origin matters.

Prader–Willi syndrome (loss of paternal expression)

  • Paternal deletion or maternal UPD
  • Hypotonia → hyperphagia, obesity
  • Developmental delay, hypogonadism, small hands/feet

Angelman syndrome (loss of maternal expression; often UBE3A)

  • Maternal deletion or paternal UPD
  • Severe intellectual disability, seizures, ataxia
  • Inappropriate laughter (“happy puppet”)

2) Isodisomy vs Heterodisomy (Quick Definitions)

  • Heterodisomy: two different homologs from one parent → suggests meiosis I error
  • Isodisomy: two identical copies of one homolog → suggests meiosis II error or postzygotic duplication
    Why it matters: Isodisomy can unmask autosomal recessive disease.

3) Best Tests to Know

  • Methylation analysis: detects abnormal imprinting patterns (often first-line confirmatory for PWS/Angelman)
  • FISH / microarray: good for deletions/duplications
  • UPD studies (SNP microarray): can show absence of heterozygosity, consistent with UPD

Exam Tip: When to Think UPD

Think UPD when you see:

  • A classic imprinting syndrome phenotype (PWS/Angelman) but deletion testing is negative
  • A normal karyotype with parent-of-origin methylation abnormalities
  • Unexpected autosomal recessive disease in a child with only one carrier parent (possible isodisomy)

Key Takeaways (Rapid Review)

  • UPD = both copies of a chromosome from one parent, often from trisomy rescue.
  • UPD causes disease via imprinting or unmasking recessive alleles.
  • PWS: loss of paternal 15q11–q13 expression → paternal deletion or maternal UPD.
  • A vignette with negative deletion testing + abnormal methylation is a major clue for UPD/imprinting defects.
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