Transcript LP7 - Inheritance and Genetic Diseases

Inheritance patterns:
Monogenic (Mendelian) Inheritance
Polygenic and Multifactorial Inheritance
Mitochondrial Inheritance
Inheritance patterns
Inheritance patterns trace the transmission of
genetically encoded traits, conditions or diseases to
offspring.
There are several modes of inheritance:
 Single Gene or Mendelian
 Polygenic and Multifactorial
 Mitochondrial
Single Gene Inheritance
 Genetic conditions caused by a mutation in a single gene follow predictable patterns of
inheritance within families. Single gene inheritance is also referred to as Mendelian
inheritance as they follow transmission patterns he observed in his research on peas.
 There are four types of Mendelian inheritance patterns:
1.
Autosomal: the gene responsible for the phenotype is located on one of the 22 pairs
of autosomes (non-sex determining chromosomes).
2.
X-linked: the gene that encodes for the trait is located on the X chromosome.
3.
Dominant: conditions that are manifest in heterozygotes (individuals with just one
copy of the mutant allele).
4.
Recessive: conditions are only manifest in individuals who have two copies of the
mutant allele (are homozygous).
5.
Y-linked (holandric): the gene that encodes for the trait is located on the Y
chromosome
Autosomal dominant (AD)
 Dominant conditions are expressed in individuals
who have just one copy of the mutant allele.
 The pedigree on the right illustrates the transmission
of an autosomal dominant trait.
 Affected males and females have an equal probability
of passing on the trait to offspring.
 Affected individual’s have one normal copy of the
gene and one mutant copy of the gene, thus each
offspring has a 50% chance on inheriting the mutant
allele.
 As shown in this pedigree, approximately half of the
children of affected parents inherit the condition and
half do not.
• Huntington Disease
· Myotonic muscular dystrophy
• Acondroplasia (short-limbed
dwarfism)
• Polycystic kidney disease
(PKDU)
· Brachydactyly
· Polydactily
· Syndactyly
· Adactyly
• Osteogenesis imperfecta
· Gout
· Familial hypercholesterolemia
· Hypercalcemia
· Marfan syndrome
· Familial polycystitis
· Neurofibromatosis
Autosomal dominant (AD)
 Huntington Disease
 Myotonic muscular dystrophy
 Achondroplasia (short-limbed dwarfism)
 Polycystic kidney disease (ADPKD)
 Brachydactyly
 Polydactily
 Syndactyly
 Adactyly
 Osteogenesis imperfecta
 Gout
 Familial hypercholesterolemia
 Hypercalcemia (familial)
 Marfan syndrome
 Familial Polycystic ovary syndrome (PCOS)
 Neurofibromatosis
Huntington Disease
 Huntington's disease (HD) is a neurodegenerative genetic disorder that affects muscle
coordination and leads to cognitive decline and psychiatric problems. It typically
becomes noticeable in mid-adult life. HD is the most common genetic cause of abnormal
involuntary writhing movements called chorea, which is why the disease used to be
called Huntington's chorea.
 The Huntingtin gene (HTT=HD=IT15) on 4p16.3 provides the genetic information for a
protein that is also called "huntingtin". Expansion of a CAG triplet repeat stretch
within the Huntingtin gene results in a different (mutant) form of the protein, which
gradually damages cells in the brain, through mechanisms that are not fully understood.
The genetic basis of HD was discovered in 1993 by an international collaborative effort
spearheaded by the Hereditary Disease Foundation.
Huntington Disease
 Increases in the number of repeats (and hence earlier age of onset and severity of
disease) in successive generations is known as genetic anticipation. Instability is
greater in spermatogenesis than oogenesis;
 Individuals with more than sixty repeats often develop the disease before age 20, while
those with fewer than 40 repeats may not ever develop noticeable symptoms;
 Life expectancy in HD is generally around 20 years following the onset of visible
symptoms;
 Most life-threatening complications result from muscle coordination and, to a lesser
extent, behavioral changes induced by declining cognitive function.
 The largest risk is pneumonia, which causes death in one third of those with HD. As the
ability to synchronize movements deteriorates, difficulty clearing the lungs and an
increased risk of aspirating food or drink both increase the risk of contracting
pneumonia. The second greatest risk is heart disease, which causes almost a quarter of
fatalities of those with HD.[
Huntington Disease
 Recommended (highly) to see what Huntington is all about
 An excellent French documentary (subtitled in English) about a family carrying such a
genetic “burden”, including aspects of their life and expectancies
 As a reminder, the disease has a complete penetrance (100%) make the disease, usually
after 35-40 years of age, and transmit it to their progenitors
 http://www.youtube.com/watch?v=0qOdGvoOXI0 (it takes 1 hour and a half)
Other AD conditions
 Myotonic muscular dystrophy (dystrophia myotonica, myotonia atrophica) is a
chronic, slowly progressing, highly variable, inherited multisystemic disease. It is
characterized by wasting of the muscles (muscular dystrophy), cataracts, heart
conduction defects, endocrine changes, and myotonia.
 Achondroplasia is a common cause of dwarfism. It occurs as a sporadic mutation in
approximately 75% of cases (associated with advanced paternal age) or may be inherited
as an autosomal dominant genetic disorder. People with achondroplasia have short
stature, with an average adult height of 131 centimeters for males and 123 centimeters for
females. Achondroplastic adults are known to be as short as 62.8 cm (24.7 inches)
 Polycystic kidney disease (PKD or PCKD, also known as polycystic kidney syndrome)
is a cystic genetic disorder of the kidneys. There are two types of PKD: autosomal
dominant polycystic kidney disease (ADPKD) and the less-common autosomal recessive
polycystic kidney disease (ARPKD). Polycystic kidney disease is one of the most
common life-threatening genetic diseases, affecting an estimated 12.5 million people
worldwide.
Other AD conditions
 Brachydactyly (short fingers/toes)
 Polydactily (extra fingers/toes)
 Syndactyly (two or more digits are fused together)
 Adactyly (congenital absence of fingers and/or toes)
 Osteogenesis imperfecta (OI and sometimes known as brittle bone
disease, or "Lobstein syndrome") is a congenital bone disorder. People with OI
are born with defective connective tissue, or without the ability to make it,
usually because of a deficiency of Type-I collagen. As a genetic disorder, OI has
historically been viewed as an autosomal dominant disorder of type I collagen.
In the past several years, there has been the identification of autosomal
recessive forms. Most people with OI receive it from a parent but in 35% of cases
it is an individual (de novo or "sporadic") mutation. There are eight different
types of OI, Type I being the most common, though the symptoms vary from
person to person.
Osteogenesis imperfecta
Other AD conditions
 Gout (also known as podagra when it involves the big toe). is a medical condition
usually characterized by recurrent attacks of acute inflammatory arthritis—a red,
tender, hot, swollen joint. The metatarsal-phalangeal joint at the base of the big toe is
the most commonly affected (approximately 50% of cases). However, it may also present
as tophi, kidney stones, or urate nephropathy. It is caused by elevated levels of uric acid
in the blood. The uric acid crystallizes, and the crystals deposit in joints, tendons, and
surrounding tissues. The occurrence of gout is partly genetic, contributing to about 60%
of variability in uric acid level.[
 Familial hypercholesterolemia (abbreviated FH) is a genetic disorder characterized
by high cholesterol levels, specifically very high levels of low-density lipoprotein (LDL,
"bad cholesterol"), in the blood and early cardiovascular disease. Many patients have
mutations in the LDLR gene that encodes the LDL receptor protein, which normally
removes LDL from the circulation, or apolipoprotein B (ApoB), which is the part of LDL
that binds with the receptor; mutations in other genes are rare. Patients who have one
abnormal copy (are heterozygous) of the LDLR gene may have premature cardiovascular
disease at the age of 30 to 40. Having two abnormal copies (being homozygous) may
cause severe cardiovascular disease in childhood. Heterozygous FH is a common genetic
disorder, inherited in an autosomal dominant pattern, occurring in 1:500 people in most
countries; homozygous FH is much rarer, occurring in 1 in a million births.
Other AD conditions
 Hypercalcemia - Familial hypocalciuric hypercalcemia is a condition that
can cause hypercalcemia, a serum calcium level typically above 10.2 mg/dL. It is
also known as familial benign hypocalciuric hypercalcemia (FBHH) where
there is usually a family history of hypercalcemia which is mild, a urine calcium
to creatinine ratio <0.01, and urine calcium <200 mg/day.
 Familial Polycystic ovary syndrome (PCOS) is one of the most common
female endocrine disorders. PCOS is a complex, heterogeneous disorder of
uncertain etiology, but there is strong evidence that it can to a large degree be
classified as a genetic disease. PCOS produces symptoms in approximately 5%
to 10% of women of reproductive age (12–45 years old). It is thought to be one of
the leading causes of female subfertility and the most frequent endocrine
problem in women of reproductive age. The genetic component appears to be
inherited in an autosomal dominant fashion with high genetic penetrance but
variable expressivity in females; this means that each child has a 50% chance of
inheriting the predisposing genetic variant(s) from a parent, and if a daughter
receives the variant(s), then the daughter will have the disease to some extent.[
Other AD conditions
 Marfan syndrome (also called Marfan's syndrome) is a genetic disorder of
the connective tissue. People with Marfan tend to be unusually tall, with long
limbs and long, thin fingers. The syndrome is inherited as a dominant trait,
carried by the gene FBN1, which encodes the connective protein fibrillin-1.
People have a pair of FBN1 genes. Because it is dominant, people who have
inherited one affected FBN1 gene from either parent will have Marfan
syndrome. Marfan syndrome has a range of expressions, from mild to severe.
The most serious complications are defects of the heart valves and aorta. It may
also affect the lungs, the eyes, the dural sac surrounding the spinal cord, the
skeleton and the hard palate.
Other AD conditions
 Neurofibromatosis (commonly abbreviated NF; neurofibromatosis type 1 is
also known as von Recklinghausen disease) is a genetically-inherited
disorder in which the nerve tissue grows tumors (neurofibromas) that may be
benign and may cause serious damage by compressing nerves and other tissues.
Neurofibromatosis is an autosomal dominant disorder, which means only one
copy of the affected gene is needed for the disorder to develop. Therefore, if
only one parent has neurofibromatosis, his or her children have a 50% chance of
developing the condition as well. The severity in affected individuals can vary;
this may be due to variable expressivity. Approximately half of cases are due to
de novo mutations and no other affected family members are seen. It affects
males and females equally.
Autosomal Recessive (AR)
 Recessive conditions are clinically manifest
only when an individual has two copies of the
mutant allele.
 When just one copy of the mutant allele is
present, an individual is a carrier of the
mutation, but does not develop the
condition.
 Females and males are affected equally by
traits transmitted by autosomal recessive
inheritance.
 When two carriers mate, each child has a 25%
chance of being homozygous wild-type
(unaffected); a 25% chance of being
homozygous mutant (affected); or a 50%
chance of being heterozygous (unaffected
carrier).
Note: Affected individuals are indicated
by solid black symbols and unaffected
carriers are indicated by the half black
symbols
• Cystic fibrosis
· Phenylketonuria (PKU)
· Albinism
· Galactosemia
· Xeroderma pigmentosum
· Fanconi anemia
· Bloom syndrome
• Tay-Sachs
• Hemochromatosis
Autosomal Recessive (AR)
 Cystic fibrosis
 Phenylketonuria (PKU)
 Albinism
 Galactosemia
 Xeroderma pigmentosum
 Fanconi anemia
 Bloom syndrome
 Tay-Sachs
 Hemochromatosis
X-linked Dominant
 Because the gene is located on the X
chromosome, there is no transmission
from father to son, but there can be
transmission from father to daughter
(all daughters of an affected male will
be affected since the father has only one
X chromosome to transmit).
 Children of an affected woman have a
50% chance of inheriting the X
chromosome with the mutant allele.
 X-linked dominant disorders are
clinically manifest when only one copy
of the mutant allele is present.
• Some forms of Retinitis
Pigmentosa
• Chondrodysplasia Punctata
• Hypophosphatemic rickets, also
called X-linked hypophosphatemia
(XLH), hypophosphatemic vitamin
D-resistant rickets (HPDR)
· Amelogenesis imperfecta
X-linked Dominant
 Some forms of Retinitis Pigmentosa
 Chondrodysplasia Punctata
 Hypophosphatemic rickets
= X-linked hypophosphatemia (XLH)
=Hypophosphatemic vitamin D-resistant rickets
(HPDR)
 Amelogenesis imperfecta
X-linked Recessive
 X-linked recessive traits are not clinically
manifest when there is a normal copy of the
gene.
 All X-linked recessive traits are fully evident in
males because they only have one copy of the X
chromosome, thus do not have a normal copy of
the gene to compensate for the mutant copy.
 For that same reason, women are rarely affected
by X-linked recessive diseases, however they are
affected when they have two copies of the
mutant allele.
• Duchenne muscular dystrophy
(DMD)
 Because the gene is on the X chromosome there
• Hemophilia A
is no father to son transmission, but there is
father to daughter and mother to daughter and
son transmission.
 If a man is affected with an X-linked recessive
condition, all his daughter will inherit one copy
of the mutant allele from him.
• X-linked severe combined
immune disorder (SCID)
• Some forms of congenital
deafness
Y-linked (holandric traits)
 Hypertrichosis of the ears
Polygenic and Multifactorial
Inheritance (1)

Most diseases have multifactorial inheritance patterns.

As the name implies, multifactorial conditions are not caused by a single
gene, but rather are a result of interplay between genetic factors and
environmental factors.

Diseases with multifactorial inheritance are not genetically determined,
but rather a genetic mutation may predispose an individual to a
disease. Other genetic and environmental factors contribute to whether
or not the disease develops.

Numerous genetic alterations may predispose individuals to the
same disease (genetic heterogeneity).

For instance coronary heart disease risk factors include high blood
pressure, diabetes, and hyperlipidemia. All of those risk factors have
their own genetic and environmental components. Thus multifactorial
inheritance is far more complex than Mendelian inheritance and is more
difficult to trace through pedigrees.
DISEASES:
• Alzheimers disease
• Heart disease
• Some cancers
• Neural tube defects
• Schizophrenia
• Insulin-dependent
Diabetes mellitus
CHARACTERS:
· Height, weight
• Intelligence
· Skin, eyes and hair color
· Dermatoglyphics
· Blood pressure
Polygenic and Multifactorial
Inheritance (2)
 A typical pedigree from a
family with a mutation in the
BRCA1 gene.
 Fathers can be carriers and
pass the mutation onto
offspring.
 Not all people who inherit
the mutation develop the
disease, thus patterns of
transmission are not always
obvious.
Polygenic and Multifactorial
Inheritance (3)
 Alzheimers disease
 Heart disease
 Some cancers
 Neural tube defects
 Schizophrenia
 Insulin-dependent diabetes mellitus
 Height, weight
 Intelligence
 Skin, eyes and hair color
 Dermatoglyphics
 Blood pressure
Mitochondrial Inheritance (1)
 Mitochondria are organelles found in the cytoplasm of cells.
 Mitochondria are only inherited from the mother’s egg, thus
only females can transmit the trait to offspring, however they
pass it on to all of their offspring.
 The primary function of mitochondria is conversion of molecule
into usable energy.
 Thus many diseases transmitted by mitochondrial inheritance
affect multiple organs with high-energy use such as the heart,
blood, skeletal muscle, liver, and kidneys, becoming a complex
texture of diseases, usually lethal in early childhood.
 The difficulty arises when no mtDNA defect can be found or
when the clinical abnormalities are complex and not easily
matched to those of more common mitochondrial disorders.
Mitochondrial Inheritance (2)
 Mitochondria are unique in that they have multiple
copies of a circular chromosome = mtDNA
Each human cell contains thousands of
copies of mtDNA. At birth these are
usually all identical (homoplasmy).
By contrast, individuals with
mitochondrial disorders resulting from
mtDNA mutations may harbor a mixture
of mutant and wild-type mtDNA within
each cell (heteroplasmy)
The percentage level of mutant mtDNA
may vary among individuals within the
same family, and also among organs and
tissues within the same individual. This is
one explanation for the varied clinical
phenotype seen in individuals with
pathogenic mtDNA disorders.