Genetics Disorders

Question 1

Pyridoxine dependent epilepsy (PDE) type of inheritance?

Answer 1

Autosomal recessive. Compound heterozygous varients are common.

Question 2

Pyridoxine dependent epilepsy (PDE) pathogenic mechanism?

Answer 2

Gene ALDH7A1 has a toxic loss of function. When it can’t break down lysine, the alternative pathway uses up Vitamin B6. Now Vitamin B6 cannot be used to create GABA (an inhibitory neurotransmitter that protects from seizures).
Solution- give Vitamin B6 to create GABA

Question 3

Beta Thalassemia is what type of inheritance?

Answer 3

Autosomal recessive.

Question 4

Beta Thalassemia gene variant?

Answer 4

The gene Hbb has various pathogenic varients. Some mutations lead to no beta globin production, some lead to limited beta globin production. GENOTYPE PHENOTYPE CORRELATION

Question 5

Beta Thalassemia pathogenic mechanism?

Answer 5

Beta chains tend to aggregate when the Alpha to Beta ratio changes. This creates cell membrane damage, ineffective erythrocytes.

Question 6

Beta Thalassemia modifier alleles?

Answer 6

Fetal hemoglobin. If you promote this varient you can keep making FHg to take the place of BHg. Genetic varients in HBA1 and HBA2 help rescue imbalance

Question 7

What offers selective advantage to heterozygotes with beta globin mutations?

Answer 7

Sickle cell anemia prevents malaria

Question 8

Cystic Fibrosis inheritance mechanism?

Answer 8

Autosomal recessive

Question 9

Cystic Fibrosis genetic etiology? How does it differ between populations?

Answer 9

CFTR. Many pathogenic variants, vary across populations.

Question 10

Cystic Fibrosis heterozygote advantage?

Answer 10

Cholera. Cholera causes chloride-secreted diarrhea, if you don’t have chloride channel, then you aren’t affected. There are modifier alleles too (RNF5)

Question 11

Spinal Muscular Atrophy inheritance pattern?

Answer 11

autosomal recessive

Question 12

Spinal Muscular Atrophy genetic etiology?

Answer 12

SMN1 - most with homozygous deletion. Loss of neurons.

Question 13

Spinal Muscular Atrophy modifier alleles?

Answer 13

SMN2. (gene duplications) if we have more than one copy, even though it is not great at making protein, if you have it it can help make a little more protein and rescue some phenotype.

Question 14

What is a potential reason for an individual being affected with an autosomal dominant disorder but neither parent is affected?

Answer 14

De Novo

Incomplete penetrance

Question 15

Pathogenic mechanisms of dominant conditions?

Answer 15

Haploinsufficiency, gain of function, dominant negative.

Question 16

Familial Amyotrophic Lateral Sclerosis (ALS) inheritance pattern?

Answer 16

autosomal dominant

Question 17

Genetic heterogeneity of ALS?

Answer 17

Yes. There are pathogenic variants in many different genes. Also displays incomplete penetrance

Question 18

ALS pathogenic mechanism?

Answer 18

SOD1 gene has a toxic gain of function. Mutant SOD1 can either: incorrectly ID substrate, Aggregate proteins, reduce chaperones, or reduce proteasome activity. Variable expressivity.

Question 19

ALS Founder effect

Answer 19

Displays founder effects and variable expressivity.

Question 20

Classic Ehlers-Danlos Syndrome inheritance (connective tissue disorder)

Answer 20

Autosomal Dominant

Question 21

cEDS pathogenic mechanism?

Answer 21

COL5A genes. Dominant negative effect and genetic heterogeneity.

Question 22

Marfan Syndrome inheritance?

Answer 22

autosomal dominant

Question 23

Marfan Syndrome pathogenic mechanism?

Answer 23

FBN1 gene. Less fibrillin means that fibers are wider and weaker. Can no longer sequence TGFB so it starts a signal cascade to make matrix metalloproteinases which degrade the ECM. Dominant negative. Has variable expressivity and de novo pathogenic variants.

Question 24

Proteus syndrome inheritance?

Answer 24

autosomal dominant

Question 25

Proteus syndrome pathogenic mechanism?

Answer 25

mTOR pathway. AKT1 gene is missense. Affects protein synthesis and cell growth. Displays somatic mosaicism.

Question 26

Duchene muscular dystrophy inheritance?

Answer 26

X linked recessive

Question 27

Duchene muscular dystrophy genetic etiology?

Answer 27

DMD gene. Displays genotype-phenotype correlation because truncations and some missense variants have no functional protein. While some missense variants and in-frame deletions have some residual function. Becker muscular dystrophy.

Question 28

Alport Syndrome inheritance?

Answer 28

X linked dominant

Question 29

Alport syndrome genetic etiology?

Answer 29

X chromosome COL4A5. Collagen mutation. Truncation means severe, missense means mild symptoms. There is a span of phenotypes. There is a dominant-negative genotype-phenotype correlation.

Question 30

Oral-facial-digital syndrome type 1 inheritance?

Answer 30

X linked dominant

Question 31

Oral-facial-digital syndrome pathogenic mechanism?

Answer 31

OFD1. females only. Males lethal. However there have been cases that go against this.

Question 32

PCDH19-associated epilepsy inheritance?

Answer 32

X linked. Female-restricted. males are carriers.

Question 33

PCDH19-associated epilepsy pathogenic mechanism?

Answer 33

PCDH19 with cellular interference. Affects cadherin - cell to cell communication. Has dominant negative effect and interferes with normal cells too. Males do not have the phenotype because they will not be heterozygous. Females will be heterozygous for the mutation and have the phenotype because both sets of cells cannot talk.

Question 34

SMC1A inheritance?

Answer 34

X linked

Question 35

SMC1A cdLs vs DEE

Answer 35

Cornelia de Lange sydrome affects males and females with males more severe. Developmental epileptic encephelopathy affects females only. This gene escapes X inactivation. But can cause either disease. They have no overlapping phenotypes. A great mystery.

Question 36

46, XY disorder

Answer 36

Y chromosome. Affects SRY gene for male development.

Question 37

Why do individuals with Turner Syndrome have clinical features?

Answer 37

45XO. Although x chromosome inactivation happens, there are psuedoautosomal regions. They do have some gene homology. SHOX has homology. 45XO creates haploinsufficiency.

Question 38

Batten Disease mechanism

Answer 38

autosomal recessive. Mobile element insertions. The insertion of a retrotransposon created an alternative splice site.