Patterns of Single gene disorders

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Patterns of Single gene disorders
Lecture 2
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Objectives for this lecture

• Gain familiarity with pedigrees family history
• Appreciate distinctions between major patterns
  of single gene inheritance
• Autosomal dominant, autosomal recessive,
  sex-linked recessive, sex-linked dominant
• Understand factors which complicate inheritance
  patterns

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Terminology

• 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.
• Genotype - An individuals genetic constitution,
  either collectively at all loci or more typically
  at a single locus.
• Phenotype - Observable expression of genotype as
  a trait (morphological, clinical, biochemical, or
  molecular) or disease
• Allele - One of the alternate versions of a gene
  present in a population.
• 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 gt 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

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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.
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Basic terminology
Single gene disorder - determined by the alleles
at a single locus
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Reminder

• Autosomes
• 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
• 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

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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.
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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
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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

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Pedigree terminology

• 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
  propositus is determined to be due to new
  mutation)

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Pedigree terminology
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• Patterns of Single Gene Inheritance depend on 2
  factors
• Whether the gene is on an autosome or a sex
  chromosome
• Whether the phenotype is dominant or recessive
• Thus, there are 4 basic patterns of single gene
  inheritance
• Autosomal Recessive
• Autosomal Dominant
• X-linked Recessive
• X-linked Dominant

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Dominant and Recessive Mechanisms
Lecture 3

• 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

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• 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

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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

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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
• 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 post-reproductive years)

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Other Factors Affecting Pedigree Patterns

• 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

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Genetic Heterogeneity

• 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

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Locus Heterogeneity

• Pedigree analysis may be sufficient to
  demonstrate locus heterogeneity
• Example-1, retinitis pigmentosa
• 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,
• 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

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Allelic Heterogeneity

• 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)
• 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

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• 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

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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.
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Lecture 3
Autosomal Recessive
Pedigree illustrating recessive inheritance
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Cystic fibrosis (CF) - an autosomal recessive
disease

• Diseased homozygotes 1/2000
• Carriers (heterozygotes) 1/22
• Caused by mutations in the cystic fibrosis
  transmembrane conductance regulator gene (CFTR)
  on chromosome 7q31
• Clinical symptoms include pancreatic
  insufficiency and pulmonary infections

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Multiorgan System Manifestations of CF
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CFTR function
Regulates the flow of chloride ions across the
cell membrane
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maternal
l
A
a
a
n
r
e
AA
A
1/4 unaffected non-carrier
Aa
t
a
p
Aa
a
1/2 unaffected carrier
aa
1/4 affected
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1. Probability of Carrier 2/3
2. Probability of Mate Carrier q2 1/2,000 q
(1/2,000)1/2 q 0.022 (use p ? 1) heterozygote
freq. 2pq ? 2q (2)(0.022) 0.044 4.4 ?
1/23 3. Put it together P(Carrier) x P(Transmit
Affected Allele) x P(Mates Carrier) x P(Transmit
Affected Allele) (2/3) x (1/2) x (1/23) x (1/2)
0.008 0.8
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Cystic Fibrosis
1/4
aa
1/2
1/4
Note also that 2/3 of the normal siblings of a
recessive child are heterozygous
Aa/(AAAa)1/2/3/4
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Consanguinity
Phenylketonuria (PKU)

• Refers to a relationship by descent from a common
  ancestor (inbreeding)
• 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
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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
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Calculating the inbreeding coefficient (F) for a
child of a first cousin mating
Measure of consanguinity is relevant because the
risk of a child being homozygous for a rare
allele is proportional to how related the parents
are
pedigree
Coefficient of inbreeding (F) -probability that
an individual has received both alleles at a
locus from an ancestral source proportion of
loci identical by descent from the common
ancestor
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Inbreeding coefficient (F) of the proband is
1/16 he has a 6 chance of being homozygous by
descent for any locus
pedigree
Path diagram
1/2
1/2
1/2
1/2
1/2
1/2
(F) 1/16
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Rare recessive disorders in genetic isolates

• 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

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Tay-Sachs Disease lysosomal storage disease
Tay-Sachs Disease
normal
GM2 ganglioside
GM2 ganglioside
hexosaminidase A
hexosaminidase A
degradation products
GM2 ganglioside accumulates in the lysosomes
removal/ recycling of sphingolipid components
Neurodegeneration
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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.

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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.
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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.
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Sex-Influenced Disorders

• 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

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2pqgtgtq2

• New mutation almost never a consideration for
  autosomal recessive diseases (follows from
  Haldanes Rule)
• Potential for heterozygote selection

Haldanes Rule Since the incidence of a disease
remains constant over time, then the mutant
alleles lost because of reduced fitness must be
balanced by alleles arising from new mutation.
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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