Summary
Fundamental concepts of genetics
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Gene: a DNA segment with a nucleotide sequence encoding an RNA product that is either directly functional or encodes a protein
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Locus: location of a gene or a particular DNA sequence (e.g., promoter) on a chromosome
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Allele: one of the variant forms a gene can have in a population (from a particular locus)
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Wild-type allele: the allele that encodes for the most common phenotype in a population
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Mutant allele: any allele that does not code for the most common phenotype in a population
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Multiple alleles: the occurrence of more than two different alleles in a population (e.g., the ABO blood group system) [1]
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Allele frequency: the prevalence of a particular allele at a genetic locus within a population
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Genetic polymorphism: a gene with more than one allele occupying the same locus of that gene [2]
Chromosomes
The mitotic spindle attaches to the kinetochores, not the centromeres.


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Genotype: the chemical composition of an organism's DNA, contributing to that organism's phenotype
- The term is often used to describe a combination of alleles at one or more specific loci.
- Based on the genotype, the following states (zygosities) can be distinguished:
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Phenotype: the observable traits of an organism
- Determined by a combination of the genotype and environmental factors
- Includes an individual's physical traits (e.g., eye or hair color) and physiological characteristics (e.g., atopy)
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Dominance: the characteristic of an allele to mask or override the phenotypical effects of the allele on the other corresponding copy of the chromosome in heterozygous individuals
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Incomplete dominance: a type of dominance in which the dominant allele fails to completely override the phenotypic expression of the recessive allele, thus producing a new intermediate phenotypic trait (e.g., sickle cell trait)
Compared to dominant alleles, that have the same phenotypical expression regardless of the zygosity, codominant alleles express two completely different phenotypes in homozygous and heterozygous individuals.
Types of genetic penetrance and expressivity |
| Definition | Example |
Penetrance |
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Complete penetrance |
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Incomplete penetrance |
- Phenotypical expression of a particular gene or genomic region is not observed in all individuals
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Variable expressivity |
- The variable phenotypic expression of a given genotype, which implies that a genetic disorder can manifest with different signs, symptoms, and degrees of severity in different individuals
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Pleiotropy |
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A phenomenon in which one gene influences the development of multiple phenotypical traits
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Compound heterozygosity |
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Anticipation (genetics) |
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A phenomenon in which disease onset occurs earlier and/or the disease manifestation is more severe in offspring than in parents.
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Allelic heterogeneity |
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A phenomenon in which different mutations of the same allele result in the same phenotype
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Locus heterogeneity |
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Linkage disequilibrium |
- The property of particular alleles at two linked loci to be expressed more or less often than would be expected in the general population
- May vary in different populations
- May occur in settings where allelic loci are within close proximity to each other on a chromosome, therefore decreasing the probability of DNA recombination
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individuals from the population who are not blood-related (i.e., in which a random association of the alleles would be expected).
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Types of mutations
Overview
Mutations according to the affected cell population
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Germline mutation (gametic mutation): a mutation of germline cells that can be passed on to offspring
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Somatic mutation (acquired mutation): a mutation of somatic cells that typically affects only one allele of a gene
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Mosaicism: the presence of two or more populations of cells within an organism, each with a different genetic composition
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Chromosomal mosaicism
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Gonadal mosaicism
- The selective presence of a mutation in individual germ cells
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Caused by a mutation in the DNA of a primordial germ cell during mitosis
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Clinical application: Suspect this type of mosaicism if no blood relatives of the affected individual have the condition.
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Somatic mosaicism
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Chimerism: The presence of two genetically distinct cell lines that arise from two different zygotes that fused into one single embryo.
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Chromosomal instability: a chromosomal state characterized by increased susceptibility to mutations
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Loss of heterozygosity (LoH): loss of a normal allele of a gene with the exclusive expression of the abnormal allele
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Two-hit hypothesis: states that two mutations (i.e., “hits”) must occur in the cellular DNA of tumor suppressor genes to induce oncogenesis

Terminology of chromosomal abnormalities
Most common terms of chromosomal abnormalities |
Abbreviation | Term | Example | Interpretation |
del | Deletion | 46,XY, del(p5) | Deletion of the short arm of chromosome 5 in a male individual (e.g., cri-du-chat syndrome) |
dup | Duplication | 46,XX, dup(q3) | Duplication of the long arm of chromosome 3 in a female individual |
inv | Inversion | 46,XY, inv(3)(p23q27) | Pericentric inversion of the chromosome 3 segment with breakpoints at position 23 on the short arm and 27 on the long arm in a male individual |
t | Translocation | 46,XY, t(14;18)(q32;q21) | Translocation between position 32 on chromosome 14 and position 21 on chromosome 18 in a male individual (e.g., follicular lymphoma) |
rob | Robertsonian translocation | 46,XX, rob(14;21) |
Chromosomal translocation with fusion of the long arms of the acrocentric chromosomes 14 and 21 in a female individual. The short arms of the two chromosomes involved are lost. |
/ | Mosaicism | 45,X/46, XX | Presence of a normal cell population and one with X monosomy in a female individual (e.g., Turner syndrome) |
Chromosomal aberrations
Introduction
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Numerical chromosomal aberrations: the presence of an abnormal number of copies of a single chromosome, which is usually caused by the failure of homologous chromosomes to separate during mitosis or meiosis, also known as nondisjunction
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Structural chromosomal aberrations: an alteration of a chromosome structure with an identical number of chromosomes



All translocations are classified as structural chromosomal aberrations.
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Balanced translocation: a type of translocation in which no genetic material is lost or duplicated, thus expressing a normal phenotype
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Unbalanced translocation
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Robertsonian translocation: a chromosomal translocation that involves the fusion of the long arms of two acrocentric chromosomes at the centromere with resulting loss of the short arms of the involved chromosomes
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One of the most frequent translocations [4]
- May be balanced or unbalanced
- Example: Unbalanced 46,XY, rob(14;21) is a possible mechanistic cause of Down syndrome.
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Balanced Robertsonian translocation: translocation of the long arm of chromosome 21 to the long arm of chromosome 14 with the elimination of the respective short arms
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Unbalanced Robertsonian translocation: clinical features of trisomy 21 caused by inheritance of a translocation chromosome and a normal chromosome
- Although there are only 46 chromosomes present, three copies of genetic material from chromosome 21 exist
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Results in the karyotypes 46,XX,+21,t(14;21) and 46,XY,+21,t(14;21)
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Reciprocal translocation: a translocation between nonhomologous chromosomes (e.g., Philadelphia translocation)

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Uniparental disomy: a chromosomal abnormality in which offspring receive two copies of one chromosome from one parent and no copies from the other parent
Uniparental disomy cannot be detected via karyotyping because the number of chromosomes is normal and there is no loss of genetic material.
HeterodIsomy: meiosis I error; IsodIsomy: meiosis II error
12–345: the chromosomes most frequently involved in Robertsonian translocations are chromosomes 21, 22, 13, 14, and 15.

Gene mutations
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Point mutation: alteration of a single DNA base pair
- Genetic transition: the replacement of one purine with another purine (e.g., G to A), or the replacement of a pyrimidine with another pyrimidine (e.g., T to C)
- Genetic transversion: the replacement of a purine with a pyrimidine (e.g., A to C, A to T, G to C, G to T) and vice versa
- Deletion: loss of one or more base pairs
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Insertion: addition of one or more base pairs
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Substitution: one or more base pairs are replaced by different base pairs
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Trinucleotide repeat expansion
- Increased repetition of base triplets that leads to faulty protein synthesis or folding
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Characterized by genetic anticipation
Trinucleotide repeat expansion diseases |
| Mode of inheritance | Affected gene | Chromosome | Trinucleotide repeat | Typical features |
Huntington disease | Autosomal dominant | HTT | 4 | CAG | Chorea, akinesia, cognitive decline, behavioral changes |
Fragile X syndrome | X-linked recessive | FMR1 | X | CGG | Large protruding chin, large genitalia (testes), hypermobile joints, mitral valve prolapse |
Myotonic dystrophy | Autosomal dominant | DMPK | 19 | CTG | Cataracts, premature hair loss in men, myotonia, arrhythmia, gonadal atrophy (men), ovarian insufficiency (women) |
Friedreich ataxia | Autosomal recessive | FXN | 4 | GAA | Ataxic gait, dysarthria, kyphoscoliosis, hypertrophic cardiomyopathy |
“Friedrich gave the fragile hunter my tonic”: Friedreich ataxia, fragile X syndrome, Huntington disease, and myotonic dystrophy are examples of trinucleotide expansion disorders.
In Huntington disease, a CAG trinucleotide repeat leads to Chorea, Akinesia, and Grotesque behavior.
In fragile X syndrome, a CGG trinucleotide repeat leads to an X-tra large Chin and Giant Genitalia.
In myotonic dystrophy, a CTG trinucleotide repeat leads to Cataracts, Thinning hair (premature hair loss), and Gonadal atrophy.
In Friedreich ataxia, a GAA trinucleotide expansion leads to an ataxic GAAit.
Grade of mutational severity in ascending order: silent < missense < nonsense < frameshift
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Frameshift mutation
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Nonsense mutation
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Missense mutation
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Silent mutation
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In-frame deletion or insertion: deletion or insertion of three, six, nine, or more base pairs (always in triplets) without a shift in the reading frame, but with deletion or insertion of one, two, three, or more amino acids in the protein during translation
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Loss-of-function mutation: a mutation resulting in the expression of the gene product with decreased or absent function
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Gain-of-function mutation: a mutation that leads to either the expression of the larger amount of the gene product or increased function of the expressed gene product
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Splice mutation: an alteration (especially point mutations) in the nucleotide sequence required for splicing (e.g., the exon-intron border or at the junction)
- Results in defective mRNA (e.g., due to a retained intron) → shortened proteins that are either defective or exert an altered function
- Examples include:
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Dominant-negative mutation
- A gene mutation that produces a nonfunctional protein that exerts a dominant effect
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This nonfunctional protein impairs the function of the normal protein encoded by the wild-type allele in heterozygous individuals (e.g., mutant, nonfunctional p53, binds DNA and prevents the attachment of the functional p53 protein) [6]
Compared to missense or silent mutations, nonsense and frameshift mutations lead to fundamental structural changes of the coded proteins. Consequently, these mutations result in more severe disease manifestations.
STOP the NONSENSE: NONSENSE mutations create early STOP codons in the RNA.

Examples of genetic disorders by chromosome
Chromosome | Disorders |
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11 |
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21 |
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22 |
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X |
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Epigenetic regulation of gene expression
Overview
Main mechanisms of epigenetic regulation
DNA methylation [7]
Epigenetic regulation mechanisms: Acetylation Activates DNA; Methylation Mutes DNA.

Histone modification [13][14]
Regulatory RNA [15]
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Definition
- A diverse class of RNA molecules that play a role in the regulation of chromatin structure and gene expression
- These RNA molecules are typically noncoding and do not produce translated protein products.
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Gene regulation occurs via RNA-interference (RNAi) pathways (i.e., molecular pathways that use PIWI and Argonaute proteins to influence histone and DNA modifications with subsequent transcriptional inhibition).
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Types of regulatory RNAs: See “RNA: Structure and characteristics” in “Nucleotides, DNA, and RNA.”
- Long noncoding RNAs (lncRNA)
- Small interfering RNAs (siRNA)
- Micro RNAs (miRNA)
- PIWI-interacting RNA (piRNA)
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Examples [16]
Examples of processes regulated by epigenetic mechanisms
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Definition
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Mechanism [17]
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Manifestation of X-linked disorders in female individuals
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Female individuals will only express alleles or genes located on the active X-chromosome.
- Therefore, the extent to which heterozygous female carriers of X-linked recessive disorders express phenotypic characteristics of the disease depends on the genetic inactivation pattern of the mutant versus the normal X-chromosome.
- This leads to phenotypic variation among heterozygous female carriers of X-linked disorders (e.g., one female carrier of an X-linked disorder may be completely asymptomatic, while another has severe manifestations of the involved disease).
- In female individuals who are homozygous for an X-linked recessive disorder, it does not matter which chromosome is inactivated

Genomic imprinting [18]
Pedigree analysis
Overview
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Definition: the study of inherited traits or disorders and their phenotypic variability over several generations in a group of blood-related individuals by way of a pedigree chart, which depicts that group's genetic history in a family tree
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Elements
- Circles: female individuals
- Squares: male individuals
- Lines between circles and squares: familial relationship
- Roman numerals: generations
- Arabic numbers: children of a generation in order of birth
- Affected family members and carriers (i.e., heterozygous individuals who have the allele but are not phenotypically affected) are represented by shaded symbols.
A basic methodological approach to pedigree analysis
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Question 1: Does every affected family member have an affected parent?
- Yes: dominant inheritance of the trait
- No: recessive inheritance of the trait
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Question 2: Are the majority of affected family members male?
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Yes: most likely X-linked recessive inheritance
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No: Proceed to the following questions and subsequent answers.
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Question 2a: Do all affected male family members have an affected mother?
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Question 2b: Do all affected male family members have unaffected sons?
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Question 2c: Do all affected male family members have affected daughters?
- If Questions 2a, 2b, and 2c have all been answered in the affirmative, the disease most likely follows an X-linked dominant pattern of inheritance.
- If Question 1 has been answered in the affirmative and either Question 2a, 2b, or 2c have been answered in the negative, the disorder is most likely autosomal dominant.
- If Question 2 and Questions 2a, 2b, and 2c have all been answered in the negative, the disorder is most likely autosomal recessive.



Autosomal dominant inheritance
Overview
Examples of AD inheritance patterns
AD inheritance pattern in homozygous parents |
| Homozygous parent (affected) |
N | N |
Homozygous parent (unaffected) | n | Nn (affected) | Nn (affected) |
n | Nn (affected) | Nn (affected) |
An autosomal dominant disease with complete penetrance will always manifest with clinical features in every generation.
Examples of AD disorders
Autosomal recessive inheritance
Overview
Examples of AR inheritance patterns
- Homozygous parents: no children will be affected, but all will be carriers
AR inheritance pattern in homozygous parents |
| Homozygous parent (unaffected) |
N | N |
Homozygous parent (affected) | n | Nn (carrier) | Nn (carrier) |
n | Nn (carrier) | Nn (carrier) |
- One heterozygous and one homozygous parent: All children inherit the allele that causes the trait or disorder, but only 50% will express the trait while other 50% will be carriers.
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Heterozygous parents
- Half of the children will be carriers, 25% will express the trait, and 25% will not express the trait.
- Healthy individuals with an affected sibling (nn) have a two-thirds-probability of being a carrier (Nn, Nn, or NN).

Examples of AR disorders
X-linked recessive inheritance
Overview
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Definition: a mode of inheritance that requires two copies of an allele on the X chromosome, one from the mother and one from the father, for the phenotypical expression of a trait or disorder in offspring
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X-linked recessive (XR) inheritance leads to the expression of the phenotype in all male children who inherit the mutated allele.
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Female individuals are more frequently carriers (unaffected) of X-linked inherited disorders than male individuals.
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Individuals with Turner syndrome only have one X chromosome and are, therefore, more susceptible to X-linked recessive disorders
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Male-to-male inheritance is impossible.
- Male individuals tend to develop a more severe form of the XR disease.
- This type of inheritance frequently skips generations.
Examples of XR inheritance patterns
XR inheritance pattern in heterozygous (carrier) mother and hemizygous (unaffected) father |
| Heterozygous mother (carrier) |
x | X |
Hemizygous father (unaffected) | X | Xx (daughter, carrier) | XX (daughter, unaffected) |
Y | xY (son, affected) | XY (son, unaffected) |
XR inheritance pattern in heterozygous (carrier) mother and hemizygous (affected) father |
| Hemizygous father (affected) |
x | Y |
Heterozygous mother (carrier) | X | Xx (daughter, carrier) | XY (son, unaffected) |
x | xx (daughter, affected) | xY (son, affected) |
XR inheritance pattern in homozygous (unaffected) mother and hemizygous (affected) father |
| Hemizygous father (affected) |
x | Y |
Homozygous mother (unaffected) | X | Xx (daughter, carrier) | XY (son, unaffected) |
X | Xx (daughter, carrier) | XY (son, unaffected) |
- Homozygous (affected) mother and hemizygous (affected) father: If both parents have the trait/disease then all children will invariably be affected.
XR inheritance pattern in homozygous (affected) mother and hemizygous (affected) father |
| Hemizygous father (affected) |
x | Y |
Homozygous mother (affected) | x | xx (daughter, affected) | xY (son, affected) |
x | xx (daughter, affected) | xY (son, affected) |

Examples of XR disorders
X-linked dominant inheritance
Overview
- Definition: a mode of inheritance that only requires one copy of a mutated allele on the X chromosome, from either the mother or father, for the phenotypical expression of the trait or disorder in offspring
- In X-linked dominant (XD) inheritance, male and female individuals have an equal probability of inheriting the trait or disorder.
- Because female individuals have two X chromosomes, the inheritance of an X-linked dominant disorder typically manifests in a less severe form than in male individuals.
Examples of XD inheritance patterns
XD inheritance pattern in heterozygous mother and hemizygous (unaffected) father |
| Heterozygous mother (affected) |
X | x |
Hemizygous father (unaffected) | x | Xx (daughter, affected) | xx (daughter, unaffected) |
Y | XY (son, affected) | xY (son, unaffected) |
- Homozygous mother and hemizygous (unaffected) father: All the children will inherit the trait/disease.
XD inheritance pattern in homozygous mother and hemizygous (unaffected) father |
| Homozygous mother (affected) |
X | X |
Hemizygous father (unaffected) | x | Xx (daughter, affected) | Xx (daughter, affected) |
Y | XY (son, affected) | XY (son, affected) |
XD inheritance pattern in heterozygous mother and hemizygous (affected) father |
| Hemizygous father (affected) |
X | Y |
Heterozygous mother (affected) | X | XX (daughter, affected) | XY (son, affected) |
x | Xx (daughter, affected) | xY (son, unaffected) |
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Homozygous (unaffected) mother and hemizygous (affected) father
- All daughters will be affected.
- Sons are invariably unaffected.
XD inheritance pattern in homozygous (unaffected) mother and hemizygous (affected) father |
| Hemizygous father (affected) |
X | Y |
Homozygous mother (unaffected) | x | Xx (daughter, affected) | xY (son, unaffected) |
x | Xx (daughter, affected) | xY (son, unaffected) |

Examples of XD disorders
Other types of inheritance
Mitochondrial inheritance
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Definition: a mode of inheritance that involves the transmission of mutated alleles in the mitochondrial genome through maternal lineage only
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Features
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Diseases caused by mutations in mitochondrial DNA are only passed down to offspring by the mother.
- The inheritance pattern is hypothesized to occur for a number of reasons, including: [19]
- Each mitochondrion has multiple copies of DNA (mtDNA), and each cell has many mitochondria.
- Typically without mutations, all copies of mtDNA in each mitochondrion will be identical (i.e., homoplasmy).
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Therefore, mutations cause a state of heteroplasmy.
- The presence of affected and unaffected mtDNA within different cells leads to variable disease expression.
- Severity often correlates with the proportion of mutated mtDNA copies.
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Examples

Polygenic inheritance
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Definition: a trait controlled by the interaction of two or more genes at different loci, without interaction with the environment
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Examples
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Skin pigmentation eye color, and most anthropometric traits (e.g., height, weight)
- Polygenic inheritance is involved in the development of many otherwise unrelated disorders (e.g., type 1 diabetes, type 2 diabetes, hypertension, androgenic alopecia, atopy, psoriasis, schizophrenia, Alzheimer disease)
Heterozygote frequency
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Definition
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The proportion of heterozygote carriers of an allele that causes a trait/disorder in the population
- Used to estimate a child's risk of a recessive inherited disorder if the genotype of the parents is unknown
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Equation: The heterozygote frequency is calculated by using the Hardy-Weinberg law, a principle that states that genetic variation in a population remains constant under a set of idealized assumptions (including random mating and no migration, mutation, or selection).
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Hardy-Weinberg equilibrium: (p+q)2 = p2 + 2pq + q2 = 1 (100%).
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The Hardy-Weinberg law is based on the biostatistically ideal assumptions that:
- There is no natural selection of alleles in the population.
- No mutations occur in the allele under investigation.
- There is random mating inside the population.
- The population is large enough to rule out the effects of genetic drift.
- There is no migration both outside and inside the population.
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Example: cystic fibrosis with an incidence of ∼ 1:2,500
- Calculate 2pq: 2pq = 2×1×1/50 = 1/25 (4%) heterozygote frequency
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Calculate p: If (p + q)2 = 1 then p + q = 1 and p = 1 – q = 1 – 1/50 = 0.98 (98%) ≈ 1
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Calculate q: If q2 = 1/2,500 then q = 1/50 = 0.02 (2%)
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Since cystic fibrosis is a recessive disorder, only homozygote carriers develop the disease. The incidence corresponds to the homozygote frequency q2.
| A (p) | a (q) |
A (p) | AA (p2) | Aa (pq) |
a (q) | Aa (pq) | aa (q2) |
Multifactorial inheritance disorders (MID)
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Definition: disorders that result from a combination of mutations in multiple genes and environmental factors (e.g., type 2 diabetes mellitus, cleft palate, neural tube defects, schizophrenia, coronary artery disease)
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Features
- Commonly manifest with the Carter effect [20]
- Individuals of the less commonly affected sex are more likely to pass on the disorder to their children if they develop the disease.
- It is hypothesized the group less commonly affected possesses a higher number of susceptibility genes and the trait/disorder will, therefore, manifest less frequently, requiring more genetic loci to be affected.
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However, the numerical increase in susceptibility genes leads to an increased probability of passing on mutated alleles to offspring.
- Population groups with a certain heritage are more commonly affected compared to the population at large (e.g., Hispanic, Ashkenazi Jewish, West African).
- One gender is more frequently affected.
- Isolated occurrence is possible, but familial clustering is frequent.
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Index case: the first person of a family to develop the trait/disorder in question
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Threshold effect: Effect observed in some MIDs, in which the disorder only develops when genetic predispositions and external factors combine to reach a certain threshold value.
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Gene-environment interaction: genetic predisposition affects susceptibility to the effects of environmental factors (e.g., individuals with a family history of type II diabetes may never develop the disease if they maintain a healthy lifestyle).