Week 5- Mitochondrial inheritance/ Mltifactorial inheritance/ mutation types and inheritance pattern

Question 1

Mitochondrial inherited disorders

Answer 1

1) DM type 1
2) 1555A> G associated deafness (Sensoeineural hearing loss)
3) LHON - Leber Hereditary Optic Neuropathy
4) Leigh syndrome

Question 2

In Mitochondrial Inheritance
* Mitochondrial DNA is ———— inherited
* ——- sexes equally affected
* Only —— transmission of disease (no male transmission at all)

Answer 2

• Mitochondrial DNA is maternally inherited
• Both sexes equally affected
• Only maternal transmission of disease (no male transmission at all)

Question 3

———– : Mitochondria contain mix of mutant and wild-type mtDNA, Proportion of mutant mtDNA differs in different tissues or even cells of same tissue

Answer 3

Heteroplasmy

Question 4

———-: * Mutant mtDNA are “selected out” with repeated mitoses, but accumulate in tissues not undergoing mitoses (e.g. neurons, muscles)

Answer 4

Replicative Segregation

Question 5

——– : Symptoms develop only when mutant mtDNA reaches certain threshold (usually high, >90%).
Threshold depends on energy metabolism of tissue

Answer 5

Thershold effect

Question 6

——— : Mitochondrial genetic in oogenesis that permits only a small subset of maternal mtDNA genomes to be effectively transmitted to progeny

Answer 6

Bottleneck effect

Question 7

Homoplasmic mtDNA mutations are transmitted to ?

Answer 7

Maternal offspring
(however, not all offsprings will manifest the disease)

Question 8

Key systems involved in mitochondrial Disease

Answer 8

1) CNS –> seizures, ataxia, dementia
2) Skeletal muscle –> myopathy
3) CVS -> cardiomyopathy
4) Liver –> hepatic dysfunction
5) Pancreatic islets -> diabetes mellitus
6) Hearing and vision -> Sensorineural deafness, optic atrophy, retinopath

Question 9

**

Mitochondrial DNA (mtDNA) deletion Syndromes (Overlapping phenotypes)

Answer 9

1) Kearns-Sayre syndrome
2) Pearson syndrome
3) Progressive External Ophthalmoplegia (PEO)

Question 10

**

CF of Kearns-Sayre syndrome

Answer 10

Triad:
1) Onset <20 yrs
2) Pigmentary retinopathy
3) Progressive external ophthalmoplegia (PEO)

Plus at least one of
* Cardiac conduction defect
* CSF protein >100mg/dL
* Cerebellar ataxia

* mtDNA deletion syndrome

Question 11

Non-Syndromic Mitochondrial deafness
(1555A>G associated deafness) is caused by mutations in?

Answer 11

MT-RNR1-Related Hearing Loss (gene for 12S rRNA)

Question 12

MOI of 1555A>G associated deafness

Answer 12

Mitochondrial inheritance
(CF: hearing loss)

Question 13

Penetrance of 1555A> G associated hearing loss
* ——% penetrance with exposure to Aminoglycoside abx (non-dose related)
* Reduced penetrance without exposure (about —-% by age 65 years)

Answer 13

• 100% penetrance with exposure (non-dose related)
• Reduced penetrance without exposure (about 80% by age 65 years

Question 14

The most frequent mitochondrial disease presentation in early childhood?

Answer 14

Leigh syndrome

Question 15

**

CF of Leigh Syndrome

Answer 15

1) Developmental delay
2) ) loss of bladder fxn
3) ) Dystonia,
4) ataxia,
5) loss of speach,
6) Dysphagia
7) Eventually , Central respiraotry failure

Question 16

Leigh Syndrome genetics?

Answer 16

can be:
1) Mitochondrial inheritance
2) AR
3) XL

Question 17

GENETICS

Leigh Syndrome –> 10-20% are Mitochondrial inheritance, where there ———– mutation in ———-

Answer 17

Leigh Syndrome –> 10-20% are Mitochondrial inheritance, where there T8993G/C mutation in MT-ATP6

Question 18

AR cases of Leigh Syndrome are caused by mutations in ———

Answer 18

SURF1/SDHA/Complex I subunit & assembly factor genes

Question 19

XL cases of Leigh Sydrome are caused by mutations in ——-

Answer 19

PDHA1

Question 20

Multifactoral disorders [Follow/ do not follow] a Mendelian pattern of inheritance

Answer 20

Do not

Question 21

Examples of Multifactorial disorders

Answer 21

1) Epilepsy
2) Diabetes mellitus type 1
3) Cleft lip and palate
4) Ischaemic heart disease

Question 22

Only small minority of Ischaemic heart disease cases are linked to Mendelian disorders, these are caused by mutations in?

Answer 22

LDLR

Question 23

Monogenic form of DM type 1

Answer 23

MODY (1-2% dibaetes)

note:
monogenic -> involving/ controlled by a single gene

Question 24

Monogenic mutations of Type 1 Diabetes

Answer 24

1. HNF1A (30-50%),
2. GCK ( 30-50%),
3. HNF4A (5%)…

Question 25

MOI of non-Syndromic Cleft lip and palate

Answer 25

Multifactorial inheritance

Question 26

Non-Syndromic CL&P are caused by mutations in?

Answer 26

No single major locus - some genes **MSX1**, **IRF6**

Question 27

Multifactorial disorders Have a Complex pattern of inheritance such as: - Multiple **-----------** - **----------** Influences

Answer 27

* Multiple **Genetic varients** * **Eviromental** influences

Question 28

Enviromental factors that cause Non-Syndromic Cleft lip and palate

Answer 28

1) anti-epileptic drugs 2) Impaired folic acid metabolism 3) Smoking

Question 29

In multifactorial inheritance there is **NO** **----------** or **--------** of genes (equal additive effect)

Answer 29

No **dominance or recessiveness**of these genes (equal additive effect)

Question 30

In multifactorial inheritance **-----------** interacts with the genotype to produce the final phenotype

Answer 30

**Enviroment**

Question 31

MOI of Epilepsy

Answer 31

Multifactorial inheritance

Question 32

cause (Etiology) of Epilepsy

Answer 32

1) Idiopathic 2) genetic (formerly idiopathic) 3) Structural/ metabolic (sympotmatic) --> HIE, trauma, tumour, infection, stroke | * HIE: Hypoxic-Ischemic Encephalopathy

Question 33

Common genetic cause of Epilepsy

Answer 33

* Common variants **(GWAS**) – few identified - **ILAE consortium** * **Rare variants** – some identified (CNVs, ion channels, others) - **Epi4K/25K**

Question 34

how does genetic variation cause Epilepsy

Answer 34

1) **Mendelian variation** (Characteristics controlled by a single gene) or 2) **Polygenic variation** (influenced by many genes)

Question 35

Monogeneic vs Polygenic Gene variation

Answer 35

Question 36

MOI in Marfan syndrome

Answer 36

AD , loss of function (Haploinsufficiency mutations)

Question 37

# ** Type of mutation in Marfan Syndrome

Answer 37

**FBN1** on chromosome **15q21**- fibrillin gene | * Loss-of-fx, AD

Question 38

loss of function of mutations in AD inheritance are based on ?

Answer 38

**Hapoloinsufficiency** (when one copy of the gene is inactivated/deleted and the remaining functional copy of the gene is inadequent- non functional **e.g. FBN1 in Marfan**)

Question 39

**---------**: Encoded proteins that in their normal state, negatively regulate proliferation (e.g, Prevent tumour growth)

Answer 39

Tumour supresser genes (loss of function mutations)

Question 40

**---------** drive tumour growth

Answer 40

Oncogene

Question 41

will loss of function of TSGs (Tumour supressor genes) cause cancer?

Answer 41

If only one allele (not both) is affected then one TSG is enough to sustain tumour supression * Note: Second allele must malfunction for tumour to develop

Question 42

At the tissue level, oncogenesis acts **[recessively /dominantly]** BUT the tumour predisposition syndrome is inherited as a **[dominant/recessive]** trait

Answer 42

At the tissue level, oncogenesis acts **recessively** BUT the tumour predisposition syndrome is inherited as a **dominant** trait

Question 43

loss of mutation in Tumour supressor genes are inherited **-----------**

Answer 43

**dominantly** * however expressed recessively at tissue level (both alleles must be "mutated" for the TSG to be non functional

Question 44

Examples of AD- Gain of Function mutations

Answer 44

1) Charchot-Marie-Tooth - PMP22 duplication 2) FGFR3 mutation in Achondroplasia 3) CAG repeat in HD

Question 45

Dominant negative mutations are comnon in genes coding structural proteins that are **----------** and **-----**

Answer 45

Dominant negative mutations are comnon in genes coding structural proteins that are **dimers** and **multimers**

Question 46

**------------** Mutant gene product results in the loss of protein activity/ function by interfering with the normal gene product of the corresponding allele

Answer 46

Dominant Negative mutations

Question 47

Examples of Dominant negative mutations

Answer 47

COL1A1/2 in osteogenesis Imperfecta (OI)

Question 48

**-------------** mutations in the COL1A1 gene in OI --> results in MILD disease

Answer 48

**Loss-of-function** mutations in the COL1A1 gene

Question 49

**----------** mutations in the COL1A1 gene in OI --> Severe disease

Answer 49

**Missense** mutations in the COL1A1 gene | * has a dominant negative effect

Question 50

MOI?

Answer 50

Question 51

MOI?

Answer 51