Introduction
Mendelian inheritance explains most single-gene disorders (AD, AR, X-linked), but many traits and diseases deviate from these simple patterns. These deviations are grouped as non-traditional (non-Mendelian) inheritance: genomic imprinting, uniparental disomy, dynamic mutations, gonadal mosaicism, incomplete penetrance, variable expressivity, pleiotropy and de novo mutations. Understanding them is crucial for genetic counseling, diagnosis, and predicting disease course. The two classic imprinting syndromes, Prader–Willi and Angelman, are described in detail.
I. Genomic imprinting
Definition and features
- Epigenetic phenomenon in which the expression of a gene depends on whether it is inherited from the mother or father.
- Only one parental copy of a gene is expressed, while the other is silenced by DNA methylation and histone modifications. This parent-of-origin–specific expression is established during gametogenesis and maintained throughout life.
- Parent-of-origin effect → phenotype depends on which parent transmitted the mutation.
- Imprints are erased and reset in the germline according to the sex of the parent.
As a result, loss of the active allele causes disease, while loss of the imprinted (silenced) allele has no effect. Imprinting disorders typically involve:
- microdeletions,
- uniparental disomy (UPD),
- imprinting center defects.
Parental origin matters
The same chromosomal region, if lost from mother vs father, can cause different syndromes. Best example: chromosome 15q11–q13.
- Prader–Willi syndrome: deletion of 15q11–q13 on the paternal chromosome. The maternal allele is normally imprinted (silenced). → Hypotonia, obesity, intellectual disability.
- Angelman syndrome: deletion of the same region, but on the maternal chromosome (UBE3A gene active only from the maternal allele). → Severe intellectual disability, ataxia, “happy puppet” behavior.