Download Single gene disorders

Patterns of Single gene
disorders
Mohamad Nusier MD. PhD.
Objectives for this lecture
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Gain familiarity with pedigrees & family history
Appreciate distinctions between major patterns of
single gene inheritance
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Autosomal dominant, autosomal recessive, sex-linked
recessive, sex-linked dominant
Understand factors which complicate inheritance
patterns
Terminology
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Gene - The basic hereditary unit, initially defined by
phenotype. By molecular definition, a DNA sequence required
for production of a functional product, usually a protein, but
may be an untranslated RNA.
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Genotype - An individual’s genetic constitution, either
collectively at all loci or more typically at a single locus.
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Phenotype - Observable expression of genotype as a trait
(morphological, clinical, biochemical, or molecular) or disease
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Allele - One of the alternate versions of a gene present in a
population.
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Locus - Literally a “place” on a chromosome or DNA molecule.
Used fairly interchangeably with “gene” and sometimes used to
refer to a collection of closely spaced genes.
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Wild-type (normal) allele: prevailing version,
present in majority of individuals
Mutant allele: usually rare, differ from wild-type
allele by mutation
Mutation: permanent change in nucleotide
sequence or arrangement of DNA
Polymorphism: ≥ 2 relatively common (each >
1% in population) alleles at a locus in the
population
Dominant trait - a trait that shows in a
heterozygote
Recessive trait - a trait that is hidden in a
heterozygote
Homozygous - Having two identical alleles
at a particular locus, usually in reference
to two normal alleles or two disease
alleles.
Heterozygous - Having two different
alleles at a particular locus, usually in
reference to one normal allele and one
disease allele.
Compound heterozygous- Having two
different mutant alleles of the same gene,
rather than one normal and one mutant.
Basic terminology
Genotype: A A
B
(Heterozygous)
(Homozygous)
A
B
A
Gene
Chromosome 6
Maternal copy
DNA
Chromosome 6
Paternal copy
Single gene disorder - determined by the alleles at a single locus
Reminder
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Autosomes
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Chromosomes 1-22
An individual inherits one chromosome from each
parent
An individual therefore inherits a paternal copy and a
maternal copy of an autosomal gene
Sex chromosomes
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X and Y
A female inherits an X from their mother and an X from
their father
A male inherits an X from their mother and the Y from
their father
Single-gene traits
are often called ‘Mendelian’ because
like the garden peas studied by Gregor
Mendel, they occur in fixed proportions
among the offspring of specific types of
mating.
Single-gene disorders are primarily disorders of the
pediatric age range
greater than 90% manifest before puberty
only 1% occur after the end of the reproductive period
Obtaining a pedigree
A three generation family history should be a
standard component of medical practice. Family
history of the patient is usually summarized in the
form of a pedigree
Points to remember:
• ask whether relatives have a similar problem
• ask if there were siblings who have died
• inquire about miscarriages, neonatal deaths
• be aware of siblings with different parents
• ask about consanguinity
• ask about ethnic origin of family branches
Pedigree terminology
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Proband (propositus or index case): is the affected
individual through whom a family with a genetic disorder
is first brought to attention.
Consultand: the person who brings the family to
attention by consulting a geneticist, may be an
unaffected/affected relative of the proband
Brothers and sisters = sibs, and a family of sibs =
sibship
Kindred = the entire family. Relatives are classified 1st
degree, 2nd degree, etc.
Consanguineous = couples who have one or more
ancestors in common
Isolated case = if only one affected member in the
kindred (= sporadic case if disorder in proband is
determined to be due to new mutation)
Pedigree terminology
proband
first degree
second degree
third degree
fourth degree
Patterns of Single Gene Inheritance depend on 2 factors:
1. Whether the gene is on an autosome or a sex
chromosome
2. Whether the phenotype is dominant or recessive
Thus, there are 4 basic patterns of single gene
inheritance
1. Autosomal Recessive
2. Autosomal Dominant
3. X-linked Recessive
4. X-linked Dominant
Dominant and Recessive Mechanisms
• Loss of function
• Usually recessive; mutation
leads to inactive gene
product but reduced activity
level still sufficient
• However, if reduced activity
not sufficient
(haploinsufficiency), the
phenotype is deemed
dominant
• A haplotype is a set of
DNA variations, or
polymorphisms, that tend
to be inherited together.
Activity
Protein 1
Protein 2
 Incomplete
dominance: phenotype in
hetrozygous is different from that seen in
both homozygous genotypes and its
severity is intermediate b/w them
 Codominant alleles: if expression of each
allele can be detected even in presence of
the other
Dominant and Recessive Mechanisms continued
• Loss of function
• Usually recessive; mutation leads to inactive gene product but
reduced activity level still sufficient
• However, if reduced activity not sufficient (haploinsufficiency),
the phenotype is deemed dominant
• Gain of function
• Novel action
• Altered mRNA expression
• Increased/decreased protein activity
• ex: huntingtin mutations
• Dominant negative
• Abnormal function that interferes with normal allele
ex: collagen mutations in osteogenesis imperfecta
Age of Onset and Other Factors Affecting
Pedigree Patterns
Age of Onset
 Not all genetic disorders are congenital; many are not
expressed until later in life, some at a characteristic age
and others at variable ages
 A genetic disorder is determined by genes, a congenital
disease is that present at birth and may or may not be
genetical
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Many genetic disorders develop prenatally and thus are both
genetic and congenital (e.g., osteogenesis imperfecta)
Some may be lethal in prenatal life
Others expressed as soon as the infant begins independent life
Others appear later, at a variety of ages (from birth to postreproductive years)
Other Factors Affecting Pedigree
Patterns
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Small family size: the patient may be the only affected
member  the inheritance pattern may not be
immediately apparent
 New mutation: is a frequent cause of AD and X-linked
disease
 Diagnostic difficulties: owing to absent or variable
expression of the gene
 Other genes and environmental factors: may affect gene
expression
 Persons of some genotypes may fail to survive to time of
birth
 Accurate info. about presence of disorder in relatives or
about family relationships may be lacking
Genetic Heterogeneity
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Genetic heterogeneity: includes a number of
phenotyopes that are similar but are actually
determined by different genotypes. May be due
to allelic heterogeneity, locus heterogeneity, or
both
 Allelic heterogeneity: different mutations at the
same locus
 Locus heterogeneity: mutations at different loci
 Recognition of genetic heterogeneity is an
important aspect of clinical diagnosis and
genetic counseling
Locus Heterogeneity
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Pedigree analysis may be sufficient to
demonstrate locus heterogeneity
 Example-1, retinitis pigmentosa
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A common cause of visual impairment due to
photoreceptor degeneration associated with abnormal
pigment distribution in retina.
Known to occur in AD, AR, and X-linked forms
Example-2, Ehndlers-Danlos syndrome,
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Skin & other connective tissues may be excessively
elastic or fragile, defect in collagen structure
May be AD, AR, or X-linked
At least 10 different loci involved
Allelic Heterogeneity
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An important cause of clinical variation
 Sometimes, different mutations at same locus 
clinically indistinguishable or closely similar disorders
 In other cases, different mutant alleles at same locus 
very different clinical presentations
 Example-1: RET gene (encodes a receptor tyrosine
kinase)
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Some mutations cause dominantly inherited failure of
development of colonic ganglia  defective colonic motility and
severe chronic constipation (Hirschsprung disease)
Other mutations in same gene  dominantly inherited cancer of
thyroid and adrenal gland (multiple endocrine neoplasia)
A third group of RET mutations  both Hirschsprung disease
and multiple endocrine neoplasia in the same individual
 In
fact, unless they have consanguineous
parents, most people with autosomal
recessive disorders are more likely to have
compound rather than truly homozygous
genotypes
 Because different allelic combinations may
have somewhat different clinical
consequences, one must be aware of
allelic heterogeneity as one possible
explanation for variability among patients
considered to have same disease
ALLELIC DISORDERS (Clinical heterogeneity)This is an extreme example of how different
mutations in the same gene can cause divergent
phenotypes, in which there are actually two
different diseases caused by the same gene.
Autosomal Recessive
Pedigree illustrating recessive inheritance
Representative Autosomal Recessive Disorders
Disease
Frequency
Chromosome
Cystic fibrosis
1/2,500
7q
-Thalassemia
High
16p
-Thalassemia
High
11p
Sickle cell anemia
High
11p
Myeloperoxidase deficiency
1/2,000
17q
Phenylketonuria
1/10,000
12q
Gaucher disease
1/1,000
1q
Tay-Sachs disease
1/4,000
15q
Hurler syndrome
1/100,000
22p
Glycogen storage disease Ia
(von Gierke disease)
1/100,000
17q
Wilson disease
1/50,000
13q
Hereditary hemochromatosis
1/1,000
6p
1-Antitrypsin deficiency
1/7,000
14q
Oculocutaneous albinism
1/20,000
11q
Alcaptonuria
<1/100,000
3q
Metachromatic leukodystrophy
1/100,000
22q
Cystic fibrosis (CF) - an
autosomal recessive disease
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Diseased homozygotes: 1/2000 (incidence)
 Carriers (heterozygotes): 1/22 (incidence)
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Caused by mutations in the cystic fibrosis
transmembrane conductance regulator gene
(CFTR) on chromosome 7q31
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Clinical symptoms include pancreatic
insufficiency and pulmonary infections
Multiorgan System Manifestations of CF
• Lung abscess
• Chronic bronchitis
• Bronchiectasis
Secondary biliary
cirrhosis
Malabsorption
• Honeycomb lung
Chronic pancreatitis
Meconium ileus
(newborn)
Obstructed vas
deferens (sterility)
Abnormal sweat
electrolytes
paternal
maternal
A
a
A
AA
Aa
1/4 unaffected non-carrier
a
Aa
aa
1/2 unaffected carrier
1/4 affected
Cystic Fibrosis
Paternal
Maternal
A
a
a
Aa
aa
1/4
A AA
Aa
1/4
Aa
aa
Aa
1/4
1/4
unaffected 1/4
non-carrier
unaffected 1/2
carrier
affected
1/4
Consanguinity
• Refers to a relationship by
descent from a common
ancestor (inbreeding)
Phenylketonuria
(PKU)
• A concern in autosomal
recessive disorders.
• If a rare disease (due to
infrequent alleles), the
disease will occur more
commonly in individuals
whose parents are related.
2nd cousin mating
Studies of the offspring of incestuous matings
indicate that everyone carries at least 8-10
mutant alleles from well-known autosomal
recessive disorders
However, the offspring of first cousin marriages
are only at twice the risk of abnormal offspring
compared to the general population
Rare recessive disorders in genetic
isolates
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Genetic isolates: groups in which the frequency
of rare recessive genes is quite different from
that in the general population
 Although such populations are not
consanguineous, the chance of mating with
another carrier of a particular recessive
condition may be as high as observed in cousin
marriages
 E.g., Tay-Sachs disease (GM2 gangliosidosis) a
lysosomal storage disease
Tay-Sachs Disease lysosomal storage disease
normal
GM2 ganglioside
Tay-Sachs Disease
GM2 ganglioside
hexosaminidase A
hexosaminidase A
degradation
products
removal/ recycling of
sphingolipid components
GM2 ganglioside
accumulates in
the lysosomes
Neurodegeneration
Tay-Sachs: the clinical picture
• Infants with Tay-Sachs appear normal until
about 3 to 6 months of age
• Motor development plateaus by 8-10 months
• loss of all voluntary movement by 2 yrs
• Visual deterioration begins within the first year,
"cherry red spot" at the macula (retina).
• Worsening seizures
• difficulty swallowing
• vegetative, unresponsive state
• Patients almost always die by 2 to 4 years of
age.
• There is no cure, and no effective treatment.
The cherry-red spot of Tay-Sachs
Tay-Sachs retina
normal retina
The "spot" is the normal retina of the fovea (at the center of
the macula) that is surrounded by macular retina made
whitish by the abnormal accumulation of GM2 ganglioside.
Tay-Sachs disease:
Autosomal recessive disorder
Rare in some populations and common in others.
Frequency of Tay-Sachs is about:
1/360,000 live births for non-Ashkenazi
North Americans, and
1/3600 for North American Ashkenazi Jews
Carrier frequencies are therefore about:
1/300 for most North Americans, and
1/30 for North American Ashkenazi Jews
Disease and carrier frequencies in some other ethnic
groups (French Canadians, Louisiana Cajuns, and
Pennsylvania Amish) are comparable to those seen
among Ashkenazi Jews.
Sex-Influenced Disorders
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Ordinarily, AR disorders occur with equal frequency
in males and females
Some AR phenotypes are sex-influenced, i.e.,
expressed in both sexes but with different
frequencies
E.g., hemochromatosis, a disorder of iron
metabolism with enhanced absorption of dietary iron
 iron overload  pathological consequences
The disease phenotype is more common in males
The lower incidence in females (one tenth that of
males) may be due to lower intake of iron &
increased iron loss through menstruation
Characteristics of Autosomal Recessive
Disorders
• If disorder appears in more than one family member,
typically it is found only within a sibship, not in other
generations.
• The recurrence risk for each sib of the proband is 25%.
• More common with consanguinity, especially for rare
diseases.
• Usually, males and females are equally likely to be
affected (with rare exceptions)
• New mutation is almost never a consideration. Parents of
an affected child are asymptomatic carriers
Rules of Inheritance
Autosomal Recessive
 •Appears
in both sexes with equal
frequency
 • Trait tend to skip generations
 • Affected offspring are usually born to
 unaffected parents
 • When both parents are heterozygotes,
approx. 1/4 of the progeny will be affected
 • Appears more frequently among the
 children of consanguine marriages
Autosomal recessive
Expressed in both sexes at approximately
equal frequency: AUTOSOMAL
Not expressed in every generation:
RECESSIVE
Autosomal Dominant
In every generation: DOMINANT
Equal in Males and Females: Autosomal
Rules of Inheritance
X-Linked Dominant
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• Both males and females are affected; often
more females than males are affected
• Does not skip generations.
• Affected sons must have an affected mother
• Affected daughters must have either an
affected mother or an affected father
• Affected fathers will pass the trait on to all their
daughters
• Affected mothers if heterozygous will pass the
trait on to 1/2 of their sons and 1/2 of their
daughters
X-Linked Dominant
Every Generation: Dominant
Father passes on to only daughters
Mothers passes on to 1/2 of offspring
Rules of Inheritance
X-Linked Recessive
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• More males than females are affected
• Affected sons are usually born to unaffected
mothers, thus the trait skips generations
• Approximately 1/2 of carrier mothers’ sons are
affected
• It is never passed from father to son
• All daughters of affected fathers are carriers
X-linked recessive Hemophilia
Only males are affected and sons do not share the
phenotype of their father - Thus X-linked
Expression of hemophilia skips generations:
RECESSIVE
Rules of Inheritance
Mitochondrial
 Trait is inherited from mother only
 • All children of a mother are at risk to be
affected or carriers
Y-Linked Dominant
 • Only males are affected
 • It is passed from father to all sons
 • It does not skip generations
A mitochondrial trait.
Note that transmission occurs only through females.
Y-Linked
Only males are affected
All sons of affected
father are affected