Lecture 30 & 31: Genetic Disease

Question 1

What are the inheritance patterns of single gene disorders?

Answer 1

Dominant (effects of variant allele are observed in the presence of a normal allele)

Recessive (effects of variant allele are observed in the absence of a normal allele)

Autosomal (chromosomes 1-22)

Sex-linked (x or y chromosomes)

Question 2

What does inheritance of autosomal dominant look like?

Answer 2

Has same probability to be passed down to male or female.

50% chance of passing trait to each child. (those not affected do not transmit disorder)

Age of onset for some autosomal dominant diseases is delayed. (EX: Huntington disease)

Question 3

What does inheritance of autosomal recessive look like?

Answer 3

If both parents have the mutant gene…
-25% chance of having an affected child
-50% chance of carrier child
-25% chance of non carrier child
*with the same probability in male/female children

Unaffected siblings can be carriers.

All children of affected parent are carriers.

Age of onset is earlier in life.

Symptoms are more uniform.

Question 4

What does inheritance of X linked recessive look like?

Answer 4

Any mutant gene on a male x chromosome will impact the male more than female due no backup chromosome with healthy gene.

Male children can have a genetic disorder due to a mutation on their x chromosome inherited from their unaffected mother.

All daughters will be carriers of a man with an x linked recessive trait.

All sons will be healthy of a man with an x linked recessive trait.

Question 5

What is penetrance?

Answer 5

How often does someone with the genotype actually show the corresponding phenotype?

Complete is 100%
Incomplete is <100%

Question 6

What is expressivity?

Answer 6

Mutations in a specific gene can give rise to different outcomes in different people.

Ranges from complete to minimal.
-narrow through broad

Affected by other genes, exposure to chemicals, environment and age.

Question 7

What is a genetic variant?

Answer 7

A permanent change in a sequence of a gene.

Question 8

What are the 5 types of varients?

Answer 8

Pathogenic (change in sequence of gene responsible for causing disease)

Likely pathogenic (change in sequence of gene probably responsible for causing disease)

Uncertain significance (change in sequence of gene we don’t know if pathogenic or benign)

Likely benign (change in sequence of gene probably not responsible for disease)

Benign (change in sequence of gene not responsible for causing disease)

Question 9

What is a silent mutation and impact?

Answer 9

Base pair is replaced with same one or one with similar properties allowing for same protein to be coded for.

Have no effect on gene activity.

Question 10

What is a missense mutation and impact?

Answer 10

Replacement of a single nucleotide which may produce a malfunctioning protein.

Question 11

What is a nonsense mutation and impact?

Answer 11

Replacement of a single nucleotide causing the shortening of protein.

Question 12

What is an insertion and impact?

Answer 12

Insertion of a single nucleotide creating an incorrect amino acid sequence which may produce a malfunctioning protein.

Question 13

What is a deletion and impact?

Answer 13

Deletion of a single nucleotide creating an incorrect amino acid sequence which may produce a malfunctioning protein.

Question 14

What are inherited (hereditary) variants?

Answer 14

Passed from parent to child.

Present through person’s life and in virtually every cell in the body.

Germline variants - present in parents egg or sperm cells

Question 15

What are non-inherited variants?

Answer 15

Occur during person’s life.

Not found in every cell in body.
-occur in somatic cells

Not passed to next generation.

Can be caused by environmental factors.

Question 16

What are new (de novo) varients?

Answer 16

Found in child but not either parent or family history of.

May occur in parent’s egg or sperm cell, in the fertilized egg, but not in somatic cells.

Variants during development can lead to mosaicism (early genetic variant having cells with and without variant)

Question 17

What effects can mutations have on gene activity?

Answer 17

no effect
complete loss of function
partial loss of function
gain of function
dominant negative
acquisition of a new property

Question 18

What are the 3 types of mutations that cause autosomal dominant disorders?

Answer 18

(LOF) Familial hypercholesterolemia
-reduce clearance of cholesterol from plasma
-single pathogenic variant in LDL receptor gene
-“if you have 1 mutation that results in loss of function of that copy you have 50% activity. Unmutated copy unable to make up for mutated copy”

(LOF) Osteogenesis imperfecta
-dominant negatives (mutated protein interferes with the function of unmutated version)
-Point mutation that change single amino acid changing function of subunit

(GOF) LDL receptor
- PCSK9 mutation can increase affinity for LDL receptor or enhance sort of receptor to lysosome
-PCSK9 binds to LDL receptor guiding it to lysosome reducing number of receptors on surface

Question 19

Which types of mutations cause recessive disorders?

Answer 19

(LOF) Cystic Fibrosis
-mutations in cystic fibrosis transmembrane conductance regulator (CFTR)

In most cases the unmutated copy of the gene is not able to make up for the loss of expression or activity from the mutated gene.

In dominant vs recessive, it is dependent on what level of expression is required for full activity.

Question 20

What is a karyotype analysis? How can it be used to diagnose genetic diseases?

Answer 20

A karyotype analysis is a genetic test that looks at the size, shape and number of chromosomes in a sample of cells from your body.

It can detect chromosomal abnormalities and diagnose genetic disease, birth defects and certain blood or lymphatic disorders.

Question 21

What are the mechanisms that give rise to abnormalities in chromosome number?

Answer 21

Translocation: transfer one part of a one chromosome to another chromosome.

Isochromosome: the centromere divides horizontally rather than vertically, resulting in two short arms and two long arms.

Deletion: lost of a portion of a chromosome.

Inversions: when there are two interstitial breaks in chromosome, the segment reunites but is flipped.

Ring chromosomes: a variant of deletion. after loss of segments from each end of the chromosome, the arms unite to form a ring.

Question 22

What are the most common genetic changes that cause Down Syndrome and Turner Syndrome?

Answer 22

Down Syndrome:
-trisomy 21 type: 47, XX, +21
-translocation type: 46, XX, der (14,21)(q10;q10), +21
-mosaic type: 46, XX/47, XX, +21

Turner syndrome:
-monosomy X

Question 23

What are triplet repeat diseases and mechanism?

Answer 23

Some genes have repeats of 3 nucleotides.

Longer repeats are associated with disruption of gene function.

40 diseases associated with triplet repeats.
-associated with neurodegeneration

Question 24

What are mitochondrial mutations and mechanism?

Answer 24

Mitochondria has separate genome responsible for coding for enzymes in ox-phos.

Mitochondria are only inherited from mother.

Daughters but not sons may transmit mutations in mitochondrial genes to progeny

Will affect organs most depended on ox-phos such as skeletal muscle, heart and brain.

Question 25

What are imprinting defects and mechanism?

Answer 25

Some regions of DNA are inactivated in the copy received from said parent
-happens in ovum or sperm, then stably transmitted to all somatic cells derived from zygote

Maternal imprinting = transcriptional silencing of the maternal allele

Paternal imprinting = transcriptional silencing of the paternal allele

EX: Prader-Willi
-similar region of chromosome 15 deleted
-deletion inherited from father
-mental retardation, short stature, hypotonia, obesity, obesity, small hands/feet, hypogonadism

EX: Angelman syndrome
-similar region of chromosome 15 deleted
-deletion inherited from the mother
-mental retardation, ataxic gait, seizures, inappropriate laughter