Prader-Willi syndrome

Prader–Willi syndrome (PWS) most commonly occurs as a simplex condition resulting from a de novo genetic event, and consequently the recurrence risk for affected families is generally below 1%. Nevertheless, the recurrence risk is highly dependent on the underlying molecular mechanism. In rare instances, particularly when an imprinting defect is caused by a microdeletion in the imprinting center or when a parent carries a structural chromosomal rearrangement involving chromosome 15, the recurrence risk may increase substantially, potentially reaching up to 50%. Therefore, precise genetic counseling necessitates comprehensive molecular characterization of the causative mechanism in the proband as well as targeted parental studies to identify predisposing genomic alterations, including balanced rearrangements or heterozygous imprinting center deletions.

The diagnosis of Prader-Willi syndrome is established molecularly by identifying abnormal DNA methylation within the Prader-Willi critical region at 15q11q13, which results in a pattern of maternal-only imprinting. This reflects a loss of normal paternal gene expression.

Many disorders with hypotonia in infancy, craniopharyngioma and hyperphagic short stature can mimic parts of PWS phenotype. Also genetic disorders with , intellectual disability and obesity with or without hypogonadism.

• Establishing the diagnosis: a molecular diagnosis confirms the clinical suspicion and provides certainty for other family members.
• Enabling specific and individualised surveillance and clinical management: a comprehensive and phase-specific overview of clinical management in Prader–Willi syndrome, encompassing infancy, early childhood, adolescence, and adulthood, has been formulated by the Clinical and Scientific Advisory Board of the International Prader–Willi Syndrome Organisation (IPWSO). These evidence-based consensus recommendations are available through the .
• Family member testing: identification of the underlying molecular cause enables predictive testing of at-risk relatives and informs reproductive counselling within the family.

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