Genetics Disorders Flashcards
Pyridoxine dependent epilepsy (PDE) type of inheritance?
Autosomal recessive. Compound heterozygous varients are common.
Pyridoxine dependent epilepsy (PDE) pathogenic mechanism?
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
Beta Thalassemia is what type of inheritance?
Autosomal recessive.
Beta Thalassemia gene variant?
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
Beta Thalassemia pathogenic mechanism?
Beta chains tend to aggregate when the Alpha to Beta ratio changes. This creates cell membrane damage, ineffective erythrocytes.
Beta Thalassemia modifier alleles?
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
What offers selective advantage to heterozygotes with beta globin mutations?
Sickle cell anemia prevents malaria
Cystic Fibrosis inheritance mechanism?
Autosomal recessive
Cystic Fibrosis genetic etiology? How does it differ between populations?
CFTR. Many pathogenic variants, vary across populations.
Cystic Fibrosis heterozygote advantage?
Cholera. Cholera causes chloride-secreted diarrhea, if you don’t have chloride channel, then you aren’t affected. There are modifier alleles too (RNF5)
Spinal Muscular Atrophy inheritance pattern?
autosomal recessive
Spinal Muscular Atrophy genetic etiology?
SMN1 - most with homozygous deletion. Loss of neurons.
Spinal Muscular Atrophy modifier alleles?
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.
What is a potential reason for an individual being affected with an autosomal dominant disorder but neither parent is affected?
De Novo
Incomplete penetrance
Pathogenic mechanisms of dominant conditions?
Haploinsufficiency, gain of function, dominant negative.
Familial Amyotrophic Lateral Sclerosis (ALS) inheritance pattern?
autosomal dominant
Genetic heterogeneity of ALS?
Yes. There are pathogenic variants in many different genes. Also displays incomplete penetrance
ALS pathogenic mechanism?
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.
ALS Founder effect
Displays founder effects and variable expressivity.
Classic Ehlers-Danlos Syndrome inheritance (connective tissue disorder)
Autosomal Dominant
cEDS pathogenic mechanism?
COL5A genes. Dominant negative effect and genetic heterogeneity.
Marfan Syndrome inheritance?
autosomal dominant
Marfan Syndrome pathogenic mechanism?
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.
Proteus syndrome inheritance?
autosomal dominant
Proteus syndrome pathogenic mechanism?
mTOR pathway. AKT1 gene is missense. Affects protein synthesis and cell growth. Displays somatic mosaicism.
Duchene muscular dystrophy inheritance?
X linked recessive
Duchene muscular dystrophy genetic etiology?
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.
Alport Syndrome inheritance?
X linked dominant
Alport syndrome genetic etiology?
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.
Oral-facial-digital syndrome type 1 inheritance?
X linked dominant
Oral-facial-digital syndrome pathogenic mechanism?
OFD1. females only. Males lethal. However there have been cases that go against this.
PCDH19-associated epilepsy inheritance?
X linked. Female-restricted. males are carriers.
PCDH19-associated epilepsy pathogenic mechanism?
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.
SMC1A inheritance?
X linked
SMC1A cdLs vs DEE
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.
46, XY disorder
Y chromosome. Affects SRY gene for male development.
Why do individuals with Turner Syndrome have clinical features?
45XO. Although x chromosome inactivation happens, there are psuedoautosomal regions. They do have some gene homology. SHOX has homology. 45XO creates haploinsufficiency.
Batten Disease mechanism
autosomal recessive. Mobile element insertions. The insertion of a retrotransposon created an alternative splice site.
