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Difficulty: HardGenetic and Molecular Mechanisms

A 16-year-old girl is brought to the clinic by her parents for a follow-up examination. She has a history of mild intellectual disability, truncal obesity, and obsessive food-seeking behavior. As an infant, she exhibited severe central hypotonia and poor feeding that required temporary nasogastric tube support. Physical examination today reveals a body mass index (BMI) of 34 kg/m² along with a narrow biparietal diameter, almond-shaped eyes, and small hands and feet.

To confirm the clinically suspected diagnosis, targeted molecular genetic testing is performed. DNA methylation analysis of the 15q11-q13 region is abnormal, showing an exclusively maternal methylation pattern. Subsequent high-resolution chromosomal microarray analysis demonstrates no evidence of genomic microdeletions or duplications across the genome.

Which of the following is the most likely underlying genetic mechanism responsible for this patient's condition?

  1. Inheritance of two structurally intact homologous chromosomes from a single parentAnswer
  2. B
    Interstitial microdeletion on the paternally inherited chromosome
  3. C
    Defective post-zygotic mitotic segregation leading to somatic mosaicism
  4. D
    Trinucleotide repeat expansion in the untranslated region of a maternal gene
  5. E
    De novo point mutation in the ubiquitin protein ligase E3A gene

Answer

The correct answer is the inheritance of two structurally intact homologous chromosomes from a single parent, describing maternal uniparental disomy.
The patient's clinical presentation is classic for Prader-Willi syndrome (PWS). The diagnosis is confirmed by abnormal DNA methylation analysis of the 15q11-q13 region, which shows only a maternally imprinted pattern, indicating an absence of functional paternally expressed genes. While the most common cause of PWS is a paternal microdeletion (approximately 70% of cases), this patient has a completely normal chromosomal microarray. Because microarrays detect copy number variations, a normal result explicitly rules out a deletion. The second most common cause of PWS (approximately 25-30% of cases) is maternal uniparental disomy (UPD). In maternal UPD, the offspring inherits two copies of chromosome 15 from the mother and zero copies from the father. Because both chromosomes are of maternal origin, they both carry the maternal imprint (which silences the genes critical for preventing PWS), leading to a complete absence of expression of these specific genes despite the chromosomes being structurally intact. Therefore, the inheritance of two structurally intact homologous chromosomes from a single parent is the correct mechanism.

Step-by-Step Solution

1
Identify the clinical syndrome based on the patient's history and physical examination findings.
The combination of infantile hypotonia, childhood hyperphagia, truncal obesity, mild intellectual disability, and characteristic facies strongly points to Prader-Willi syndrome (PWS).
Recognizing the phenotype establishes the differential diagnosis and directs the interpretation of specific genetic tests.
2
Analyze the DNA methylation assay results.
The presence of an exclusively maternal methylation pattern at 15q11-q13 confirms the diagnosis of PWS by demonstrating the lack of a functional paternally imprinted allele.
Methylation testing is highly sensitive for PWS but does not identify the specific molecular mechanism (deletion, uniparental disomy, or imprinting center defect).
3
Integrate the chromosomal microarray results to deduce the specific genetic mechanism.
The microarray shows no genomic microdeletions. Therefore, the lack of paternal expression must be due to the presence of two maternal copies of chromosome 15 (maternal uniparental disomy).
Microarray analysis detects copy number variations. A normal result rules out the most common cause of PWS (paternal microdeletion), isolating uniparental disomy or an imprinting defect as the cause.

Key Concept

Molecular mechanisms and diagnostic test interpretation in Prader-Willi syndrome.
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Topics

Genetic and Molecular Mechanisms

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