MONOGENIC!
DISEASES"
Some definitions"
Monogenic disease: a genetic disease in which a mutation in only one
gene (in one or the two alleles) is sufficient for an individual to be
affected."
It should be noted that in some cases, different genes might be the cause
of the disease in different families. But in a given person (or family) only
one gene is responsible for the disease. "
It also should be noted that in some cases other genes could contribute to
the disease."
More definitions"
Genotype: genetic constitution of an individual. Although it may refer to"
all loci, it generally refers to one locus."
Phenotype: normally we will refer to two phenotypes, NORMAL and"
AFFECTED. Other features could also be included: severity, affected "
systems (presence or absence of neuropathy, etc.)"
Allele: each of the copies of a gene. Each individual has two "
alleles from each gene (except men for X-linked genes). "
The term “allele” is also used to refer to all the variants of a gene (for "
example, we have identified forty mutant alleles in Spanish Gaucher
patients) "
And it is also used for genetic markers (that are not genes)."
More definitions"
Homozygous: two identical alleles."
Heterozygous: the two alleles are different. "
We generally would refer to a NORMAL (or wild-type) allele "
and a MUTANT allele."
Compound Heterozygous: the two alleles are different but both of them "
are MUTANT alleles.!
Two concepts that seem to be similar but are not"
Prevalence: total number of disease cases in the population "
(in a given time) divided by the number of individuals in the population. "
It is normally expressed as cases per 1000 inhabitants, etc."
Incidence: number of new disease cases within a specified period of
time, divided by the size of the population."
It can be expressed as new cases per year per 1000 persons, etc."
TYPES OF INHERITANCE"
ACCORDING TO THE CHROMOSOME TYPE"
Autosomal inheritance: the gene is one of the autosomes "
(chromosomes 1-22)"
X-linked inheritance: the gene is the X chromosome"
(there are nearly no Y-linked diseases)"
In the X-linked inheritance, it should be noted that: "
"- Men are hemizygotes"
"- In women, each cell has only one active X chromosome"
TYPES OF INHERITANCE"
ACCORDING TO THE NECESSARY NUMBER OF ALLELES!
TO EXPRESS THE PHENOTYPE"
Dominant inheritance: ONE mutant allele is sufficient to "
be affected."
Recessive inheritance: to be affected, BOTH alleles should be "
mutant alleles."
TYPES OF INHERITANCE"
There are 4 possible cases: "
Dominant (D) Recessive (R)"
Autosomal (A) AD AR "
X-linked (XL) XL-D * XL-R"
* XL-D cases are rare!
CRITERIA FOR"
AUTOSOMAL DOMINANT INHERITANCE"
•! There are affected individuals in each generation. Each affected !
individual has one affected parent (except new mutations)!
CRITERIOS
CRITERIA
PARA
FOR"LA"
AUTOSOMAL
HERENCIA AUTOSÓMICA
DOMINANT INHERITANCE"
DOMINANTE"
•! Every son or daughter of an affected parent has a 50% risk !
of being affected!
CRITERIA FOR"
AUTOSOMAL DOMINANT INHERITANCE"
•! Healthy family members do not pass the phenotype!
CRITERIA FOR"
AUTOSOMAL DOMINANT INHERITANCE"
•! Men and women pass the phenotype to children of any sex with!
the same probability. In particular, there is male-to-male !
transmission (that does not exist in X-linked inheritance)!
CRITERIA FOR"
AUTOSOMAL RECESSIVE INHERITANCE"
•! If more than one family member is affected, the affected individuals!
are normally sibs!
CRITERIA FOR"
AUTOSOMAL RECESSIVE INHERITANCE"
•! The recurrence risk for each of the sibs of the index case is 1/4 !
CRITERIA FOR"
AUTOSOMAL RECESSIVE INHERITANCE"
•! The parents of the affected individuals are frequently !
consanguineous!
CRITERIA FOR"
AUTOSOMAL RECESSIVE INHERITANCE"
•! For most of the autosomal recessive phenotypes, men!
and women have the same probability of being affected!
(RECESSIVE)"
(RECESSIVE)"
CRITERIA FOR"
X-LINKED RECESSIVE INHERITANCE"
•! The incidence is clearly higher in males !
(RECESSIVE)"
CRITERIA FOR"
X-LINKED RECESSIVE INHERITANCE"
•! The mutant allele is transmitted from the father to ALL the !
daughters. Thus, all of them will be carriers!
(RECESSIVE)"
CRITERIA FOR"
X-LINKED RECESSIVE INHERITANCE"
•! The sons of a carrier woman has a 50 per cent chance of !
inherit the disease!
(RECESSIVE)"
CRITERIA FOR"
X-LINKED RECESSIVE INHERITANCE"
•! All affected males in a family are connected through carrier !
women!
(RECESSIVE)"
CRITERIA FOR"
X-LINKED RECESSIVE INHERITANCE"
•! Carrier women are not normally affected!
(RECESSIVE)"
CRITERIA FOR" •! Affected fathers: ALL the sons
X-LINKED DOMINANT are healthy and ALL the
INHERITANCE" daughters are affected!
CRITERIA FOR" •! Children (of any sex) of
X-LINKED DOMINANT affected women have a 50% !
INHERITANCE" risk!
CRITERIA FOR" •! In rare diseases, there are
twice as many affected
X-LINKED DOMINANT
women than men. However,
INHERITANCE" they present a milder and
more variable phenotype!
GENETIC HETEROGENEITY"
NON ALLELIC HETEROGENEITY (gene heterogeneity)!
Now: LOCUS HETEROGENEITY!
•! Defects in different genes cause the same disease !
•! Example: RETINITIS PIGMENTOSA (more than 20 genes)!
ALLELIC HETEROGENEITY !
•! There are different mutations in the same gene. !
They can cause CLINIC HETEROGENEITY or NOT!
GENETIC HETEROGENEITY"
ALLELIC HETEROGENEITY !
Without clinical heterogeneity !
•! Different mutations in the same gene cause the same disease.!
•! Thay may cause different subtypes of the disease: !
!Type I, II or III Gaucher disease!
With clinical heterogeneity !
•! Different mutations in the same gene cause different diseases!
•! Examples: HURLER (severe) and SCHEIE (milder) SYNDROMES!
are caused by different mutations in the !-L-iduronidase gene!
•! DUCHENNE (severe) and BECKER (milder) MUSCULAR !
DYSTROPHIES are caused by different mutations in the dystrophin gene!
•! GM-1 gangliosidosis and Morquio B disease are caused by different !
mutations in the GLB1 gene!
ASPECTS OF PHENOTYPIC EXPRESSION"
PENETRANCE:"
•! Percentage of individuals with a given genotype that present!
the phenotype (affected)!
•! It is an all or nothing concept!
•! The term “reduced penetrance” is used when the penetrance is !
below 100% (i.e., there are individuals that are healthy in spite of!
bearing the disease genotype)!
EXPRESSIVITY:"
•! Variation in the phenotypic expression in individuals with the!
same genotype. It can occur in the same family.!
•! We use the term “variable expressivity”.!
ASPECTS OF PHENOTYPIC EXPRESSION"
EXAMPLE of REDUCED PENETRANCE:"
DOMINANCE AND RECESSIVITY"
In general:"
•! In DOMINANT INHERITANCE, the phenotype of !
the homozygous = the phenotype of the heterozygous!
•!We call RECESSIVE INHERITANCE when the phenotype!
is only expressed in the homozygous!
In medical genetics:!
•! We call DOMINANT INHERITANCE whenever a!
a phenotype is expressed in the heterozygous!
•! Although, in general, individuals homozygous for the!
mutant allele present a more severe phenotype!
DOMINANCIA Y RECESIVIDAD"
DOMINANCE AND RECESSIVITY"
INCOMPLETE DOMINANCE :!
•! When the phenotype of the homozygous > the phenotype !
of the heterozygous => INCOMPLETE DOMINANCE!
•! Nearly all dominant diseases have incomplete dominance !
(that is why the term is not normally used).!
Huntington disease is an exception (it is really DOMINANT).!
CODOMINANCE:"
•! When the two alleles can be independently detected!
•! Clear example : A and B blood groups!
•! It is normally used for markers.!
DOMINANCIA Y RECESIVIDAD"
DOMINANCE AND RECESSIVITY"
A CLEAR EXAMPLE OF INCOMPLETE DOMINANCE :!
FAMILIAL HYPERCOLESTEROLEMIA!
•! It is considered an AUTOSOMAL DOMINANT disease !
•! Affected individualr (heterozygous for mutations in the !
LDL receptor gene) have a 50% risk of heart attack !
at age 50.!
•! Prevalence: about 1/500!
But HOMOZYGOUS individuals, with a prevalence of 1/1.000.000,!
have coronary disease in infancy and most of them do not!
live longer than 30 years.!
DOMINANCIA Y RECESIVIDAD"
DOMINANCE AND RECESSIVITY"
Everything is relative:"
•! Dominance and recessivity depend on our level of !
observation.!
Example: SICKLE CELL ANEMIA"
•! It is considered as an AUTOSOMAL RECESSIVE disease.!
•! Patients are HOMOZYGOUS for the HbS allele of !
the " globin gene.!
•! HETEROZYGOUS have: !
!- one HbS allele and one normal allele (HbA). !
!- a mild anemia (not considered disease).!
!- some sickle cells!
DOMINANCE AND RECESSIVITY"
SICKLE CELL ANEMIA, is it DOMINANT or RECESSIVE?"
•! At the level of Hb synthesis, the two alleles are codominant !
•! At the physiological level, there is incomplete dominance !
•! At the clinical level, sickle cell anemia is recessive !
DOMINANCE AND RECESSIVITY"
IN GENERAL:"
•! Enzymatic defects => RECESSIVE INHERITANCE!
•! Structural protein defects => DOMINANT INHERITANCE!
•! Loss of function => RECESSIVE INHERITANCE!
•! Gain of function => DOMINANT INHERITANCE!
COMPLICATIONS IN MENDELIANS PATTERNS"
RECESSIVE PATTERN THAT SEEMS TO BE DOMINANT"
COMPLICATIONS IN MENDELIANS PATTERNS"
IMPRINTING: Familial Paraganglioma, the phenotype is only expressed !
if inherited from the father"
COMPLICATIONS IN MENDELIANS PATTERNS"
IMPRINTING: Beckwith-Wiedemann, the phenotype is only expressed !
if inherited from the mother!
COMPLICATIONS IN MENDELIANS PATTERNS"
Incontinentia pigmenti: XL dominant. !
Affected males end up in spontaneous abortions"
COMPLICATIONS IN MENDELIANS PATTERNS"
Consanguinity in an XL-recessive pattern with affected women and !
apparent male-to-male transmission !
COMPLICATIONS IN MENDELIANS PATTERNS"
A de novo dominant mutation may suggest an autosomal recessive or an!
XL-recessive pattern!
