Single Gene Disorders

square

male

circle

female

diamond

sex unstated

unfilled symbol

unaffected

filled symbol

affected

symbol with dot in middle

obligate carrier (who will not manifest disease)

symbol with line inside

carrier who may go on to manifest disease

symbol with strike through

deceased

symbols connected with straight line

mating

symbols connected with two lines

consanguineous mating

symbols connected with bracket

siblings

symbols connected by pointed bracket

twins

symbols connected by triangle

identical twins

diamond with 4 inside

four children, sex unstated

triangle

spontaneous abortion

filled triangle with strike through

termination of affected pregnancy

pedigree

graphical representation of a family tree that uses standard symbols  

sibship

a series of brothers and sisters

probrand

the affected individual through whom a family with the genetic disorder comes to medical attention

generations

• 1^0: parent and child; sibs  

• 2^0: grandparent and grandchild; uncle/aunt and nephew/niece; half-sibs  

• 3^0: first cousins 

dominant, recessive

When a human monogenic disorder (or trait) is determined by a nuclear gene, the disorder (or trait) is said to be ______ if it is manifested in the heterozygote (who carries a normal allele and a mutant allele), or _____ if it is not

5 basic Mendelian inheritance patterns

• Autosomal dominant  

• Autosomal recessive  

• X linked dominant  

• X linked recessive  

• Y linked  

dominant conditions

50% chance

(assuming parent is heterozygous dominant)

recessive conditions

25% chance

(assuming both parents are carriers)

NO

__ male to male transmission in X linked diseases

• male is not an X carrier because there is no normal copy

autosomal dominant

only one abnormal gene copy is required for the individual to be affected 

autosomal dominant pedigree

• Both sexes are affected and may transmit the gene to the offspring of either sex  

• When an affected person has children with an unaffected person, each child would normally have a 50% chance of developing the disease

autosomal recessive

two mutant alleles are required (one from each parent) at the disease locus 

autosomal recessive pedigree

• a person affected can be of either sex and is usually born to unaffected parents (heterozygotes – asymptomatic carriers)  

• the chance that each future child born the carrier parent is also affected is 25%  

consanguinity

• Couples who have one or more recent ancestors in common are said to be consanguineous  

• A feature of many recessive disorders, especially rare conditions, is that affected individuals often have two identical mutant alleles because the parents are close relatives; such couples are said to be consanguineous  

X linked inheritance

• Most whole-autosome aneuploidies are incompatible with survival, except trisomies 13, 18, and 21 – can result in live birth; also several sex-chromosome aneuploidies, including 45, X, 47, XXX, and 47,XXY – problems with gene dosage  

• Most of the very few genes on the Y chromosome have male specific functions, or they have an equivalent gene copy on the X  

X inactivation

a mechanism to compensate for having different numbers of X chromosomes in males in females  

• stage it occurs: Initiated after a cellular mechanism counts the number of X chromosomes in each cell of the early embryo  

• If the number of X chromosomes is two (or more), all except one is randomly inactivated (only in somatic cells) à induced to form a transcriptionally inactive Barr body  

X linked dominant inheritance

• Affected individuals can be of either sex and at least one parent is affected  

• There are significantly more affected females than affected males  

• Affected females typically have milder (but more variable) expression than affected males  

• Excess of affected females – because there is no-male-to-male transmission of the disorder  

X linked dominant pedigree

• All children born to an affected mother (and unaffected father) have a 50% chance of being affected  

• An affected father with a single X chromosome will consistently have unaffected sons (they do not inherit this X chromosome); But his daughters will always be at risk (they will always in inherit his affected X) 

X linked recessive pedigree

• Affected individuals are mostly male, and affected males are often born to heterozygous carrier mothers and unaffected mothers  

• There is no father to son transmission  

• A distinguishing feature is that there is no male to male transmission because males pass a Y chromosome to sons  

Matrilineal inheritance

• Tissues that have a high energy requirement (ex. Muscle and brain) are primarily affected in mtDNA disorders  

• The sperm does not contribute mtDNA to the zygote, but the paternal mtDNA is destroyed in the very early embryo  

• Inheritance occurs exclusively through the mother (matrilineal inheritance)  

• Individuals with a mitochondrial DNA disorder can be of either sex, but affected males do not transmit the condition to any of their children  

penetrance

probability that a person who has a mutant allele will express the disease phenotype  

dominantly inherited disorders

100% penetrance (ex. Huntington disease)  

variable penetrance or non penetrance

ex. BRCA1

age related penetrance

• some disorders: late age at onset

• severity increases with age; harmful products slowly build up

locus heterogeneity

• Production of identical phenotypes by mutations at two or more different loci/genes  

• Explains how parents who are both affected with a recessive disorder that has a common phenotype produce multiple unaffected children  

• Ex. Recessively inherited deafness  

compound heterozygote

• the presence of two different mutant alleles at a particular gene locus, one on each chromosome of a pair  

• Ex. HFE gene – patients who inherit one C282Y mutation from one parent and another H63D mutation from another parent  

anticipation

• Some disorders show consistent generational differences in phenotype  

• Ex. Fragile X syndrome, myotonic dystrophy, and Huntington disease  

• It can be expressed at an earlier age and become increasingly severe with each new generation of affected individuals – anticipation  

Purifying (negative) selection

selective removal of deleterious alleles 

Assertive/non-random mating

humans seldom mate at random and prefer phenotypes like themselves  

genetic drift

random changes in allele frequencies, particularly in small populations  

bottleneck effect

genetic drift resulting from a marked reduction in population size 

founder efect

altered allele frequencies when a new population is established by a small number of individuals  

influx of migrants

if a population absorbs a large influx of migrants with rather different allele frequencies – gene pool change  

neurofibromatosis type 1 mutation

mutations in the gene neurofibromin at chromosome location 17q11.2  

neurofibromatosis pattern of inheritance

autosomal dominant  

neurofibromatosis genetic mechanisms

• Neurofibromin gene is a tumor suppressor gene – mutation causes lots of tumors – neurofibromas  

• Neurofibromas originate from non-myelinating Schwann cells  

neurofibromatosis clinical features

• Very painful  

• When you remove they come back  

• Benign tumors  

• Café au lait spots  

• Bone defects, scoliosis  

• Lisch nodules (eyes)  

• Optic nerve glioma  

• Can have other tumors —> shorten lifespan  

Duchenne muscular dystrophy mutation

mutations in the dystrophin gene located in X chromosome  

Duchenne muscular dystrophy pattern of inheritance

X linked recessive

Duchenne muscular dystrophy age of onset

2-3 years

Duchenne muscular dystrophy genetic mechanisms

• Dystrophin gene —> cell membrane integrity  

• Progressive degeneration  

• Affect heart and respiratory muscles   

Duchenne muscular dystrophy clinical features

• Boys with this condition show a progressive degeneration of muscle that leads to weakness  

• Problems with ambulation, respiration  

• Pass away in 30s  

• Extremely expensive and mutation specific gene therapy  

• Increased creatinine phosphokinase (CPK or CK) correlate with the degree of muscle deterioration – diagnostic biomarker