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Autosomal Dominant Diseases:
Locus beta, 1 gene
2 Alleles
A (dominant) # a (recessive)
Genotypes
AA #Aa
# aa
Phenotype
Affected
# Healthy
1
A
a
a
Aa
aa
a
Aa
aa
A couple in which one parent is heterozygous for a dominant allele (Aa) and the other is
homozygous for the recessive allele (aa) will have 50% of children carrying the dominant allele, and thus showing the related phenotype
Autosomal Dominant Inheritance
The disease is observed in each generation
Both males and females affected
Each affected subject has inherited the disease from one
parent
50% of children of an affected subject are expected to be
similarly affected
3
In pedigrees showing dominant diseases, every affected individual has an affected biological parent. Usually there is no skipping of generations.
Males and females have an equally likely chance of inheriting the mutant allele and being affected. The recurrence risk of each child of an affected parent is 1/2.
Normal siblings of affected individuals do not transmit the trait to their offspring.
The defective product of the gene is usually a structural protein, not an enzyme.
Achondroplasia
Homozygosity for the
dominant allele is lethal
Aa x Aa
AA Aa aa
1 :
2
: 1
Dominant disorders:
What happens for a
double dose of the
dominant allele?
A
a
A
AA
Aa
a
Aa
aa
Autosomal dominant
# OMIM 143100 HUNTINGTON DISEASE; HD
Gene map locus 4p16.3
A number sign (#) is used with this entry because
Huntington disease (HD) is caused by an expanded
trinucleotide repeat in the gene encoding huntingtin
(HTT; 613004) on chromosome 4p16.3.
Disease characteristics. Huntington disease (HD)
is a progressive disorder of motor, cognitive, and
psychiatric disturbances. The mean age of onset
is 35 to 44 years and the median survival time is
15 to 18 years after onset.
Homozygotes for HD appear to have a similar age
of onset to heterozygotes, but may exhibit an
accelerated rate of disease progression
[Squitieri et al 2003].
Basal ganglia region in HD (top) and
controls (bottom)
The age at onset of symptoms in the homozygote cases was
within the range expected for heterozygotes with the same CAG
repeat lengths, whereas homozygotes had a more severe clinical
course. Our analysis suggests that although homozygosity for
the Huntington disease mutation does not lower the age at onset
of symptoms, it affects the phenotype and the rate of disease
progression. These data, once confirmed in a larger series of
patients, point to the possibility that the mechanisms underlying
age at onset and disease progression in Huntington disease may
differ.
When studying the relationships between genotype and phenotype, it is important to examine the statistical occurrence of phenotypes in a group of known genotypes.
You might be surprised to learn that, for some traits, the phenotype might not occur as often as the genotype.
For example, say everyone in population W carries the same allele combinations for a certain trait, yet only 85% of the population actually shows the phenotype expected from those allele combinations.
The proportion of genotypes that actually show expected phenotypes is called penetrance.
Thus, in the preceding example, the penetrance is 85%. This value is calculated from looking at populations whose genotypes we know. Studies of penetrance help us predict how likely it is that a trait will be evident in those who carry the underlying alleles. In general, when we know that the genotype is present but the phenotype is not observable, the trait shows incomplete penetrance.
Basically, anything that shows less than 100% penetrance is an example of incomplete penetrance. Therefore, the penetrance of a trait is a statistically calculated value based on the appearance of a phenotype among known genotypes. Age Related Penetrance
Dominant disease with reduced (80%) penetrance
Parent Aa >> abnormal phenotype caused by the A allele
Child, of course 50% chance of inheriting the A allele
But the chance of demonstrating the abnormal phenotype will be
80% of 50% >> 40% only
The shaded individuals (red and pink) all
have a genetic variant. Due to reduced
penetrance, only the individuals in pink
actually have the disease associated with
the variant.
Treacher Collins Syndrome as an Example
of Variable Expressivity
Inheritance pattern: Autosomal dominant
Gene: TCOF1 Locus: 5q32-q33.1
Major clinical features:
Down-slanting palpebral fissures
Eyelid colobomas
Partial to total absence of lower
eyelashes
Malar hypoplasia
Cleft palate
Mandibular hypoplasia
Ear deformities
Hearing loss
Genotype- phenotype correlation
Genotype-Phenotype Correlations
NF1 is characterized by extreme clinical variability, not only between unrelated patients but also
among affected individuals within a single family. Some investigators interpret this variability
as evidence that most complications of NF1 result from the effects of additional random events in
individual patients.
Evidence in support of this interpretation is provided by the occurrence of acquired "second hit“
mutations and loss of heterozigosity at the NF1 locus in some neurofibromas, malignant peripheral
nerve sheath tumors, pheochromocytomas, pilocytic astrocytomas, and juvenile chronic
myelogenous leukemia cells from patients with NF1.
Genetic heterogeneity in AD diseases
Clinical Diagnosis
The diagnosis of hereditary hemorrhagic
telangiectasia (HHT) is based on the presence
of arteriovenous malformations (AVMs), which
may be cutaneous or mucocutaneous
telangiectases or large visceral AVMs.
[Marchuk et al.1998]
Diagnostic criteria include
•Epistaxis: spontaneous and recurrent -night-time nosebleeds
heighten the concern for HHT
•Mucocutaneous telangiectases, multiple: small blanchable red spots that
are focal dilatations of post-capillary venules or delicate, lacy red
vessels with markedly dilated and convoluted venules at
characteristic sites, as lips, oral cavity, fingers, and nose
•Visceral arteriovenous malformation (AVM): an arteriovenous
malformation lacks capillaries and consists of direct connections
between arteries and veins.
AVMs may be: # Pulmonary # Cerebral # Hepatic # Spinal #
Gastrointestinal
•Family history: a first-degree relative with a definite HHT diagnosis
• Vascular dysplasia
• OMIM#187300
• Autosomal Dominant
• Penetrance complete > 40 yrs
• Incidence?
- Haut Jura (Lyon, France)
53/1000
(Plauchu et al. 1980)
- Vermont (USA)
1/8000-1/50000
(Shovlin et al. 1997)
- Fyn (Denmark)
15.6/100 000
(Kjeldsen et al. 2001)
- Bergamo (Italy) population 1,021,700 – 40 pts
(Olivieri et.al 2007)
HHT -- Known genes
ENG
(MIM # 131195)
9q 34
Endoglin
HHT1
ACVRL1
(MIM # 601284)
12q11-14
Activin A Receptor, Type IIlike1
HHT2
MADH4
(MIM # 600993)
18q21.1
Mothers against
decapentaplegic, Drosophila,
homolog of, 4
JP/HHT
Kaplan-Meier survival curve showing probability of
remaining free of epistaxis.
Lesca et al., 2006
Genotype‐Phenotype Correlations
(Lesca, Olivieri, et al, J Med Genet 2007, 9:14‐22)
Families with a known mutation
11 +2+2
# families with
a common ENG
mutation
1
2
25
6
2
6
2
9
# families with a
common ACVRL1
mutation
2
4
3
2
7
1
1
8
6
5
3
2+3
2
1 Belgium
1 France
C. Danesino‐University of Pavia
HHT Northern Italy
8
4
1 Germany
1 India
: #160900 DYSTROPHIA MYOTONICA 1
Gene map locus 19q13.2-q13.3
Disease characteristics. Myotonic dystrophy type 1 (DM1)
is a multisystem disorder that affects skeletal and smooth
muscle as well as the eye, heart, endocrine system, and
central nervous system. The clinical findings, which span a
continuum from mild to severe, have been categorized into
three somewhat overlapping phenotypes: mild, classic,
and congenital. Mild DM1 is characterized by cataract and
mild myotonia (sustained muscle contraction); life span is
normal. Classic DM1 is characterized by muscle weakness
and wasting, myotonia, cataract, and often cardiac
conduction abnormalities; adults may become physically
disabled and may have a shortened life span. Congenital
DM1 is characterized by hypotonia and severe generalized
weakness at birth, often with respiratory insufficiency and
early death; mental retardation is common.
Typical appearance in myotonic dystrophy (ie, Steinert disease)
includes frontal baldness, temporal atrophy, and narrow facies.
If we know that the child is
affected with an AD disease,
than we can deduct the
genotypes.
Be aware of exceptions!
Chromosomes and inheritance
X-Linked Traits
32
Sutton’s Hypothesis
Genes are structures localized on
chromosomes
Each of the two alleles is on one chromosome
of a couple of chromosomes
33
Each allele of a
gene is located on
one chromosome of
a couple.
At the end of
meiosis each
gamete contains
only one allele of
each gene.
If two genes (4 alleles ) are
considered we can observe
independent segregation of
the alleles of the two genes
(Mendel’s 3rd
law)
35
Chromosomal sex determination
Insect, protenor belfragei (Stevens, 1900)
FEMALE
14
7
MALE
CHROMOSOMES
BIVALENTI
GAMETES [F >>7]
13
6+1
[M>>6] [M>>7]
7 + 7 = 14
FEMALE
XX
7 + 6 = 13
MALE
X0
36
37
HUMAN KARYOTYPE
38
Sex and Chromosomes
FEMALE
MALE
XX
XY
BIRDS, SOME REPTILES
ZW
ZZ
39
In some species environmental factors are relevant for
sex determination
40
HUMAN KARYOTYPE
41
zanzara
Meiotic pairing between
X and
topo
Y
is at terminal regions
called pseudo-autosomal
renna
marmott
a
hamster
cinese
42
DIAKINESIS IN MAN
43
Homologous regions between X and Y: pseudo autosomal
region
Testis Determining Factor=TDF
(sex
determinig region Y)
TDF = SRY
44
Drosophila Melanogaster
45
Inheritance of X-linked Gene for Eye
Colour in Drosophila
The first X-linked gene found in Drosophila
was the recessive white eye mutation
(Morgan, 1910). When a homozygous redeyed female (dominant) is crossed with a
white-eyed male (recessive), all individuals
in the F1 are red-eyed.
X*
Y
X
X X*
XY
X
X X*
XY
47
When we cross the individuals from F1………
X
Y
X
XX
XY
X*
XX*
X*Y
48
…but when the cross is between a white-eyed female and red-eyed
male, male offspring in the F1 have white eyes.
X
Y
X*
XX*
X*Y
X*
XX*
X*Y
49
When heterozygous red eyed females are crossed with
white-eyed males, both sexes segregate 1: 1
X*
Y
X*
X*X*
X*Y
X
XX*
XY
These experiments demonstrate that one gene in this case is carried by the
X chromosome, but not by the Y.
50
X-Linked Recessive Diseases
51
X-Linked Recessive Disease
Rare Gene: Haemofilia
2:10.000
no male to male transmission
52
Haemophilia in old ages
Circumcision
53
Pedigree showing inheritance of hemophilia, an X-linked trait, in the
descendants of Queen Victoria. Many of the descendants in the third
and fourth generations (third and fourth rows) have been omitted
because the mutant gene was not transmitted to them.
Daltonism
Normal reads: 74
Daltonic reads: 21
55
X-Linked Recessive Disease
Common Allele
G6PDH Deficiency
VICIA FABA
56
Some drugs can cause haemolysis in
GSPDH deficient subjects
this peripheral smear of RBCs shows Heinz bodies. Heinz bodies are
precipitated, oxidized hemoglobin. They are found in glucose-6-phosphate
dehydrogenase deficiency (G6PD).
310200 MUSCULAR DYSTROPHY,
DUCHENNE TYPE; DMD
Gene map locus Xp21.2
310200 MUSCULAR
DYSTROPHY, DUCHENNE
TYPE; DMD
Gene map locus Xp21.2
a | In Duchenne muscular dystrophy (DMD) patients, with a deletion of exons 45–54, an
out-of-frame transcript is generated in which exon 44 is spliced to exon 55. Owing to the
frame shift, a stop codon occurs in exon 55, which prematurely aborts dystrophin
synthesis. b | Using an exon-internal antisense oligonucleotide (AON) in exon 44, the
skipping of this exon can be induced in cultured muscle cells. Accordingly, the transcript
is back in-frame and a Becker muscular dystrophy (BMD)-like dystrophin can be
synthesized
Fabry disease: symptoms in carriers:
Late onset of symtoms.
MacDermot et al. (2001) reported clinical manifestations and impact of
disease in 60 females with Fabry disease. The median cumulative survival
was 70 years, representing an approximate reduction of 15 years from
the general population.
Six of 32 women had renal failure, 9 of 32 (28%) died of cerebrovascular
complications, and 42 (70%) had experienced neuropathic pain. Twenty
(30%) female patients had some serious or debilitating manifestation of
Fabry disease.
X-Linked Dominant Diseases
•Females are affected twice as males
•Affected males transmit the disease to all daughters but to no sons
63
#300049 HETEROTOPIA, PERIVENTRICULAR,
X-LINKED DOMINANT
Alternative titles; symbols
HETEROTOPIA, FAMILIAL NODULAR
PERIVENTRICULAR NODULAR HETEROTOPIA 1;
PVNH1
HETEROTOPIA, PERIVENTRICULAR NODULAR,
WITH FRONTOMETAPHYSEAL DYSPLASIA,
INCLUDED
Gene map locus Xq28
TEXT
A number sign (#) is used with this entry because Xlinked periventricular heterotopia is caused by mutation
in the gene encoding filamin-A (FLNA; 300017).
DESCRIPTION
Periventricular heterotopia (PVNH) is a genetically
heterogeneous condition. See also PVNH2 (608097),
PVNH3 (608098), PVNH4 (300537), and PVNH5
(612881)
If we know that the child is
affected with an X-linked
disease, than we can deduct
the genotypes.
Be aware of exceptions!
Genetic and phenotypic heterogeneity
A
B
*
*
C
*
D
E
*
*
A-E: different genes
Same phenotype
* mutation
Different phenotypes
*
*
*
*
*
One gene, different mutations
*
Same phenotype
*
*
Different phenotypes
Same phenotype
One gene, identical mutations
The HHT1 mouse
Y linked inheritance
No diseases are known as Y linked
Some proposed examples are still uncertain
(porcupine man, 146600; hairy ear, 425500)
Y linked genes are related to maleness;
Their alterations will mainly cause male infertility, and of
course, no pedigrees will be observed
68
69
Sinclair et al. (1990) identified a gene, which they named SRY (sexdetermining region Y), within a 35-kb sex-determining region on the
human Y chromosome that was adjacent to the pseudoautosomal
boundary.
Sekido and Lovell-Badge (2008) concluded that their results permitted
further characterization of the molecular mechanisms regulating sex
determination, their evolution, and the failure of these mechanisms in
cases of sex reversal.
#415000 SPERMATOGENIC FAILURE, NONOBSTRUCTIVE, YLINKED AZOOSPERMIA FACTOR REGIONS, INCLUDED
Gene map locus Yq11.2
70
Autosomal dominant trait with expression limited to males
Precocious puberty
71
Traits sex influenced
Male pattern baldness is a sex-linked characteristic
that is passed from mother to child. A man can more
accurately predict his chances of developing male
pattern baldness by observing his mother's father
than by looking at his own father.
72