3. complications to pedigree inheritence

Question 1

GENERAL OVERVIEW: factors affecting pedigree patterns (11)

Answer 1

1. Pseudo Dominance
2. Penetrance
3. Espressivity
4. Age of onset
5. De novo mutation
6. Genetic heterogeneity
7. Phenocopy
8. Complementation
9. Paternity exclusion
   10.Digenic or Triallelic Inheritance
   11.Genomic Imprinting

Question 2

Pseudodominance explanation

Answer 2

-situation where the inheritence of a recessive trait mimicks a dominant pattern (vertical transmission + affected offspring has 1+ affected parent)
-this means a single recessive allele is received but is still expressed in the phenotype
REASON: the recessive trait is very common in pop and so it is very common for a homozygote and heterozygote to mate
EG –> ALKAPTONURIA

Question 3

disease modelling pseudodominance

Answer 3

ALKAPTONURIA:
-actually an autosomal recessive disorder
-defect in phenylalanine and tyrosine metabolism

Question 4

Reduced penetrance explanation

Answer 4

-Penetrance of a characteristic (for a given genotype) is the probability that a person with that genotype will manifest the characteristic. ie- a dominant trait should have 100% penetrance in heterozygotes
-if not, then then the trait has reduced penetrance among the population
AFFECTS DOMINANT DISEASES
-some characteristics skip generations bcos carriers are produced, but these carriers still have the possibility to transmit the mutation. This complicates genetic counselling
!!! for a condition showing reduced penetrance the risk of an affected child from heterozygotes = 1/2P [where P is the proportion of heterozygotes affected]

Question 5

disorder showing incomplete penetrance

Answer 5

ECTRODACTYLY: absence of one or more central toes in the foot
-in a generation some individuals have the disease and some dont, but the ones that dont are still able to pass on the mutation to further offspring.

!! if an individual doesnt have kids then molecular testing needs to be used to evaluate the presence of a mutation

Question 6

variable expressivity explanation

Answer 6

Expressivity: the range of phenotypes expressed by a certain genotype
-variable expression is when the severity of the disease differs in people of the SAME genotype
-in the same family people can show diff features of the disorder
MOSTLY AFFECT DOMINANT DISEASES

EG: NF-1, WS

Question 7

disorders (2) than model variable expression

Answer 7

1. NEUROFIBROMATOSIS 1:
   -3 modes of diagnosis = cutaneous NF (benign tumours all over the body), pigmented skin lesions called cafe au lait macules, or 2+ lisch nodules (iris benigh spots)
   -however certain presentations also include: scoliosis, tumours of CNS, adrenal gland tumour) affecting hypertension
   HENCE: variable phenotype, means physician cant asses the severity and hence cannot give a genetic risk
2. WAARDENBURG SYNDROME:
   -hearing loss and pigmentation of hair, skin and eyes. Usually autosomal DOM
   -gravity of disease is unpredicatble bcos each individual can express all/some combination of symptoms

Question 8

disorder modelling BOTH reduced penetrance and variable expression

Answer 8

CAMPTODACTYLY: fixed flexion deformity of the little finger interphalangeal joint)
-can affect either hand

Question 9

what are the causes of reduced penetrance and variable expression

Answer 9

1. interaction of the genotype with the environment (age, gender, diet)
2. modifier genes: genes that indirectly infulence a trait via gene interactions. Hence, a modifier passed by parents can influence the expression of the inherited mutated gene
3. Allellic variants: multiple alleles present in poopulation
4. Allelic dosage: The coexistance of wild type and mutated alleles in a heterozygote should usually cause 50% of protein to be produced due to WT. However in the case of mutation in promoter influence expression of the allele, there are can a hyper or hypofunction, changing the % of protein that is made (both cis and trans elements need to be considered)
5. Epigenetic modification
6. Isoalleles –> functional variants of a wild type allele that might modify the penetrance or expression of the mutant allele. Can cause diff phenotype depending on whether these alleles are hyper or hypomorphic

Question 10

why do reduced penetrance and variable expression mainly affect dominant disorders?

Answer 10

-when they affect dominant conditions it means that in heteroxygotes, the wildtype allele is affecting the expression of the mutant one.
-in recessive conditions there are 2 recessive alleles expressed (hence a DOUBLE mutation) in which case they are not easy to influence bcos both chromosomes carry mutates trait

Question 11

cis vs trans elements

Answer 11

cis acting: short DNA stretches of a defined sequence that act as binding sites (ie present on the same molecule of DNA as they gene they regulate)

trans acting: proteins (eg. TFs/repressors) that bind to cis acting factors (ie. can regulate genes far away from which they were transribed)

Question 12

hypermorphic vs hypomorphic alleles

Answer 12

A WILD TYPE ISOALLELE THAT:
1. hypomorphic: works worse
2. hypermorphic: works better

!! a hypomorphic allele in a heterozygous individual can actually manifest the disorder phenotype, and hypermorphic allele in a homozygous recessive individual (with double mutation) can absolve them of the phenotype manifesting

Question 13

modifier gene definition + evidence for their existance

Answer 13

DEF: a locus at which DNA sequence variation alters phenotypes normally associated with independent (target) genes

evidence: the existance of reduced penetrance and variable expression, same mutations having diff phenotypes or siblings with same mutation expressing diff features of a disorder, aminal models showing diff expression in diff strains of animals

Question 14

classes of modifier genes (4)

Answer 14

classifies based on the phenotypic aspect they influence.

If we take an example of a recessive disease causing obesity (mm):

1. dominant modifier allele: causes m/+ individuals to develop obesity phenotypes indistinguishable from homozygotes
2. penetrance modifier allele: causes reduced penetrance amongst mm individuals so that occurance of obesity in population decreases
3. expressivity modifier allele: produces an intermediate phenotype for mm individuals (between the original ++ and mm), hence decreasing its severity
4. pleiotropic modifier gene: doesnt affect the obesity of the phenotype, but eliminates other features of the disease such as glucose intolerence

Question 15

examples of human modifier genes

Answer 15

1. dom modifier: ROM1 gene modifies peripherin 1 and modifies the phenotype to cause retinitis pigmentosa
2. penetrance modifier: DFNB26 gene causing non syndromic deafness is modified by the DFNM1 gene which supresses deafness
3. CF gene modifies CFTR acting as a supressor for meconium ileus (when a baby’s first stool blocks the last part of the ileum)
4. pleiotropic modifier: Serum amyloid A gene modifies familial mediterranean fever (inflammatory disorder) which results in pleiotropy and adds renal amyoidosis to the symptoms of the disorder

Question 16

age of onset explanation

Answer 16

-usually we consider genetic disorders as congenital (ie exist from birth)
-complications arise if the phenotype arises later in life (eg due to slow accummulation of toxic substances)

ANTICIPATION: refers to a phenomenon where the earlier the age of onset of a disease, the more severe the manifestations (mainly affects aut dom)

EG: huntington’s (aut dom): average onset in 30s/40s

Question 17

De novo mutations def

Answer 17

-can occur in the germline during any of the mitotic or meiotic divisions (spermatogenesis or oogenesis)
-occurs almost exclusively for dom disorders bcos for recessive ones a mutation in BOTH germlines is necessary to cause phenotype (lower prob of this happening)
-80% of dom mutations are de novo
-the recurance risk for an individual’s siblings is very low (bcos it is a new mutation)

Question 18

are denovo mutations more common in males or females?

Answer 18

MALES: diff in mitotic and meiotic division between the 2 sexes

in females: 22 mitotic divisions before birth and 1ary oocyte is paused in meiosis 1 until puberty –> older women have higher chance of mutations with increase in age bcos the time in which oocytes are arrested increases and there is a larger window for disjunction

in males: continuous sperm production, 30 mitotic divisions until puberty and then 20-25 more per year. Hence more divisions than in females leading to more replication errors. The increase in divisions with age (due to 25 extra per year) also increase frequency of mutation with paternal age.

SUMMARY: both sexes have higher fr with increase in age, but due to higher divisions in males in general they have higher fr overall

Question 19

Mosaicism explanation

Answer 19

-post zygotic mutations produce mosaics with 2+ genetically different cell lines - number of cells affected depends on what time the mutation occurs at (earlier mutations have larger effects)
1. germline: only cells in the gonads are affected
2. somatic: cells all over the body can be affected
-germline mosaicism can be passed to offpring

Question 20

how can you identify germline mosaicism

Answer 20

MEN: easy bcos there can be direct sperm analysis.
!! in a blood sample, the mutation wont be seen if there is germline mosaicism bcos you arent analysing gonads or germ cells

WOMEN: almost impossible bcos ovaries are internal organs and dont have homogeneous tissue (due to diff follicles present). Potential to analyse combination of CT (fibroblasts) and blood and a +ve test in conjunction with an affected child proves mosaicism. However a -ve test result cant rule it out bcos it could be germline and the ovary wasnt tested

Question 21

genetic heterogenity explanation

Answer 21

DEF: a number of similar phenotypes that are actually caused by different genotypes
3 diff types:
-locus HG
-allelic HG
-phenotypic HG

!! interfamilial variation can exist (diff alleles at the same locus) that can cause phenotype variations - diff modifier genes or epigenetic controls that can decrease or increase impact of mutation on phenotype

Question 22

locus heterogenity explanation

Answer 22

-when similar disease phenotype is caused by different genes

EG: retinitis pigmentosa (degeneration of phosphoreceptors causing abnormal distribution in retina). There are 3 genes causing X-linked, 12 causing aut dom, and 5 causing aut res. Hence it is important to identify the mode of inheritance

Question 23

allelic heterogenity explanation

Answer 23

-similar phenotypes are caused by alternate genotypes

EG. CFTR gene: very long gene which allows a spectrum of mutation locations and these cause diff forms of the disorder. If the parents aer both carriers of CFTR mutations but these mutations are of a DIFF type, most homozygous offsprings with both mutations become COMPOUND heterozygotes –> this means a diff presentation of phenotype than in homozygous of equal allele mutations.

Question 24

phenotypic heterogenity explanation

Answer 24

-VERY DIFF phenotypes are caused by alternative genotypes at the same locus

EG1 -> mutation in dystrophin gene can cause either becker muscular dystrophy (milder) or duchenne (very severe) - this depends on whether the mutation affects the reading frame. Hence even a tiny mutation can cause the duchenne form if the reading frame is changed, and a huge mutation can cause becker form is the reading frame isnt affected.

EG2 -> RET proto-oncogene mutation depending on the area affected can cause:
1. hirschsprungs disease (ansence of bowel neuronal ganglia causing megacolon)
2. MEN2A causing hereditary cancer usually thyroid or parathyroid carcinoma
3. MEN2B causing skeletal malformations resembling marfan’s

Question 25

Phenocopy explanation

Answer 25

-when a phenotype is NOT controlled by genetic factors (ie, environmentally induced), but it APPEARS to be
-prominent in cases where cogenital malformations are caused by chemical exposure or viral infections of the mother during pregnancy, but they are

EG –> thalidomide effect, rubella virus effect

Question 26

complementation explanation

Answer 26

• a situation where 2 alleles (usually in 2 different loci) in combination restore the wild type phenotype

EG -> hearing loss: 2 parents that have hearing loss can produce all offsprings with 0 hearing loss
If hearing loss = AAbb or aaBB, their offsprings can have AaBb and hence show completely normal phenotype (the WT alleles will complement the mutation).

Question 27

Digenic/Triallelic inheritence explanation

Answer 27

-when mutations are present in 2/3 unlkinked genes in a single individual and the combination of these alleles causes a diseased phenotype (that doesnt occur when an individual only has 1 of these mutations)
-effect of these alleles can either be:
1. synergistic = mutations at BOTH loci are needed for the phenotype, or 3 alleles overall in the case of triallelic (eg retinitis pigmentosa)
2. additive = can change the onset of a disease, where individuals with 1 mutation have late age onset, but those with BOTH mutations manifest disorder at a very young age

Question 28

paternal exclusion explanation

Answer 28

when there is doubt over the true paternity of an offspring and the alleged father’s genotype can be excluded since his genetic makeup is inconsistent with that of the mother and the child

Question 29

genomic imprinting

Answer 29

-nonmendelian inheritence
-only one copy of a gene in an individual is expressed (either the paternal or maternal)
-the other copy is supressed by epigenetic modifications
-controlled by imprinting centers located nearby imprinted areas on the same chromosome

EX -> prader willi syndrome and angelman syndrome (first ones discovered in humans)