Autosomal Recessive Inheritance Flashcards
What type of mutations are autosomal recessive?
All loss-of-function mutations
What are the pedigree characteristics of autosomal recessive mutations?
- Only individuals in a sibship in one generation are affected
- Other relatives are typically not affected, except in consangunity
- In small sibships, the condition may appear sporadic or isolated
- Males + females are equally likely
- If it’s a very rare condition, parents may be related by blood (consanguinity)
What is the exception of the two phenotype rule for autosomal recessive conditions?
In some genetic conditions, i.e. ataxia-telangectasia, carriers are at in increased risk for cancer (different phenotype)
What is meant by recurrence risk?
If the parents of an affected child have another child, what are the chances that their next child will have the condition again?
What is the definition of consanguinity? Why is this an issue?
Mating between individuals related by blood -> second cousins or closer.
Each of us have 50-100 mutant alleles in our genome that can lead to genetic disease in recessive conditions, and consanguinous relationships are more likely to be heterozygous
What is a genetic isolate?
Group which separates from larger population for a number of factors, including geographical, religious, or linguistic
One example is an ethnic group
Why are ethnic groups more susceptible to autosomal recessive disease?
They mate within their own genetic isolate. These isolates have many mutant heterozygous alleles.
These matings are NOT consanguinous
What are Ashkenazi Jews, and what diseases do they have the highest incidence of?
Jews from Central and Eastern Europe - highest incidence of Tay-Sachs disease and Gaucher disease, as well as autosomal recessive congenital deafness
What disease do Africans have the highest incidence of?
Sickle cell disease
What disease do North Europeans have the highest incidence of?
Cystic fibrosis
What is the normal function of alpha-1 antitrypsin (AAT)?
It is a protease inhibitor produced in liver, which protects the lungs from neutrophil elastase. Neutrophils produce elastase to respond to infection or lung irritants
What is protease inhibitor (PI) typing, and what are the three alleles?
Three alleles for deficiency of AAT
M - normal allele
S - moderate deficiency
Z - worst deficiency
What are the four PI types and their clinical manifestations?
MM = normal MZ = Slightly increased risk for decreased lung function, with smokers having the greatest risk SZ = slightly increased risk for COPD among smokers, but no liver involvement ZZ = COPD and liver involvement, ~18% of normal AAT
What are the clinical findings of AAT deficiency (AATD)?
COPD, including emphysema and asthma, chronic bronchitis. AAT can also become trapped in liver and cause liver damage.
Symptoms are worse in smokers.
How is diagnosis of AATD confirmed?
Low plasma AAT, and AAT protein variant (PI typing) or molecular testing for SERPINA1 (Gene encoding AAT)
What are the treatment options for AATD?
Inhaled purified AAT, abstaining from smoking / pollutants which may trigger neutrophils, lung / liver transplant
What can you not rule out when assessing the parents of someone affected with AATD?
They could also be homozygous affected, since it is so common.
What is DFNB1? What is the most common birth defect in the developed world?
Autosomal recessive deafness -> bilateral permanent sensorineural hearing loss which may be mild to profound
Hearing loss is the most common birth defect in the developed world
What mutations are involved in DFNB1?
GJB2 - protein encoding connexin 26
GJB6 - protein encoding connexin 30
They are both gap junctions proteins important in recycling of K+ back into endolymph
What is a compound heterozygote and how does it relate to DFNB1?
Two different mutant alleles at the same locus, can cause an autosomal recessive condition at that locus, as in two different mutations of GJB2
How does double heterozygosity play into DFNB1 and what is inheritance of an autosomal recessive mutation via this way cold?
A mutation at GJB2 and GJB6 can both be inherited, and although they are heterozygous for these genes, they can have “digenic inheritance” which still causes deafness. This is interaction of two gene loci
What are the best treatments for DFNB1?
Cochlear implants or hearing aids
What is spinal muscular atrophy (SMA)?
Progressive muscle weakness resulting from degeneration and loss of anterior horn cells (LMN) in spinal cord and brainstem nuclei.
What are common clinical manifestations of SMA?
Poor weight gain, sleep difficulties, pnuemonia, scoliosis, failure to hit motor milestones.
There are 5 different types based on age of onset, as a result of the amount of survival motor neuron that remains
What genes are involved in SMA?
- Survival motor neuron 1 (SMN1) - primary gene to produce SMN protein. Critical to survival of motor neurons, otherwise cells shrink and die
- Survival motor neuron 2 (SMN2) - secondary gene which produces SMN protein, encodes a single nucleotide change in exon-7 which decreases its efficiency of SMN production
Genes are adjacent on chromosome 5
How many copies of SMN1 and SMN2 will normal individuals have?
SMN1 = 1 on each chromosome SMN2 = 0-5 on each chromosome
What is one complication with carrier testing of SMA?
Some people have two copies of SMN1 on a single chromosome (4% of population). This will lead to no detection via array-CGH, however if they pass the empty chromosome to the offspring, the child will be affected
For someone with only one functioning copy of SMN1, what percentage of normal protein do they make? When does it become a problem?
Carriers make 45-55% of normal protein. Becomes a problem at <23% of normal amounts (double gene knockout, autosomal recessive)
How does each type of SMA scale with protein levels?
SMA 1: ~9% of full length SMN
SMA 2: ~14% of full length SMN
SMA 3: ~18% of full length SMN
SMA 4: ~23% of full length SMN = normal until adulthood
What is the function of SMN2 in SMA outcomes?
It is a gene modifier. When SMN1 is mutated, SMN2 can compensate for lack of SMN1 depending on its copy number. The higher the copy number, the the milder the phenotype. >3 copies = milder phenotype of SMA
What is the genetic etiology of SMA?
2% de novo mutations, paternal origin. The rest are from heterozygous parents (carriers). Remember, you can have parents who are carriers who have two copies of SMN1 (will have 2 SMN1 on the same chromosome).
