5. Non-Traditional Genetics

Question 1

List the different categories of non-traditional inheritance (objective)

Answer 1

Answer later

Question 2

Define mosaicism and distinguish between somatic and germline mosaicism (objective)

Answer 2

Answer later

Question 3

Explain genomic imprinting including the multiple mechanisms that may cause disease (objective)

Answer 3

Answer later

Question 4

List important diseases caused by trinucleotide expansion and how this expansion affects the genes involved (objective)

Answer 4

Answer later

Question 5

Recognize a mitochondrial disease pedigree, the mode of mitochondrial DNA inheritance and to define heteroplasmy (objective)

Answer 5

Answer later

Question 6

Non-Traditional Genetics (list)

Answer 6

Non-Mendelian or atypical inheritance

• Mosaicism
• Genomic imprinting
• Unstable triplet repeat mutations
• Mitochondrial inheritance

Question 7

Mosaicism

Answer 7

2 or more genotypes in an individual from one zygote

Typically from mitotic error during development

Somatic- 1st then 2nd hit, unilateral Rb
Germline- reproductive organs, passed on

Question 8

Chimerism

Answer 8

Two genomes present in one individual (twin zygotes fused)

Question 9

Somatic Mosaicism

Answer 9

Mosaicism in the body which usually develops post-conception (mosaic trisomy 8)

Question 10

Germline Mosaicism

Answer 10

Confined to the germ cells, also called gonadal mosaicism.

Consequently, an individual may produce multiple offspring with a mutation without manifesting the disorder him/herself

*Acquired post-conception: high risk to offspring that is not clinically present in parent (multiple offspring affected with what is usually felt to be a sporadic disease)
Ex. DMD son, tell family recurrence as high as 15% due to maternal germline mosaicism.

Question 11

Congenital Hyper-pigmentation reflecting chromosomal mosaicism

Answer 11

Male with mental retardation and SWIRLING pigmentation (somatic mosaicism for chromosomal abnormality)

Differs from incontinentia pigmenti: pigment pattern present at birth and patient is a male.

Diagnosed by chromosome study-skin cells

Question 12

Duchenne Muscular Dystrophy

Answer 12

5 brothers with it, X-linked recessive.
No other affected relatives. Mother does not have the mutation in her lymphocytes and likely has germline mosaicism for the DMD mutation (involving ovaries mutation)

Question 13

Genomic Imprinting

Answer 13

Autosomal chromosomes also has X-inactivation type shutting off (ex. Chromosome 15)

Parent-of-origin difference in gene expression (dependent whether from mother or father)

Different functioning due to epigenetic modification, not a chance in DNA sequence, but a reversible regulation of gene expression

Question 14

Genomic Imprinting (how)

Answer 14

Usually by methylation or changes in chromatin structure
Most imprints erased and restored each new generation
200 genes know to be imprinted

In every cell in body, monoallelic expression

Question 15

Imprinting Disorders (list)

Answer 15

Number of different mechanisms by which imprinting disorders can occur:

• Uniparental disomy (both came from mom or dad)
• Microdeletion
• Imprinting Defects

Question 16

Uniparental Disomy (UPD)

Answer 16

Both members of chromosome pair are inherited from one parent

Thought to be from trisomy with a loss of one of the extra chromosomes around fertilization

Question 17

Human Imprinting Disorders

Answer 17

Prader-Willi Syndrome

Angelman Syndrome

Question 18

Prader-Willi Syndrome

Answer 18

S: Neonatal hypotonia, cryptorchidism, hypothalamic dysfunction (lack of satiety and subsequent obesity, hypogonadotropic hypogonadism, growth hormone deficieny and short stature and diminished muscle), cognitive/behavioral impairment

M: Lack of expression of paternal genes at 15q11-13

Deletion of paternal 70%
Maternal UPD 25%
Imprinting defect (silence fathers) 5%

Question 19

Angelman Syndrome

Answer 19

S: Severe mental retardation with limited speech; ataxic gait; spontaneously happy affect; seizures
1/15000 births

M: Lack of brain expression of the maternally inherited UBE3 gene at 15q11-13

Deletion 70%
UBE 3A mutation 11%
Paternal UPD 7%
Imprinting Defect (maternal silenced) 3%

Question 20

Fragile X Syndrome

Answer 20

S: Long narrow face, prominent ears and jaw/forehead, enlarged testes, mental impairment, ADD and hyper, motor delays
Most common cause of mental retardation in males
Anticipation: number of triplet repeats may in subsequent generations cause worse mental deficiency (imprint expansion)

Female heterozygotes for triplet expansions often develop problems such as ovarian failure and ataxia

M: CGG repeats in 5’ UTR

Question 21

Mitochondrial Diseases (general)

Answer 21

Energy production, fatty acid oxidation, urea cycle, porphyrin synthesis

Defects aerobic metabolism

Can affect any tissue and cause variety of signs and symptoms
Mostly neurologic, muscular and cardiac

Question 22

Mitochondrial Diseases (list)

Answer 22

MELAS (mitochondrial encephalopathy lactic acidosis and stroke-like episodes)

MERRF (myclonic epilepsy and ragged red fibers)

NARP (neurogenic ataxia and retinitis pigmentosa)

CPEO (chronic progressive external ophthalmoplegia)

Question 23

Mitochondrial DNA

Answer 23

Comes from the oocyte (maternally inherited)

Mutations in MC can occur anytime in life and passed on

Cells may end up with a mixture of normal and mutant mitochondria- Heteroplasmy

Question 24

Heteroplasmy

Answer 24

Cells may end up with a mixture of normal and mutant mitochondria

Question 25

Mitochondrial DNA Pedigree

Answer 25

Both males and females are affected The condition is transmitted through the female to her offspring If male has the trait and spouse does not, their offspring won't have the trait Probably will not skip generation

Question 26

Mitochondrial Disorders (treatment)

Answer 26

No real effective treatment Often try cofactors like coenzyme Q10, thiamine, vitamin E and carnitine Diet manipulation not effective Often progressive steadily with increasing involvement of additional systems