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Difficulty: MediumGenetic and Molecular Mechanisms

A 3-year-old boy is evaluated in the pediatric genetics clinic due to excessive food-seeking behavior and rapid weight gain. His parents report that he had profound muscle hypotonia and required nasogastric tube feeding during his first month of life. Physical examination demonstrates central adiposity, small hands and feet, and undescended testes. Initial diagnostic testing with fluorescence in situ hybridization (FISH) for a microdeletion on chromosome 15q11-q13 is negative. Subsequent molecular testing with DNA methylation analysis reveals the presence of only maternally methylated alleles at the 15q11-q13 locus. Which of the following molecular mechanisms best explains these diagnostic findings?

  1. Inheritance of two homologous chromosomes from the maternal lineage and none from the paternal lineageAnswer
  2. B
    Abnormal expansion of a trinucleotide repeat sequence in a promoter region leading to hypermethylation
  3. C
    A post-zygotic mitotic error resulting in the presence of two genetically distinct cellular lineages
  4. D
    Presence of pathogenic mutations at multiple distinct genetic loci that converge to produce a uniform phenotype
  5. E
    Altered pharmacodynamic sensitivity of hypothalamic receptors secondary to a missense mutation

Answer

Inheritance of two homologous chromosomes from the maternal lineage and none from the paternal lineage
The correct answer is the inheritance of two homologous chromosomes from the maternal lineage and none from the paternal lineage. This patient's presentation of neonatal hypotonia followed by childhood hyperphagia, central obesity, and cryptorchidism is classic for Prader-Willi syndrome (PWS). PWS is caused by the loss of expression of paternally inherited genes on chromosome 15q11-q13. While a paternal microdeletion is the most common cause (~70% of cases), this was ruled out by the negative FISH test. The subsequent DNA methylation analysis showing exclusively maternally methylated alleles confirms that no paternal DNA is present at this locus. This combination of findings indicates maternal uniparental disomy (UPD), which occurs in ~25% of PWS cases. Because the maternal genes at this specific locus are normally silenced by epigenetic methylation (imprinting), inheriting two maternal copies results in a complete lack of active gene expression, leading to the clinical phenotype.

Step-by-Step Solution

1
Identify the underlying clinical syndrome based on the patient's presentation.
Prader-Willi syndrome (PWS).
The biphasic history of severe neonatal hypotonia and feeding difficulties followed by early childhood hyperphagia, obesity, and cryptorchidism is highly characteristic of PWS.
2
Interpret the sequential genetic testing results.
FISH is negative for a deletion, but DNA methylation analysis shows exclusively maternal patterns.
A negative FISH rules out a paternal microdeletion (the most common cause of PWS). The methylation analysis confirms that paternal alleles are entirely absent or inactive at this locus.
3
Determine the molecular mechanism that unifies the clinical diagnosis and laboratory findings.
Maternal uniparental disomy.
When a microdeletion is absent but only maternal alleles are detected, the patient has inherited two copies of chromosome 15 from the mother and zero from the father. Because maternal genes at 15q11-q13 are normally silenced (imprinted), the patient has no active copies.

Key Concept

Maternal uniparental disomy as a molecular etiology of Prader-Willi syndrome when a microdeletion is excluded.
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Topics

Genetic and Molecular Mechanisms

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