Prader-Willi Syndrome (PWS) is a complex, non-inherited genetic disorder affecting the expression of specific genes located on chromosome 15. The condition arises from the absence of functional paternal genes in the specialized region 15q11-q13. This absence disrupts the function of the hypothalamus, which regulates many basic functions, leading to a wide range of symptoms. Because PWS presentation can be subtle or overlap with other conditions, a definitive diagnosis relies on specialized genetic testing, following clinical observation.
Recognizing the Clinical Indicators
Suspicion of Prader-Willi Syndrome begins with recognizing distinct clinical features that change dramatically as an individual ages. In infancy, the syndrome is signaled by severe muscle weakness (hypotonia), which causes the baby to appear “floppy” and results in a weak cry. This muscle weakness leads to significant feeding difficulties, as the infant is unable to suck or swallow effectively, often requiring specialized nipples or tube feeding to prevent a failure to thrive.
These feeding problems typically resolve or improve within the first few months, but the clinical picture shifts significantly as the child enters the toddler and preschool years. Between the ages of one and six, the child develops an uncontrollable, excessive drive to seek and consume food, known as hyperphagia. If not strictly managed, this insatiable appetite leads to rapid weight gain and the onset of morbid obesity.
Childhood presentation includes global developmental delays, with motor milestones like sitting and walking achieved later than usual. Physicians also look for physical signs, such as small hands and feet, short stature, and distinctive facial features like almond-shaped eyes. These age-specific features prompt a physician to recommend definitive genetic testing for PWS.
The Essential Screening Test
The first and most reliable step in laboratory confirmation is the DNA methylation analysis, which detects over 99% of all PWS cases. This test is considered the best initial diagnostic tool because it identifies the functional absence of the necessary paternal genetic material, regardless of the underlying cause. The test focuses on a chemical process called methylation, which is a tag on the DNA that determines which parental copy of a gene is “active” or “silent”.
In the PWS region of chromosome 15, the paternal genes are normally active (unmethylated), while the maternal genes are naturally silent (methylated)—this is a phenomenon called genomic imprinting. When PWS is present, the test shows only the methylated, or silent, maternal pattern. This abnormal result confirms that the individual is missing the active paternal copy required for normal function.
The methylation analysis does not distinguish between the various genetic mechanisms that lead to PWS, but its high accuracy confirms the diagnosis, establishing the need for immediate clinical intervention and management. If the methylation analysis is negative, the diagnosis of PWS is virtually ruled out, and other conditions are explored. This test is typically performed on a blood sample, sometimes referred to as a methylation-sensitive PCR or MS-MLPA.
Identifying the Specific Genetic Cause
Once the diagnosis of PWS is confirmed by the methylation analysis, secondary genetic tests are performed to determine the specific molecular subtype. This distinction is important for accurate genetic counseling, as the recurrence risk for future pregnancies varies significantly depending on the subtype.
The most common cause, accounting for approximately 60–70% of cases, is a paternal deletion of the 15q11-q13 region. This deletion means the paternal chromosome segment is physically missing, and it is usually detected using a specialized test like a chromosomal microarray (CMA) or fluorescent in-situ hybridization (FISH). Chromosomal microarray is often preferred because it can precisely map the size of the deletion, which may correlate with subtle differences in the clinical presentation.
The second most frequent cause (20–35% of cases) is maternal uniparental disomy (UPD). This occurs when a person inherits both copies of chromosome 15 from the mother and none from the father. Since the maternal copies are naturally silenced through imprinting, the result is the same functional absence of paternal genes.
This subtype is identified using specialized DNA analysis methods, such as SNP arrays or microsatellite analysis, which compare genetic markers in the child to those of both parents. The rarest cause, affecting 1–5% of individuals, is an imprinting defect, where the paternal chromosome is present but incorrectly marked as “silent”.