Basics of human genetics

Fundamental concepts of genetics

Genes
 Gene: a DNA segment with a nucleotide sequence encoding an RNA product that is either directly
functional or encodes a protein
 Locus: location of a gene or a particular DNA sequence (e.g., promoter) on a chromosome
 Allele: one of the variant forms a gene can have in a population (from a particular locus)
 Allele frequency: the prevalence of a particular allele at a genetic locus within a population
 Genetic polymorphism: a gene with more than one allele occupying the same locus of that gene

Chromosomes
 Chromosome: a structure found in the nucleus of eukaryotic cells that contains nucleic acids and
associated proteins (e.g., nucleosomes)
o Each human cell contains 23 pairs of homologous chromosomes (corresponding in structure
and genetic information, i.e., 23 chromosomes are inherited from each parent).
 Allosome (sex chromosome)
o Human cells contain one pair of allosomes: XX in female individuals and XY in male individuals
 Autosome
o Human cells contain 22 pairs of homologous autosomes.
 Ploidy: the number of chromosome sets present in a cell
o Haploid cell: contains one single unpaired set of chromosomes (n = 23)
o Diploid cell: carries a complete set of paired chromosomes (2n = 46)
 Chromatid: one of the two identical strands of a replicated chromosome
 Sister chromatids: two identical chromatids joined at the centromere (i.e., the duplicated chromosome)
 Centromere: a condensed region of chromosomes where sister chromatids join
o Divides the chromatids into a short p arm and a long q arm
 Kinetochore: a protein complex found at the centromere that allows for the attachment of mitotic
spindle microtubules during mitosis
The mitotic sp

The mitotic spindle attaches to the kinetochores, not the centromeres.

Chromosome morphology

Chromosomal DNA is most condensed during metaphase in mitosis. As a result, the sister chromatids, which are
joined to the centromere, become visible under the light microscope. Chromosomes have a short (p) and a long (q)
arm. The centromeres and the telomeres are composed of specific DNA sequences. Kinetochores are special protein
structures, which assemble on the centromere. Microtubules attach to kinetochores during anaphase and pull the
sister chromatids to opposite poles of the cell. Telomeres are repetitive DNA sequences at the ends of the
chromosomes that protect from cellular degeneration.
 Metaphase chromosomes are classified based on their position on the centromeres:

(A) Metacentric: The p and q arms are of approximately identical length.

(B) Submetacentric: The p arm is short and the q arm is long.
(C) Acrocentric: The p arm is much shorter than the q arm.

Satellites can be found on the short arm of acrocentric chromosomes and have a button-like shape.

Genotype and phenotype
 Genotype: the chemical composition of an organism's DNA, contributing to that organism's phenotype
o Based on the genotype, the following states (zygosities) can be distinguished:
 Homozygote: The two homologous chromosomes contain identical alleles at a
given locus.
 Heterozygote: The two homologous chromosomes contain different alleles at a
given locus.
 Hemizygote: having only one copy of a chromosome pair (e.g., genes located on a male
individual's X or Y chromosomes).
 Phenotype: the observable traits of an organism
o Determined by a combination of the genotype and environmental factors
 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
o Dominant allele: the allele which is phenotypically apparent in heterozygous individuals
(overrides the phenotypical effects of the corresponding allele in heterozygous individuals)
o Recessive allele: an allele whose effects are overridden by the corresponding dominant
allele in heterozygous individuals
o Codominance: a state in which both alleles are fully expressed and contribute to
the heterozygote phenotype
 Examples
 ABO blood group system
 Human leukocyte antigens (HLA)
 α1-antitrypsin deficiency
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.

Genetic penetrance and expressivity
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 Types of genetic penetrance and expressivity

Definition Example

 The proportion of individuals in which a

specific genotype manifests with a specific phenotype

Penetrance
 Probability of expressing a specific phenotype =  -

(probability of inheriting the genotype) x

(the penetrance of that genotype)

 All individuals with a gain-of-

function mutation in the FGFR3 gene will
Complete  Phenotypical expression of a trait in all carriers of a develop achondroplasia.
penetrance
specific gene  All individuals with

an NF1 gene mutation will

develop neurofibromatosis type 1.

 Approx. half of patients

Incomplete  Phenotypical expression of a particular gene or
penetrance with BRCA1 gene mutations develop breast
genomic region is not observed in all individuals
cancer  [3]

 The variable phenotypic expression of a
Variable given genotype, which implies that a genetic disorder can  Marfan syndrome, neurofibromatosis
expressivity
manifest with different signs, symptoms, and degrees of type 1

severity in different individuals

 PAH gene mutations result in multiple

clinical features of phenylketonuria, including

 A phenomenon in which one gene influences the psychomotor impairment, musty body odor,

Pleiotropy
development of multiple phenotypical traits and light skin pigmentation.

 Other examples: Marfan

syndrome, sickle cell disease

Compound  A phenomenon in which both alleles of a gene at a

heterozygosity  Hemochromatosis
particular locus on homologous chromosomes are
 Types of genetic penetrance and expressivity

Definition Example

mutated.

 Compound heterozygosity explains the occurrence

of recessive diseases in heterozygous individuals.

 A phenomenon in which disease onset occurs

Anticipation  Trinucleotide repeat diseases
(genetics) earlier and/or the disease manifestation is more severe in
(e.g., Huntington disease, myotonic dystrophy)
offspring than in parents.

Allelic  A phenomenon in which different mutations of the  G6PD deficiency, familial

heterogeneity
same allele result in the same phenotype hypercholesterolemia, β-thalassemia

Locus  A phenomenon in which gene mutations at

heterogeneity  Osteogenesis imperfecta, albinism
different loci produce the same phenotype

 The property of particular alleles at two

linked loci to be expressed more or less often than would

be expected in the general population

 individuals from the population who are
Linkage  May vary in different populations
disequilibrium not blood-related (i.e., in which a random
 May occur in settings where allelic loci are within
association of the alleles would be expected).
close proximity to each other on a chromosome,

therefore decreasing

the probability of DNA recombination

Mutations according to the affected cell population

 Somatic mutation (acquired mutation): a mutation of somatic cells that typically affects only
one allele of a gene
o Does not occur in germline cells and, therefore, cannot be passed on to offspring.
o A common mechanism of carcinogenesis
 Mosaicism: the presence of two or more populations of cells within an organism, each with a different
genetic composition
o Chromosomal mosaicism
  The presence of cell populations with different karyotypes in one organism
 Example: sex chromosome mosaicism is frequently seen in Turner syndrome
o Gonadal mosaicism
 The selective presence of a mutation in individual germ cells
 Caused by a mutation in the DNA of a primordial germ cell during mitosis
 Clinical application: Suspect this type of mosaicism if no blood relatives of the affected
individual have the condition.
o Somatic mosaicism
 The selective presence of a mutation in individual somatic cells
 Caused by a mutation during mitosis after fertilization
 Usually, multiple tissues or organs are affected
 Example: McCune-Albright syndrome
 Chimerism: The presence of two genetically distinct cell lines that arise from two different zygotes that
fused into one single embryo.
 Loss of heterozygosity (LoH): loss of a normal allele of a gene with the exclusive expression of the
abnormal allele
o The occurrence of LoH in tumor suppressor genes leads to malignant transformation of the cell.
o Example: Lynch syndrome
 Two-hit hypothesis: states that two mutations (i.e., “hits”) must occur in the cellular DNA of tumor
suppressor genes to induce oncogenesis
o Does not apply to oncogenes
o Examples: retinoblastoma, Li-Fraumeni syndrome, Lynch syndrome, familial adenomatous
polyposis

Chromosomal aberrations
Introduction
 Numerical abnormalities can be visualized on a karyogram, while structural chromosomal defects can
be detected using fluorescence in situ hybridization (FISH).

Subtypes of  chromosomal aberrations

 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
o Monosomy
 Presence of a single copy of a chromosome
 Usually results in embryonic death due to high probability of recessive trait expression of
the respective chromosome
o Hyperploidy: the presence of extra chromosomes within a cell
 Trisomy: the presence of a triplicate instead of a duplicate set
of chromosomes (e.g., trisomy 21, trisomy 13, trisomy 18)
 Structural chromosomal aberrations: an alteration of a chromosome structure with an identical
number of chromosomes
o Deletion is definined as a loss of a chromosome segment. Examples include:
 Cri-du-chat syndrome, which is characterized by 46,XX, del(5)
o Duplication: duplication of a chromosome segment
 Meiotic nondisjunction
 A numeric chromosome aberration, i.e., a differing number of chromosomes, can occur through an incorrect
distribution of chromosomes during meiosis. The homologous chromosome pairs usually separate during
the reduction division (meiosis I), while the homologous sister chromatids do so during the equational
division (meiosis II).
 The occurrence of nondisjunction during one of these two steps leads to the development of aneuploid
gametes, in which the chromosome is either duplicated (24 chromosomes in total) or missing (only 22
chromosomes in total). This results in trisomy (e.g., trisomy 21) or monosomy (e.g., Turner syndrome).

Types of  chromosomal translocations

 Balanced translocation: a type of translocation in which no genetic material is lost or duplicated, thus
expressing a normal phenotype
 Unbalanced translocation
o Unbalanced translocations can result in chromosomal imbalance (e.g., Patau syndrome),
multiple malformations, stillbirth, and repeated miscarriages
 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
o One of the most frequent translocations
o Example: Unbalanced 46,XY, rob(14;21) is a possible mechanistic cause of Down syndrome.
o 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
 Karyogram shows a total number of 45 chromosomes
 Results in a normal phenotype
 phenotypically normal parent
 Pregnancies with balanced translocations have an increased risk of miscarriage.
o 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
 karyotypes 46,XX,+21,t(14;21) and 46,XY,+21,t(14;21)

Other  chromosomal aberrations

 Uniparental disomy: a chromosomal abnormality in which offspring receive two copies of
one chromosome from one parent and no copies from the other parent
 o Heterodisomy: error in meiosis I → two different homologous chromosomes from one parent
passed to offspring
o Isodisomy can have two different causes:
 Error in meiosis II → identical homologous chromosomes from one parent passed to
offspring
 Postzygotic chromosomal duplication leads to duplication of one chromosome of one
pair and subsequent loss of the other
o Usually results in normal phenotype and euploidy in affected individuals
o Should be suspected if an individual presents with an autosomal recessive condition but only
one parent is a carrier
o Examples
 Angelman syndrome (5% of cases)
 Prader-Willi syndrome (25% of cases)
12–345: the chromosomes most frequently involved in Robertsonian translocations are chromosomes 21, 22,
13, 14, and 15.

Gene mutations
Types of  gene mutations
 Point mutation: alteration of a single DNA base pair
o 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)
o 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
 Trinucleotide repeat expansion
o Increased repetition of base triplets that leads to faulty protein synthesis or folding
o Characterized by genetic anticipation

Trinucleotide repeat expansion diseases

Trinucl
Mode of Affected  Chromosom
eotide Typical features
inheritance gene e
repeat

Huntington Autosomal Chorea, akinesia, cognitive decline,

HTT 4 CAG
disease dominant behavioral changes

Large protruding chin, large genitalia

Fragile X X-linked
FMR1 X CGG (testes), hypermobile joints, mitral
syndrome dominant
valve prolapse
 Trinucleotide repeat expansion diseases

Trinucl
Mode of Affected  Chromosom
eotide Typical features
inheritance gene e
repeat

Cataracts, premature hair loss in

Myotonic Autosomal men, myotonia, arrhythmia,

DMPK 19 CTG
dystrophy dominant gonadal atrophy (men), ovarian

insufficiency (women)

Ataxic
Friedreich Autosomal
FXN 9 GAA gait, dysarthria, kyphoscoliosis, hypert
ataxia recessive
rophic cardiomyopathy

Huntington's disease

An autosomal-dominant neurodegenerative movement disorder characterized by chorea (involuntary and

irregular movements of the limbs, neck, head, and/or face), dementia, and psychiatric symptoms. Caused by
mutations in the huntingtin gene that lead to an increased number of CAG trinucleotide repeats.

Fragile X syndrome
Martin-Bell syndrome
Abbreviation: FXS

An X-linked dominant disease caused by trinucleotide repeat expansion in the FMR1 (fragile X mental retardation
1) gene. Causes intellectual disability, delayed language development, long facies, large ears, macroorchidism,
mitral valve prolapse, and hyperactivity.

Myotonic dystrophies
Dystrophic myotonic syndromes, Myotonic muscular dystrophy
Abbreviation: MMD

An autosomal dominant myopathy characterized by myotonia (slow relaxation of muscles after cessation of
contraction) and slowly progressive weakness of muscles in the face and/or limbs. Type 1 myotonic dystrophy
predominantly affects distal muscles, while type 2 myotonic dystrophy affects proximal muscles. Other systemic
manifestations such as cardiomyopathy, cataracts, smooth muscle weakness, and endocrine deficiency may also
be present.

Friedreich ataxia

An autosomal recessive disorder involving trinucleotide repeat expansion that leads to progressive
neurodegeneration. It affects multiple spinal cord tracts, causing muscle weakness and impaired coordination of
all limbs. A staggering gait in childhood is the resulting main symptom. Other features include skeletal
abnormalities, cardiomyopathy, and diabetes.
 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.

Classification of  gene mutations

Grade of mutational severity in ascending order: silent < missense < nonsense < frameshift

 Frameshift mutation
o A shift in the reading frame caused by the insertion or deletion of a number
of nucleotides not divisible by 3 that leads to modified amino acid coding in the gene segments
downstream
o Results in the synthesis of shorter or longer proteins with a modified or absent function
o Examples: Tay-Sachs disease, Duchenne muscular dystrophy
 Nonsense mutation
o The substitution of a nucleotide that produces a stop codon (UAA, UGA, UAG) and leads to
alterations in the splicing process with early termination of translation
o Typically results in nonfunctional proteins
 Missense mutation
o A point mutation resulting in the formation of a triplet that codes for another amino acid
o Considered a conservative missense mutation when the new amino acid is similar in chemical
structure to the original amino acid
o Example: sickle cell disease (glutamate is substituted with valine)
 Silent mutation
o A point mutation that forms a triplet that codes for the same amino acid
o Often involves a base change at the tRNA wobble position (3  position of the codon)
rd

 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
 Splice mutation: an alteration (especially point mutations) in the nucleotide sequence required
for splicing (e.g., the exon-intron border or at the junction)
o Results in defective mRNA (e.g., due to a retained intron) → shortened proteins that are either
defective or exert an altered function
o Examples include:
 Some forms of β-thalassemia
 Gaucher disease
  Marfan syndrome
 Dementia
 Epilepsy
 Dominant-negative mutation
o A gene mutation that produces a nonfunctional protein that exerts a dominant effect
o 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)
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.

Autosomal dominant inheritance

Overview
 usually due to mutations in structural genes
 Every child with one parent who is affected and heterozygous has a 50% probability of inheriting
the allele that causes the trait and, therefore, the associated trait or disorder
 Autosomal dominant disorders are pleiotropic and their expressivity is often variable.
 Knowing about an individual's family history can provide vital information for diagnosis,
since autosomal dominant conditions usually affect multiple generations, regardless of sex.

Examples of AD inheritance patterns

 Homozygous parents: children have a 100% probability of inheriting the allele that causes the
trait/disorder.
 One heterozygous and one homozygous parent: Children have a 50% probability of
inheriting the allele that causes the trait/disorder.
An autosomal dominant disease with complete penetrance will always manifest with clinical features in every
generation.

Examples of AD inheritance patterns

 Homozygous parents: children have a 100% probability of inheriting the allele that causes the
trait/disorder.
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 AD inheritance pattern in homozygous parents

Homozygous parent (affected)

N N

n Nn (affected) Nn (affected)

Homozygous parent (unaffected)

n Nn (affected) Nn (affected)

 One heterozygous and one homozygous parent: Children have a 50% probability of inheriting

the allele that causes the trait/disorder.
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AD inheritance pattern in heterozygous and homozygous parent

Heterozygous parent (affected)

N n

n Nn (affected) nn (unaffected)

Homozygous parent (unaffected)

n Nn (affected) nn (unaffected)

 Heterozygous parents: Children have a 75% probability of inheriting the allele that causes the

trait/disorder.
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AD inheritance pattern in heterozygous parents

Heterozygous parent (affected)

N n

N NN (affected) Nn (affected)

Heterozygous parent (affected)

n Nn (affected) nn (unaffected)
 Ehlers-Danlos syndrome
Abbreviation: EDS

A genetic disorder caused by mutations in the genes controlling the synthesis of collagen. There can be a wide
range of clinical features depending on the specific mutation, but the classical presentation involves
hyperextensible skin, joint hypermobility, and a tendency to bleed.

Familial hypercholesterolemia
Type IIa hyperlipoproteinemia

An autosomal dominant condition associated with mutations in the LDL receptor that lead to elevated LDL levels
with early atherosclerotic complications (cardiovascular disease).

Marfan syndrome
Abbreviation: MFS

An autosomal dominant connective tissue disorder that affects microfibrils and elastin in connective tissue
throughout the body. Caused by fibrillin 1 deficiency due to FBN1 gene mutation. Can result in pathological
manifestations in the cardiovascular system (e.g., mitral valve prolapse), the musculoskeletal system (e.g., joint
hypermobility), and the eyes (e.g., lens subluxation).

von Hippel-Lindau syndrome

Abbreviation: VHL

A disease resulting from the deletion of the VHL gene on chromosome 3, which encodes a tumor suppressor.
Subsequently, activity of hypoxia inducible factor 1a is increased. VHL is associated with hemangioblastomas,
bilateral renal cell carcinoma, pheochromocytoma, and renal/pancreatic cysts.

Autosomal recessive inheritance

Overview
 Autosomal recessive (AR) disorders manifest early in childhood and typically feature more severe
symptoms than autosomal dominant disorders
 Normally seen only in one generation of a pedigree.
 Families arising from consanguineous partnerships have an increased risk for autosomal
recessive diseases.

Examples of AR inheritance patterns

 Homozygous parents: no children will be affected, but all will be carriers
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 AR inheritance pattern in homozygous parents

Homozygous parent (unaffected)

N N

n Nn (carrier) Nn (carrier)

Homozygous parent (affected)

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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AR inheritance pattern in heterozygous and homozygous parent

Heterozygous mother (carrier)

N n

n Nn (carrier) nn (affected)

Homozygous father (affected)

n Nn (carrier) nn (affected)

 Heterozygous parents
o Half of the children will be carriers, 25% will express the trait, and 25% will not express the trait.
o Healthy individuals with an affected sibling (nn) have a two-thirds-probability of being a carrier
(Nn, Nn, or NN).
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AR inheritance pattern in heterozygous parents

Heterozygous parent (carrier)

N n

Heterozygous parent (carrier) N NN (unaffected) Nn (carrier)

 AR inheritance pattern in heterozygous parents

Heterozygous parent (carrier)

N n

n Nn (carrier) nn (affected)

Phenylketonuria
Abbreviation: PKU

A congenital disorder characterized by the accumulation of phenylalanine in the central nervous system. Can be
caused by a defect of phenylalanine hydroxylase (classic PKU) or deficiency in tetrahydrobiopterin (malignant
PKU). Causes psychomotor retardation, seizures, a musty odor, and pale skin/hair (from lack of melanin
production).

Cystic fibrosis
Abbreviation: CF

An autosomal recessive disorder caused by mutation of the cystic fibrosis transmembrane conductance regulator
(CFTR) gene, which leads to defective chloride channels and hyperviscosity of exocrine gland secretions. Can
result in meconium ileus, chronic respiratory infections leading to bronchiectasis, pancreatic insufficiency, and
obstructive azoospermia in males. Associated with congenital bilateral absence of the vas deferens.

X-linked recessive inheritance

Overview
 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
 X-linked recessive (XR) inheritance leads to the expression of the phenotype in all male children who
inherit the mutated allele.
 Female individuals are more frequently carriers (unaffected) of X-linked inherited disorders than male
individuals.
o Female individuals typically require the inheritance of one mutated allele from their father and
one allele from their mother (affected homozygous) to phenotypically express XR disorders.
o However, female individuals may also express XR phenotypes if
the nonaffected X chromosome is inactivated in the majority of cells
 Individuals with Turner syndrome only have one X chromosome and are, therefore, more susceptible
to X-linked recessive disorders
 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

 Heterozygous (carrier) mother and hemizygous (unaffected) father
o Sons have a 50% probability of inheriting the trait or disorder.
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XR inheritance pattern in heterozygous (carrier) mother and hemizygous (unaffected) father

Heterozygous mother (carrier)

x X

X Xx (daughter, carrier) XX (daughter, unaffected)

Hemizygous father (unaffected)

Y xY (son, affected) XY (son, unaffected)

 Heterozygous (carrier) mother and hemizygous (affected) father

o Children have a 50% probability of developing the trait/disorder.
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XR inheritance pattern in heterozygous (carrier) mother and hemizygous (affected) father

Hemizygous father (affected)

x Y

X Xx (daughter, carrier) XY (son, unaffected)

Heterozygous mother (carrier)

x xx (daughter, affected) xY (son, affected)

 Homozygous (unaffected) mother and hemizygous (affected) father

o None of the children will be affected.
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 XR inheritance pattern in homozygous (unaffected) mother and hemizygous (affected) father

Hemizygous father (affected)

x Y

X Xx (daughter, carrier) XY (son, unaffected)

Homozygous mother (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.
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XR inheritance pattern in homozygous (affected) mother and hemizygous (affected) father

Hemizygous father (affected)

x Y

x xx (daughter, affected) xY (son, affected)

Homozygous mother (affected)

x xx (daughter, affected) xY (son, affected)

X-linked recessive inheritance

In X-linked recessive inheritance, two copies of the allele located on the X-chromosome should be passed from the
parents to the female offspring and only one should be passed to the male offspring to cause the expression of the
phenotype (since men are hemizygous for X-linked genes). Affected individuals are present not in each generation.
Males are affected much more than females who are usually carriers having one copy of the allele. Females can only
be affected if they carry two alleles; in such cases, all their sons will be affected, and all their daughters will be
carriers. Affected males transmit the allele to all their daughters who thus become carriers, but to none to their sons
who receive Y-chromosome.

The overlay indicates the carriers.

Glucose-6-phosphate dehydrogenase deficiency

 Favism
Abbreviation: G6PD deficiency

An enzyme deficiency that results in the decreased ability to regenerate glutathione, an antioxidant, which in
turn increases the susceptibility of RBCs to oxidative stress, resulting in periodic hemolytic anemia with exposure
to oxidative conditions.

Hemophilia A

An X-linked recessive disease that results in the deficiency of factor VIII. Most often presents in boys with
recurrent episodes of epistaxis, bruising, and/or hemarthrosis. Lab studies show normal platelet counts, BT, PT,
but prolonged aPTT

Hemophilia B

An X-linked recessive disease that results in the deficiency of factor IX. Presents in boys with signs of bleeding,
such as recurring epistaxis, bruising, and/or hemarthrosis. Lab values show normal platelet counts, BT, and PT,
but prolonged aPTT.

Duchenne muscular dystrophy

Abbreviation: DMD

An X-linked recessive genetic disease in which mutations in the dystrophin gene result in a defective protein
product. Results in subsequent degeneration of muscle fibers, causing proximal muscle weakness along with
cardiomyopathy and bone fragility. Progresses relatively rapidly; most patients become wheelchair-dependent in
late childhood and die during or before the third decade of life due to respiratory insufficiency or
cardiomyopathy.

X-linked dominant inheritance

Overview
 In X-linked dominant (XD) inheritance, male and female individuals have an equal probability of inheriting the
trait or disorder.

Examples of XD inheritance patterns

 Heterozygous mother and hemizygous (unaffected) father: Children have a 50% probability of inheriting the
trait/disease.
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 XD inheritance pattern in heterozygous mother and hemizygous (unaffected) father

Heterozygous mother (affected)

X x

x Xx (daughter, affected) xx (daughter, unaffected)

Hemizygous father (unaffected)

Y XY (son, affected) xY (son, unaffected)

 Homozygous mother and hemizygous (unaffected) father: All the children will inherit the trait/disease.
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XD inheritance pattern in homozygous mother and hemizygous (unaffected) father

Homozygous mother (affected)

X X

x Xx (daughter, affected) Xx (daughter, affected)

Hemizygous father (unaffected)

Y XY (son, affected) XY (son, affected)

 Heterozygous mother and hemizygous (affected) father: Children have a 75% probability of inheriting the

trait/disease.
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XD inheritance pattern in heterozygous mother and hemizygous (affected) father

Hemizygous father (affected)

X Y

X XX (daughter, affected) XY (son, affected)

Heterozygous mother

(affected)
x Xx (daughter, affected) xY (son, unaffected)

 Homozygous (unaffected) mother and hemizygous (affected) father

 o All daughters will be affected.
o Sons are invariably unaffected.
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XD inheritance pattern in homozygous (unaffected) mother and hemizygous (affected) father

Hemizygous father (affected)

X Y

x Xx (daughter, affected) xY (son, unaffected)

Homozygous mother (unaffected)

x Xx (daughter, affected) xY (son, unaffected)

Examples of XD disorders
 Alport syndrome
 Fragile X syndrome
 Hypophosphatemic rickets
 Rett syndrome

Other types of inheritance

Mitochondrial inheritance
 Features
o Diseases caused by mutations in mitochondrial DNA are only passed down to offspring by the
mother.
o Each mitochondrion has multiple copies of DNA (mtDNA), and each cell has many mitochondria.
 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.
 Examples
o Mitochondrial myopathies (e.g., MELAS syndrome)
o Leber hereditary optic neuropathy
 Mitochondrial inheritance
  Mitochondrial inheritance implies transmission of the disease only through the mother. All the offsprings of
affected females may express the phenotype. Variable expression is observed due to heteroplasmy.

Polygenic inheritance
 Definition: a trait controlled by the interaction of two or more genes at different loci, without
interaction with the environment
 Examples
o 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
 Definition
o The proportion of heterozygote carriers of an allele that causes a trait/disorder in the population
 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).
o Hardy-Weinberg equilibrium: (p+q)  = p  + 2pq + q = 1 (100%).
2 2 2 

 The frequency of the independent alleles A and a are represented by p and q,

respectively, where p + q = 1.
 p  = homozygote frequency of allele A
2

 q  = homozygote frequency of allele a
2

 2pq = heterozygote frequency (probability of carrying both an altered and an allele that

does not cause the trait/disorder)
 For X-linked recessive disease, the frequency in male individuals = q and in female
individuals = q 2

o 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.
 Example: cystic fibrosis with an incidence of ∼ 1:2,500
o Calculate 2pq: 2pq = 2×1×1/50 = 1/25 (4%) heterozygote frequency
o Calculate p: If (p + q)  = 1 then p + q = 1 and p = 1 – q = 1 – 1/50 = 0.98 (98%) ≈ 1
2

o Calculate q: If q  = 1/2,500 then q = 1/50 = 0.02 (2%)

2

o Since cystic fibrosis is a recessive disorder, only homozygote carriers develop the disease.

The incidence corresponds to the homozygote frequency q 2
 Multifactorial inheritance disorders (MID)
 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)
 Features
o Commonly manifest with the Carter effect  [21]

 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.
 However, the numerical increase in susceptibility genes leads to an
increased probability of passing on mutated alleles to offspring.