mendelian/ non-mendelian/ complex inheritance

Question 1

sickle cell anaemia:

Answer 1

autosomal recessive inherited diseases

caused by a single-point mutation on the HB gene.

Adenine to Thymine substitution leads to → encoding changes from Glutamate to Valine

Characterized by:

→ sickle-shaped erythrocytes

→ pain & tissue damage & infection

→ widespread in Africa, Middle-East, India

Question 1

sickle cell anaemia and cf:

Answer 1

Sickle cell disorders (SCD) & Cystic fibrosis are autosomal recessive traits

Requires two allele mutations to be affected

Homozygote (AA) → normal

Homozygote (aa) → affected
(nonfunctional protein)

Heterozygote (Aa) → carrier
(reduced protein function)

Question 2

cystic fibrosis:

Answer 2

an autosomal recessive inherited disease

characterized by the buildup of thick mucus in the airways causing bacterial infection.

Question 3

punnet square:

Answer 3

a square diagram that is used to predict the genotypes of a particular cross or breeding experiment

Question 4

achondroplasia and Huntington:

Answer 4

Achondroplasia & Huntington’s disease
- autosomal dominant traits

Requires one allele mutation to be affected

Homozygote (aa) → normal

Homozygote (AA) → affected
(nonfunctional protein)

Heterozygote (Aa) → affected
(nonfunctional protein)

Question 5

Features of Autosomal Dominant Inheritance:

Answer 5

• Each child has a 50% chance of inheriting the mutation
• No “skipped generations”
• Equally transmitted by men and women
• Male-to-male transmission

Question 6

Huntington’s disease:

Answer 6

is an autosomal dominant inheritance that is progressively neuro-degenerative.

Question 6

achondroplasia:

Answer 6

Dominant inheritance disease-associated Mutations Alter Protein Function:

1- non-functional/missing protein

2- {{c1::gain of function}} alteration

e.g. (achondroplasia) → slows down growth of bone
Glycine → Arginine

Question 7

Duchenne muscular dystrophy:

Answer 7

an x-linked disease that causes muscle weakness
due to a mutation in the dystrophin gene.

→ fatal in early adult life & prenatal diagnosis done to check for risk

Haemophilia - an x-linked disease that is a bleeding disorder.

Question 8

x linked disease inheritance:

Answer 8

If the father has it, and the mother is unaffected

None of the sons will have it, all the daughters will carry it.

If the mother has it, and the father is unaffected

50% chance that a son will have it
50% chance that a daughter will carry it.

Question 9

x linked/ sex-linked inheritance features:

Answer 9

Only males affected classically

Can skip generations (through unaffected women)

Unaffected women and affected men can transmit the condition

• No male-to-male transmission
  → only inherits Y chromosome from father

Question 10

mendelian disease:

Answer 10

Multiple Genes in the same Molecular Pathway can cause the same Mendelian Disease

→ each gene has a strong effect

e.g. Long QT, ARVC & Cardiomyopathy

Mode of inheritance can differ:

– Autosomal Dominant
– Autosomal Recessive
– XL variants in >1 gene

Question 11

mendelian/non-mendelian inheritance laws:

Answer 11

Mendelian Inheritance:

• The Law of Dominance
• The Law of Segregation
• The Law of Independent Assortment

non-Mendelian Inheritance: does not fit in with Mendelian’s Law

e.g. Several variants in several genes acting together.

Question 12

The contributions of genetic and environmental factors to human diseases:

Answer 12

Rare disorders:

Genetics simple
Uni-factorial
High recurrence rate in following generations

Common disorders:

Genetics complex
Multi-factorial
Low recurrence rate in following generations

Question 13

Inheritance Patterns & Mechanisms of Non-Mendelian Inheritance:

Answer 13

[1] Incomplete Penetrance
Environmental factors
Genetic Modifiers

[2] Genomic Imprinting
Variants from parents

[3] Extranuclear Inheritance
e.g. Mitochondria mutations

[4] Anticipation
e.g. Triplet repeat expansion
→ bigger and more severe as generations continue

[5] Complex
Multi-genic risk

Question 14

Different levels of genetic penetrance:

Answer 14

e.g. Cystic fibrosis - mutations in CFTR gene

→ 100% penetrance

→ mild mutations only have congenital absence of vas deferens (infertility)
with no chest mucus build-up

Question 14

penetrance

Answer 14

the frequency with which a trait is manifested by individuals carrying the gene.

Question 15

Personalised / Precision Medicine, BRCA1 mutation:

Answer 15

BRCA1 mutation → targeted chemotherapy with olaparib (if metastatic)

A mastectomy is an operation to remove the breast

An oophorectomy is a surgical procedure to remove one or both of your ovaries

Question 15

genetic modifiers and environmental factors:

Answer 15

CFTR mutation alone does not explain the severity of CF in organs and variation within families.

We have to take into account:

[1] Genetic modifiers

Genes that have small quantitative effects on the level of expression of another gene.
May involve polymorphism, maybe intra- or extra-genic

[2] Environmental factors

Lifestyle, Diet, Smoke, Alcohol, Drug,
Stress, Air pollution, Chemicals,
Infection, etc.

Question 16

genomic imprinting:

Answer 16

an epigenetic phenomenon that causes genes
to be expressed in a parent-of-origin-specific manner.

Some regions of the genome are imprinted, where only one of the two copies of the gene is active
and the other is switched off through methylation.

Maternally Expressed Gene (MEG)

Paternally Expressed Gene (PEG)

Question 17

Epigenetic modifications:

Answer 17

heritable changes in gene function not explained by changes in DNA sequences

→ mediated by DNA methylation → gene isn’t available to be copied

Methylcytosine (mC) induces the structural adaptation of chromosomal regions to perpetuate altered activity states
- stops it being available for translation

Question 18

Genetic mechanisms of imprinting disorders:

Answer 18

Deletions

Point mutations

Imprinting errors

Uniparental disomy

Question 18

uniparental diomy:

Answer 18

inheritance of a chromosome pair from one parental origin

refers to the situation where a child has inherited both copies of a chromosome from just one parent

[1] Trisomy

[2] Monosomy

[3] Mitotic Error

Question 19

uniparental diploidy:

Answer 19

when a cell line has all 46 chromosomes derived from one parent.

Gynogenic
- 2 maternal genomes
- Mass of embryo
- Ovarian teratoma

Androgenic
- 2 paternal genomes
- Mass of placenta
- Hydatidiform mole (molar pregnancy)

Question 20

why is mitochondria a mutation hotspot?

Answer 20

High mutation rate: 100-fold higher than the nuclear genome.

→ Lack of efficient DNA repair system.

→ Lack of protective proteins, such as histones.

→ Damaged by reactive oxygen species (ROS), such as free radicals.

Question 21

Mitochondria-associated disease mutations:

Answer 21

always inherited maternally

→ Affect tissues with high metabolic demand.

3 major myopathies:

• Myoclonic epilepsy with ragged red fibres (MERRF)
• Mitochondrial myopathy, encephalomyopathy, lactic acidosis, stroke-like symptoms (MELAS)
• Chronic progressive external ophthalmoplegia (CPEO)

Leber’s hereditary optic neuropathy (LHON)
- loss of central vision

Leigh’s syndrome - encephalopathy

Diabetes mellitus and deafness (DAD)

Question 22

anticipation:

Answer 22

a phenomenon whereby as a genetic disorder is passed on to the next generation,
the symptoms of the genetic disorder become apparent at an earlier age with each generation.
In most cases, an increase in the severity of symptoms is also noted.

Triplet repeat diseases - mutation in which repeats of three nucleotides (trinucleotide repeats) increase in copy numbers until they cross a threshold above which they become unstable.

e.g. Triplet repeat diseases
- Huntington’s disease
- Myotonic dystrophy (DM1)
- Fragile X syndrome

Question 23

multigenic/ complex inheritance:

Answer 23

when genes interact additively to influence a phenotypic trait.

Features:

• Often seen in common conditions
  e.g.
  – Heart disease
  – Breast cancer
  – Autism
• Multiple low penetrance variants
  – Breast cancer e.g. CHK2, ATM, polygenic risk scores becoming tested in clinical practice
  – Heart disease - genome-wide polygenic risk score under evaluation
  – Often extra-genic affecting expression rather than DNA code
• Rare high penetrance variants in many genes causing the same phenotype
  – schizophrenia