14. Non-traditional (non-Mendelian) inheritance: genomic imprinting, uniparental disomy, dynamic mutations, gonadal mosaicism, incomplete penetrance, variable expressivity, pleiotropy, de novo mutations.
Covers the main non-Mendelian inheritance mechanisms, beginning with genomic imprinting and its parent-of-origin effect, illustrated by Prader–Willi and Angelman syndromes. It then takes uniparental disomy with its isodisomy and heterodisomy mechanisms, dynamic repeat-expansion disorders with anticipation, and gonadal mosaicism. The note also reviews incomplete penetrance, variable expressivity, pleiotropy and de novo mutations, closing with their implications for genetic counselling and testing.
Topic 14 of 65 in the MU Sofia syllabus for Genetics (Medicine, Year 3). The free AceMed note covers it in 11 sections, about 585 words (4 min of reading), with 13 flashcards.
In this note
Non-Traditional (Non-Mendelian) Inheritance
I. Introduction
II. Genomic Imprinting
III. Uniparental Disomy (UPD)
IV. Dynamic Mutations (Repeat Expansion Disorders)
V. Gonadal Mosaicism
VI. Incomplete Penetrance
VII. Variable Expressivity
VIII. Pleiotropy
IX. De Novo Mutations
X. Clinical Importance
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).
