Patterns of Inheritance -Mendelian – Single Gene Disorders
1) AUTOSOMAL DOMINANT
Incomplete Dominance: Phenotype is intermediate between two dominant allelels
2) AUTOSOMAL RECESSIVE
Pseudo-Autosomal Dominant: Recessive condition present in 2 or more generations. Due to Affected aa mating with Aa
heterozygote carrier.
Results in ½ affected and ½ carriers
Due to:
High carrier frequency of disorder in population
Higher incidence of consangunuity in population
Increased carrier frequency because of small population
3) X-LINKED DOMINANT
4) X-LINKED RECESSIVE
5) Y-LINKED INHERITANCE
MOLECULAR BASIS FOR AUTOSOMAL DOMINANT DISORDERS
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Haplo-insufficiency: Loss-of-function mutations in which half normal levels (50%) of the gene product result in phenotypic
effects. Reduced but normal protein levels (50%) are not sufficient to carry out the normal functions of that protein
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o
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Examples include cell membrane receptors (familial hypercholesterolemia)
Acute intermittent porphyria (AIP is one of the only autosomal dominant enzyme deficiencies, heme can’t be
produced fast enough)
Osteogenesis imperfecta (OI) type I (half the amount of collagen causes brittle bones. OI type I
will be discussed more in the MSK module)
Dominant-negative mutations: A mutant gene product interferes with the function of the normal gene product; In some
cases, the assembly of the multimeric protein is affected (hindered) by the presence of the mutant protein
o Examples include collagenopathies such as severe OI Type II, III, or IV;
o Marfan syndrome (defect in fibrillin-1)
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Gain-of-function mutations: Increased levels of gene expression or gene activity OR the development of a new function of
the gene - “attainment of a novel function”
- Examples include Huntington disease and achondroplasia
- Most oncogene mutations are gain of function mutations
MOLECULAR BASIS FOR AUTOSOMAL RECESSIVE DISORDERS
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Loss-of function mutations: result in either reduced activity (hypomorph) or complete loss of gene product (null allele or
amorph); examples include enzyme deficiencies
The protein produced from the normal allele (50%) in a carrier is generally sufficient to carry out the normal functions of
the gene in the carrier state.
- The carrier usually does not have phenotypic manifestations
- A heterozygous carrier has 50% of the normal level of enzyme activity
Codominance:
Incomplete Dominance: Phenotype is intermediate between two dominant allelels
Manifesting Heterozygote: X-linked- when female has symptoms - X-lyonization -X-Inactivation -Mosaic
Variable Expression: individuals who have inherited the same mutant allele, some individuals are severely affected and others are
mildly affected. Can be due to random chance ; other genetic factors (modifier loci) or sex influence; environmental exposure.
Examples:
Hemochromatosis
Xeroderma pigmentosum
Incomplete/Reduced Penetrance: Non-penetrance- has mutation but does not manifest phenotype. A disorder is said to be fully
penetrant, if all the people carrying the
mutation, express the phenotypic manifestations of the disorder
Pleiotropy: disease causing mutation affects more than one organ system
Locus Heterogeneity: Mutations at different loci that cause the same disease phenotype. Mutations of different genes cause the
same disease phenotype.
Allelic Heterogeneity:
Compound Heterozygote-(Allelic Heterogeneity):
New Mutation- Denovo Mutation:
Germline Mosaicism:
Delayed Age of Onset:
Heteroplasmy:Variable Expressivity Mitochondrial Syndromes
Digenic Disorders: Two Genes
Imprinting - Parent of Origin:
Prader Willi Syndrome
Angelman Syndrome
Triple Repeat Disorders - Unstable Anticipation: Degree of severity and age of onset increases with increase number of repeats - Triple Repeat Disorders
Mosaicism:
AD
Familial Hypercholesteremia - Xanthomas
Huntington Disease
Myotonic Dystrophy
Marfa Syndrome
Osteogenesis Imperfecta
Achondroplasia
Neurofibromatosis
Acute Intermittent Porphyria
Breast Cancer
AR
Cystic Fibrosis
Alpha Anti trypsin
Tay Sachs
Sickle Cell
SCID
Phenylketonuria
Hemochromatosis
Galactosemia
Homocystenuria
Xeroderma Pigmentosa
X-Lyonization - Skewed X- Inactivation
X-linked - Recessive
DB HeXLe
Duchene Muscular Dystrophy
Becker Muscular Dystrophy
Hemophelia A
X-SCID
LESH-Nyhan Syndrome
X-Linked Dominant -RIVD
Rhett Syndrome
Incontinentia Pigmenti
Vitamin D Resistant Rickets
Mitochondrial - Variable Heteroplasmy
Imprinting-Epigenetic - Parent of Origin
Prader
Angelman