Prader-Willi and Angelman syndromes

The fellowship mark goes to the candidate who thinks in three layers at once. The first layer is the child in front of you: the hypotonic neonate failing to feed (PWS) or the ataxic toddler with seizures and a happy demeanour (AS). The second is the molecular mechanism: a parent-of-origin-specific imprinting error at 15q11-q13 that silences one parental allele and leaves the other unable to compensate. The third is the family: the subtype (deletion, uniparental disomy, imprinting defect, or UBE3A mutation) sets the recurrence risk, and counselling must be imprinting-aware — because imprinting-centre defects and UBE3A mutations carry up to 50 per cent recurrence, while typical deletions and UPD are sporadic. [1] [2] [4]

Overview & Definition

Prader-Willi syndrome and Angelman syndrome are the prototypical disorders of genomic imprinting in humans, and they arise from reciprocal errors at the same chromosomal locus — 15q11-q13. Genomic imprinting is the parent-of-origin-specific expression of certain genes, where only the maternal or paternal copy is active in specific tissues. In the 15q11-q13 region, paternally expressed genes (including SNRPN, MAGEL2, NDN, and the SNORD116 snoRNA cluster) are active on the paternal chromosome, while UBE3A, a ubiquitin-protein ligase, is active primarily on the maternal chromosome in the brain. [3] [5]

Loss of the paternal contribution produces Prader-Willi syndrome: the child has no functional paternally expressed genes, and the maternal copies are silenced by imprinting. The neonate presents with profound hypotonia, poor feeding, and failure to thrive, and the phenotype shifts after infancy to hyperphagia, obesity, intellectual disability, short stature, and hypogonadism. Loss of the maternal contribution at the same locus — specifically of UBE3A — produces Angelman syndrome: the child lacks functional UBE3A protein in the brain because the paternal allele is silenced in neurons, and the result is severe intellectual disability, ataxia, a characteristic happy demeanour, seizures, and microcephaly. [1] [2]