Inheritance - imprinting

Definition

Genomic imprinting - certain genes are expressed from only one parental copy (either the maternal or the paternal allele), with the other copy epigenetically silenced - meaning the parent of origin, not just which gene is affected, determines the clinical outcome of a given deletion/mutation
Relatively few genes in the genome are imprinted, but disorders involving imprinted regions produce some of the most instructive examples in clinical genetics of how the same genetic region can cause completely different phenotypes depending on parental origin

Imprinting is established via differential DNA methylation of the maternal versus paternal allele during gametogenesis - silencing one copy means the individual is functionally dependent on the single active (non-imprinted) copy for that gene's function, making them effectively "haploid" for that specific locus

Prader-Willi syndrome (paternal 15q11-13 deletion/dysfunction - hyperphagia, obesity, hypotonia, intellectual disability) vs Angelman syndrome (maternal 15q11-13 deletion/dysfunction - severe intellectual disability, ataxia, inappropriate laughter, seizures) - the same chromosomal region, but a completely different phenotype depending on whether the deletion/dysfunction affects the maternal or paternal copy - the paradigm example of imprinting's clinical relevance
Imprinting disorders can arise via deletion, uniparental disomy (see parental disomy), or an imprinting defect (abnormal methylation without a structural change) - genetic testing needs to specifically assess all three mechanisms, not just look for a deletion alone

Diagnosis requires methylation-specific testing (not standard sequencing alone, since the DNA sequence itself may be entirely normal in an imprinting defect - it is the epigenetic mark that is abnormal) alongside deletion/UPD testing
Genetic counselling addresses the specific mechanism found, since recurrence risk differs substantially between a deletion (usually low recurrence risk, sporadic), UPD (usually low recurrence risk), and a primary imprinting centre defect (which can be inherited and carry a higher recurrence risk)

Prader-Willi syndrome, Angelman syndrome, Beckwith-Wiedemann syndrome (another well-characterised imprinting disorder), uniparental disomy

Imprinting explains why "the same gene, deleted" can produce two entirely different clinical syndromes depending on parental origin - a concept with no equivalent in standard Mendelian inheritance, where the parent of origin does not usually matter for autosomal genes

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