Non-Classical Patterns of Inheritance

Introduction

Refers to patterns of gene transmission that do not follow standard Mendelian laws of segregation and independent assortment.
Explains genetic disorders that lack predictable recurrence risks based on simple dominant or recessive models.

Mitochondria contain their own circular DNA (mtDNA) encoding 37 genes.
Maternal Transmission: Inherited exclusively from the oocyte; affected mothers transmit the mutation to all children, but affected fathers transmit to none.
Heteroplasmy: Cells contain a mixture of normal and mutated mtDNA; clinical severity correlates with the ratio of mutant to wild-type mtDNA.
Threshold Effect: A specific level of mutant mtDNA (typically >60-90%) must be reached before clinical symptoms appear in a specific tissue.
Mitotic Segregation: Random distribution of mitochondria during cell division leads to varying heteroplasmy levels across different tissues over time.
Genetic Bottleneck: A small number of mitochondria are sampled during oogenesis, causing significant variability in mutant load among siblings.

Condition	Gene/Mutation Features	Clinical Phenotype
MELAS	Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes	Stroke-like episodes, lactic acidosis.
MERRF	Myoclonic Epilepsy with Ragged Red Fibers	Myoclonic epilepsy, ataxia, sensorineural deafness.
LHON	Leber Hereditary Optic Neuropathy	Rapid optic nerve atrophy, blindness in young adults.

Involves DNA segments where three nucleotides are repeated multiple times, which can expand as the gene is passed to offspring.
Anticipation: The genetic disorder becomes more severe or appears at an earlier age in successive generations due to expansion of the repeat.
Premutation versus Full Mutation: Individuals with premutation repeats are usually asymptomatic but are at high risk of having children with a full mutation.
Parental Bias: Expansion often occurs preferentially during either oogenesis or spermatogenesis.

Condition	Repeat Sequence	Parental Expansion Bias	Clinical Phenotype
Fragile X Syndrome	CGG	Maternal	Intellectual impairment, large ears, macroorchidism.
Huntington Disease	CAG	Paternal	Loss of motor control, dementia, chorea.
Myotonic Dystrophy	CTG	Maternal (for congenital form)	Muscle loss, cardiac arrhythmia, cataracts.
Friedreich Ataxia	GAA	Inherited from both (Autosomal Recessive)	Progressive limb ataxia, hypertrophic cardiomyopathy.

Epigenetic process where specific genes are expressed in a parent-of-origin-specific manner.
One allele is silenced, typically via DNA methylation, while the other remains active.
Reversibility: Imprints are erased and reset during gametogenesis in each generation to match the individual’s sex.
Cluster Arrangement: Imprinted genes often occur in clusters regulated by an Imprinting Control Center.

Condition	Genetic Defect	Clinical Phenotype
Prader-Willi Syndrome	Loss of paternal expression at 15q11-13	Neonatal hypotonia, hyperphagia, obesity.
Angelman Syndrome	Loss of maternal expression at 15q11-13	Seizures, severe intellectual disability, inappropriate laughter.
Russell-Silver Syndrome	Loss of paternal IGF2	Severe intrauterine growth restriction, body asymmetry.

Occurs when an individual inherits both copies of a chromosome from one parent and none from the other.
Trisomy Rescue: A trisomic zygote loses one extra chromosome to survive, leaving two from the same parent.
Gametic Complementation: Fusion of a disomic gamete with a nullisomic gamete.
Clinical Significance: Causes imprinting disorders or autosomal recessive disorders if the single parent is a carrier and the child inherits two identical copies (Uniparental Isodisomy).

Presence of two or more genetically distinct cell lines in one individual, derived from a single zygote.
Somatic Mosaicism: Occurs after fertilization; early development affects many tissues, while late occurrence causes localized disease (e.g., McCune-Albright Syndrome).
Germline Mosaicism: Mutation is restricted to gonadal precursor cells; parent is phenotypically normal but carries a transmission risk to offspring.

Phenotype is determined by the additive effect of mutations in two or more different genes, rather than a single locus.
Clinical Examples: Retinitis Pigmentosa (requires mutations in both ROM1 and PRPH2) and Bardet-Biedl Syndrome (triallelic inheritance across two loci).