Autosomal Recessive Inheritance/Complications of Patterns of Inheritance Flashcards
What are the six characteristics of an Autosomal Recessive disease?
- Males and females are affected equally
- 1/4 of offspring from a mating between 2 heterozygous carriers will be affected (aa)
- When parents are both carriers, multiple affective siblings are likely (especially if several children are produced)
- There is sometimes no prior family history of disease although disease allele may be present in the family (silently passed until mating between 2 carriers)
- Carrier individuals are present in “skipped generations” (only genotype pedigrees can show this, not phenotype)
- Consanguinity (incest) is present more with pedigrees involving autosomal recessive disease, specially rare diseases
With Autosomal Recessive diseases, what is the typical genotype of the two parents of an affected child?
Both parents are heterozygous carriers if the child is affected
What do most gene mutations involved with Autosomal Recessive diseases encode for?
Most mutations involve genes that encode for enzymes
What is the Hardy Weinberg Equation?
(p+q)^2 = p^2 + 2pq + q^2 = 1
p + q = 1
Differentiate between population gene frequency versus individual gene frequency.
- Population gene frequency: percent by which a disease appears in a certain population (CF is 0.8% in Caucasian population)
- Individual gene frequency: known genotype of an individual and its frequency (if an individual is a carrier of CF mutation, they have a 50% chance of passing the mutant allele to offspring)
What are six examples of Autosomal Recessive diseases?
- Hurler Syndrome
- Tay-Sachs Disease
- Cystic Fibrosis
- Sickle Cell Anemia
- Beta-Thalassemia
- Hereditary Hemochromatosis (HH)
What is the gene name and function, symptoms/features (7), and treatments (3) of Hurler Syndrome?
Hurler Syndrome
- Gene name/symbol: alpha-L-iduronidase
- Gene function: catalyzes the breakdown of glycosaminoglycans so deficiency in this causes a buildup of glycosaminoglycans in lysosomes
- Symptoms/Features: progressive intellectual disability, skeletal abnormalities, short stature, corneal clouding, course facial features, deafness, heart/joint problems
- Treatment: targeted enzyme replacement therapy, stem cell transplant or combination of both
What is the gene name and function involved in Tay-Sachs Disease? What are the three populations affected by Tay-Sachs Disease?
Tay-Sachs Disease
- Gene name/symbol: Hexosaminidase A (hex A)
- Gene function: lysosomal storage
Most common Ashkenazi Jewish population, as well as certain Cajun and French Canadian populations
What are the two most common mutation types of hexA gene found in the Ashkenazi Jewish population? Explain each and what they result in clinically
- 4 base insertion in the hexA gene which leads to a frameshift mutation and premature stop codon
- Point mutation (G to C) that alters proper splicing of mRNA at the boundary point between exon 12 and intron 12
Both result in infantile Tay-Sachs (death before age 5)
What is the gene name and function, most common mutation, and symptoms/features (2) of Cystic Fibrosis?
Cystic Fibrosis
- Gene name: CFTR (Cystic Fibrosis Transmembrane conductance Regulator) -
Most common mutation is deletion of 3 nucleotides within the coding region → leads to loss of a single amino acid from the protein (in-frame mutation)
- Gene function: CFTR is a chloride channel so this mutation prevents the channel from reaching the plasma membrane (disrupts movement of chloride ions outside the cell)
- Symptoms/Features: affects lung function and digestive system function (mucous thickened)
What is the mutation and one general feature of Sickle Cell Anemia? What population is this disease most common in, and what disease does it help to protect against?
Sickle Cell Anemia
- Missense mutation (A to T) that causes the incorporation of a wrong amino acid into the beta-globin protein
- Symptoms/Features: changes the shape of RBCs
- Incidence: African-Americans
Note: sickle cell carriers are more likely to survive malaria
What is the gene name, four most common mutations, and one general feature of Beta-Thalassemia?
Beta-Thalassemia
- Gene name/symbol: beta-globin gene
- Gene function: point mutations that can affect transcriptional levels of the gene (promoter region mutations), splicing of genes (splice site mutations), amino acid sequence of the coding region (missense, nonsense), stability of protein (nonsense, sometimes missense)
- Symptoms/Features: affects hemoglobin (results in a decrease in beta-globin production)
What is the gene name and function, and most common mutation of Hereditary Hemochromatosis (HH)?
Hereditary Hemochromatosis (HH)
- Gene name/symbol: HFE (high iron)
- Gene function: HFE protein detects the amount of iron in the body and regulates the production of hepcidin, a hormone BUT single missense mutation results in iron overload
What are the symptoms and common cause of death (if untreated) associated with Hereditary Hemochromatosis (HH)? What is the treatment?
- Symptoms/Features: iron accumulates in liver, heart, pancreas, joints and endocrine glands – most common cause of death is cardiac failure, if untreated; delayed age onset (about 30 years)
- Treatment: blood letting
What are the ten complications to pattern inheritance?
- Sporadic occurrence
- Germline mosaicism
- Delayed age of onset
- Reduced penetrance (incomplete penetrance)
- Variable expression
- Pleiotropy
- Heterogeneity
- Genomic imprinting
- Anticipation
- Consanguinity
