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Transcript of Medtech gen-2 a-single-gene-disorders
Patterns of Single gene Patterns of Single gene disordersdisorders
Lecture 2
Objectives for this lectureObjectives for this lecture
Gain familiarity with pedigrees & family historyGain familiarity with pedigrees & family history
Appreciate distinctions between major patterns of Appreciate distinctions between major patterns of single gene inheritancesingle gene inheritance
Autosomal dominant, autosomal recessive, sex-linked Autosomal dominant, autosomal recessive, sex-linked recessive, sex-linked dominantrecessive, sex-linked dominant
Understand factors which complicate inheritance Understand factors which complicate inheritance patternspatterns
TerminologyTerminology 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 individual’s 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.
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.
Compound heterozygous- Having two different mutant alleles of the same gene, rather than one normal and one mutant.
Heterozygous - Having two different alleles at a particular locus, usually in reference to one normal allele and one disease allele.
Basic terminologyBasic terminologyGenotype: Genotype: A AA A(Homozygous)(Homozygous)
AA AA
GenotypeGenotype: : AA BB(Heterozygous)(Heterozygous)
AA BB
Single gene disorder - determined by the alleles at a single locusSingle gene disorder - determined by the alleles at a single locus
Chromosome 6 Chromosome 6 Maternal copyMaternal copy DNADNA
GeneGene
Chromosome 6 Chromosome 6 Paternal copyPaternal copy
ReminderReminder AutosomesAutosomes
Chromosomes 1-22Chromosomes 1-22 An individual inherits one chromosome from each An individual inherits one chromosome from each
parentparent An individual therefore inherits a paternal copy and a An individual therefore inherits a paternal copy and a
maternal copy of an autosomal genematernal copy of an autosomal gene
Sex chromosomesSex chromosomes X and YX and Y A female inherits an X from their mother and an X from A female inherits an X from their mother and an X from
their fathertheir father A male inherits an X from their mother and the Y from A male inherits an X from their mother and the Y from
their father their father
Single-gene traits are often called ‘Mendelian’ because likethe garden peas studied by Gregor Mendel, they occurin 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 pedigreeObtaining a pedigree
A three generation family history should be a standard A three generation family history should be a standard component of medical practice. Family history of component of medical practice. Family history of the patient is usually summarized in the form of a the patient is usually summarized in the form of a pedigreepedigree
Points to remember:Points to remember:• ask whether relatives have a similar problemask whether relatives have a similar problem• ask if there were siblings who have diedask if there were siblings who have died• inquire about miscarriages, neonatal deathsinquire about miscarriages, neonatal deaths• be aware of siblings with different parentsbe aware of siblings with different parents• ask about consanguinity ask about consanguinity • ask about ethnic origin of family branchesask about ethnic origin of family branches
Pedigree terminologyPedigree 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)
Pedigree terminologyPedigree 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 Recessive2. Autosomal Dominant3. X-linked Recessive4. X-linked Dominant
Dominant and Recessive MechanismsDominant and Recessive Mechanisms• Loss of functionLoss of function
• Usually recessive; mutation leads to inactive gene Usually recessive; mutation leads to inactive gene product but reduced activity level still sufficientproduct but reduced activity level still sufficient
• However, if reduced activity not sufficient However, if reduced activity not sufficient (haploinsufficiency), the phenotype is deemed dominant(haploinsufficiency), the phenotype is deemed dominant
Activity
Protein 1 Protein 2
Lecture 3
Incomplete dominance: phenotype in Incomplete dominance: phenotype in hetrozygous is different from that seen in hetrozygous is different from that seen in both homozygous genotypes and its both homozygous genotypes and its severity is intermediate b/w themseverity is intermediate b/w them
Codominant alleles: if expression of each Codominant alleles: if expression of each allele can be detected even in presence of allele can be detected even in presence of the otherthe other
Dominant and Recessive Mechanisms continuedDominant 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 alleleex: collagen mutations in osteogenesis imperfecta
Age of Onset and Other Factors Affecting Age of Onset and Other Factors Affecting Pedigree PatternsPedigree Patterns
Age of OnsetAge of Onset Not all genetic disorders are congenital; many are not Not all genetic disorders are congenital; many are not
expressed until later in life, some at a characteristic age expressed until later in life, some at a characteristic age and others at variable agesand others at variable ages
A genetic disorder is determined by genes, a congenital A genetic disorder is determined by genes, a congenital disease is that present at birth and may or may not be disease is that present at birth and may or may not be geneticalgenetical
Many genetic disorders develop prenatally and thus are both Many genetic disorders develop prenatally and thus are both genetic and congenital (e.g., osteogenesis imperfecta)genetic and congenital (e.g., osteogenesis imperfecta)
Some may be lethal in prenatal lifeSome may be lethal in prenatal life Others expressed as soon as the infant begins independent lifeOthers expressed as soon as the infant begins independent life Others appear later, at a variety of ages (from birth to post-Others appear later, at a variety of ages (from birth to post-
reproductive years) reproductive years)
Other Factors Affecting Pedigree Other Factors Affecting Pedigree PatternsPatterns
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 HeterogeneityGenetic Heterogeneity Genetic heterogeneity: includes a number of Genetic heterogeneity: includes a number of
phenotyopes that are similar but are actually phenotyopes that are similar but are actually determined by different genotypes. May be due determined by different genotypes. May be due to allelic heterogeneity, locus heterogeneity, or to allelic heterogeneity, locus heterogeneity, or bothboth
Allelic heterogeneityAllelic heterogeneity: different mutations at the : different mutations at the same locussame locus
Locus heterogeneityLocus heterogeneity: mutations at different loci: mutations at different loci Recognition of genetic heterogeneity is an Recognition of genetic heterogeneity is an
important aspect of clinical diagnosis and important aspect of clinical diagnosis and genetic counseling genetic counseling
Locus HeterogeneityLocus Heterogeneity
Pedigree analysis may be sufficient to Pedigree analysis may be sufficient to demonstrate locus heterogeneitydemonstrate locus heterogeneity
Example-1, Example-1, retinitis pigmentosaretinitis pigmentosa A common cause of visual impairment due to A common cause of visual impairment due to
photoreceptor degeneration associated with abnormal photoreceptor degeneration associated with abnormal pigment distribution in retina.pigment distribution in retina.
Known to occur in AD, AR, and X-linked formsKnown to occur in AD, AR, and X-linked forms Example-2, Example-2, Ehndlers-Danlos syndromeEhndlers-Danlos syndrome,,
Skin & other connective tissues may be excessively Skin & other connective tissues may be excessively elastic or fragile, defect in collagen structureelastic or fragile, defect in collagen structure
May be AD, AR, or X-linkedMay be AD, AR, or X-linked At least 10 different loci involved At least 10 different loci involved
Allelic HeterogeneityAllelic 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
In fact, unless they have consanguineous In fact, unless they have consanguineous parents, most people with autosomal parents, most people with autosomal recessive disorders are more likely to have recessive disorders are more likely to have compound rather than truly homozygous compound rather than truly homozygous genotypesgenotypes
Because different allelic combinations may Because different allelic combinations may have somewhat different clinical have somewhat different clinical consequences, one must be aware of consequences, one must be aware of allelic heterogeneity as one possible allelic heterogeneity as one possible explanation for explanation for variability among patients variability among patients considered to have same disease 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.
Pedigree illustrating recessive inheritance
Autosomal Recessive
Lecture 3
Disease Frequency Chromosome
Cystic fibrosis
-Thalassemia
-Thalassemia
Sickle cell anemia
Myeloperoxidase deficiency
Phenylketonuria
Gaucher disease
Tay-Sachs disease
Hurler syndrome
Glycogen storage disease Ia(von Gierke disease)
Wilson disease
Hereditary hemochromatosis
1-Antitrypsin deficiency
Oculocutaneous albinism
Alcaptonuria
1/2,500
High
High
High
1/2,000
1/10,000
1/1,000
1/4,000
1/100,000
1/100,000
1/50,000
1/1,000
1/7,000
1/20,000
<1/100,000
7q
16p
11p
11p
17q
12q
1q
15q
22p
17q
13q
6p
14q
11q
3q
Representative Autosomal Recessive Disorders
Metachromatic leukodystrophy 1/100,000 22q
Cystic fibrosis (CF) - an Cystic fibrosis (CF) - an autosomal recessive diseaseautosomal recessive disease
Diseased homozygotes: 1/2000Diseased homozygotes: 1/2000 Carriers (heterozygotes): 1/22Carriers (heterozygotes): 1/22
Caused by mutations in the cystic fibrosis Caused by mutations in the cystic fibrosis transmembrane conductance regulator gene transmembrane conductance regulator gene (CFTR) on chromosome 7q31(CFTR) on chromosome 7q31
Clinical symptoms include pancreatic Clinical symptoms include pancreatic insufficiency and pulmonary infectionsinsufficiency and pulmonary infections
Multiorgan System Manifestations of CF
Secondary biliary cirrhosis
Malabsorption
Obstructed vasdeferens (sterility)
Meconium ileus(newborn)
Chronic pancreatitis
Abnormal sweat electrolytes
• Lung abscess
• Chronic bronchitis
• Bronchiectasis
• Honeycomb lung
CFTR functionCFTR functionRegulates the flow of chloride ions Regulates the flow of chloride ions
across the cell membraneacross the cell membrane
Example: cystic fibrosis
P
What is the probability that th is pregnancy will
lead to an affected child?
What is the probability he will have a child with CF?
AA
Aa
A
a
1/4 unaffected non-carrier
1/2 unaffected carrier
AaA a
aa
1/4 affected
maternal
pate
rnal
1 2 A
m a t e r n a l
p a t e r n a l
1 2 a 1
2 A
1 2 a
1 2 A
1 2 a
1 4 aa affected
1 4 aA
1 4 Aa
1 4 AA unaffected, non-carrier
unaffected carrier
p = freq. of one allele (here M) q = freq. of other alle le(s), by convention the less common (here N)
(M /M)thus, the 3 genotypes are ....
p = freq. of non-carriers2
(M /N ) pq(N/ M) qp
(N/N ) q = freq. of homozygous affecteds2
2pq = frequency of heterozygote carriers
2. Probability of Mate Carrier:
q2 =1/2,000q = (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(Mate’s Carrier) x P(Transmit Affected Allele)
(2/3) x (1/2) x (1/23) x (1/2) = 0.008 = 0.8%
AA
Aa
A
a
AaA a
aa
maternal
pate
rnal
X1. Probability of Carrier = 2/3
Cystic FibrosisCystic FibrosisA aMaternal
a
APate
rnal
AA
aa
Aa
Aa1/4 1/4
1/4 1/4
unaffected non-carrier
unaffected carrier
affected
1/4
1/2
1/4What is the probability that this pending pregnancy will be affected?
aa
Aa Aa
Note also that 2/3 of the normal siblings of a recessive child are heterozygous: Aa/(AA+Aa)=1/2/3/4
ConsanguinityConsanguinity
• Refers to a relationship by Refers to a relationship by descent from a common descent from a common ancestor (inbreeding)ancestor (inbreeding)
• A concern in autosomal A concern in autosomal recessive disorders.recessive disorders.
• If a rare disease (due to If a rare disease (due to infrequent alleles), the infrequent alleles), the disease will occur more disease will occur more commonly in individuals commonly in individuals whose parents are related.whose parents are related.
Phenylketonuria Phenylketonuria
(PKU)(PKU)
2nd cousin mating2nd cousin mating
Studies of the offspring of incestuous matings indicate that everyone carries at least 8-10mutant alleles from well-known autosomal recessive disorders
However, the offspring of first cousin marriages are only at twice the risk of abnormal offspringcompared to the general population
pedigree
Calculating the inbreeding coefficient (F) for a child of a first cousin mating
Measure of consanguinityis relevant because the riskof a child being homozygous for a rare allele is proportionalto how related the parents are
Coefficient of inbreeding (F)-probability that an individualhas received both alleles at a locus from an ancestral source= proportion of loci identical by descent from the common ancestor
A1
1/2
1/2
1/2 1/2
1/2
1/2
pedigree Path diagram
(F) = 1/16
Inbreeding coefficient (F) of the proband is 1/16; he has a 6% chance of being homozygous by descent for any locus
A1
E xam ple consangu inity : re la tionship by descent from a com m on ancestor. S een m ore com m only w ith au tosom al recessive inheritance
P
2nd cousin m ating
P robab ility P KU 1 /4 x 1/4 x 1 /4 = 1/64
phenylke tonuria (P KU)
1
1 /2
1 /4
1
1 /2
1 /4
Rare recessive disorders in genetic Rare recessive disorders in genetic isolatesisolates
Genetic isolates: groups in which the frequency Genetic isolates: groups in which the frequency of rare recessive genes is quite different from of rare recessive genes is quite different from that in the general populationthat in the general population
Although such populations are not Although such populations are not consanguineous, the chance of mating with consanguineous, the chance of mating with another carrier of a particular recessive another carrier of a particular recessive condition may be as high as observed in cousin condition may be as high as observed in cousin marriagesmarriages
E.g., Tay-Sachs disease (GM2 gangliosidosis) a E.g., Tay-Sachs disease (GM2 gangliosidosis) a lysosomal storage diseaselysosomal storage disease
Tay-Sachs Disease lysosomal storage disease
normal Tay-Sachs Disease
GM2 ganglioside
hexosaminidase A
GM2 ganglioside
hexosaminidase A
removal/ recycling ofsphingolipid components
GM2 ganglioside accumulates in the lysosomes
degradationproducts
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
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 retina normal retina
Tay-Sachs disease: Autosomal recessive disorderRare in some populations and common in others.
Disease and carrier frequencies in some other ethnic groups (French Canadians, Louisiana Cajuns, and Pennsylvania Amish) are comparable to those seen among Ashkenazi Jews.
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, and1/30 for North American Ashkenazi Jews
Sex-Influenced DisordersSex-Influenced Disorders
Ordinarily, AR disorders occur with equal frequency Ordinarily, AR disorders occur with equal frequency in males and femalesin males and females
Some AR phenotypes are sex-influenced, i.e., Some AR phenotypes are sex-influenced, i.e., expressed in both sexes but with different expressed in both sexes but with different frequenciesfrequencies
E.g., hemochromatosis, a disorder of iron E.g., hemochromatosis, a disorder of iron metabolism with enhanced absorption of dietary iron metabolism with enhanced absorption of dietary iron iron overload iron overload pathological consequences pathological consequences
The disease phenotype is more common in malesThe disease phenotype is more common in males The lower incidence in females (one tenth that of The lower incidence in females (one tenth that of
males) may be due to lower intake of iron & males) may be due to lower intake of iron & increased iron loss through menstruation increased iron loss through menstruation
2pq>>q2
• New mutation almost never a consideration for autosomal recessive diseases (follows from Haldane’s Rule)
• Potential for heterozygote selection
Haldane’s 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.
• If disorder appears in more than one family member, If disorder appears in more than one family member, typically it is found only typically it is found only within a sibshipwithin a sibship, not in other , not in other generations.generations.
• The recurrence risk for each sib of the proband is 25%.The recurrence risk for each sib of the proband is 25%.
• More common with More common with consanguinityconsanguinity, , especially for rare especially for rare diseases.diseases.
• Usually, males and females are Usually, males and females are equallyequally likely to be likely to be affected (with rare exceptions)affected (with rare exceptions)
• New mutation is almost never a consideration. Parents of New mutation is almost never a consideration. Parents of an affected child are asymptomatic carriers an affected child are asymptomatic carriers
Characteristics of Autosomal Recessive Characteristics of Autosomal Recessive DisordersDisorders