13. Non-traditional inheritance: dynamic mutations, imprinting, uniparental disomy, mitochondrial and digenic inheritance, incomplete penetrance, variable expressivity, mosaicism.

I. Introduction

• Mendelian inheritance explains most single-gene disorders (AD, AR, X-linked).
• However, many traits and diseases deviate from these simple patterns.
• These deviations are grouped as non-traditional (non-Mendelian) inheritance mechanisms.
• Understanding them is crucial for genetic counseling, diagnosis, and predicting disease course.

II. Genomic Imprinting

Definition

• Epigenetic phenomenon where the expression of a gene depends on whether it is inherited from the mother or father.
• One parental allele is silenced by DNA methylation and histone modifications, leaving only the other allele expressed.

Features

• Parent-of-origin effect → phenotype depends on which parent transmitted the mutation.
• Imprints are erased and reset in germline according to sex of parent.

Examples

• Prader–Willi syndrome: deletion of 15q11–q13 on the paternal chromosome. Maternal allele is normally imprinted (silenced). → Hypotonia, obesity, intellectual disability.
• Angelman syndrome: deletion of same region, but on the maternal chromosome (UBE3A gene active only from maternal allele). → Severe intellectual disability, ataxia, “happy puppet” behavior.

III. Uniparental Disomy (UPD)

Definition

• Both copies of a chromosome (or part of it) are inherited from one parent, instead of one from each.

Mechanisms

• Isodisomy: two identical copies from one parent (meiosis II error).
• Heterodisomy: both homologues from one parent (meiosis I error).

Consequences

1. May unmask recessive mutations if both copies carry same mutation.
2. May disturb imprinting (since both alleles come from one parent).

Examples

• Maternal UPD15 → Prader–Willi syndrome.
• Paternal UPD15 → Angelman syndrome.
• Maternal UPD7 → Russell–Silver syndrome (growth retardation).