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 A three generation family history should be a standard component of medical practice. Family standard component of medical practice. Family history of the patient is usually summarized in the history of the patient is usually summarized in the form of a pedigreeform of a pedigree

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 (haploinsufficiency), the phenotype is deemed dominantdominant

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 allele

ex: 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

Aa

A 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 alle le (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

Aa

A a

aa

maternal

pate

rnal

X1. Probability of Carrier = 2/3

Cystic FibrosisCystic FibrosisA aMaternal

a

APa

tern

al

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 ancesto r. 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