Autosomal Recessive Inheritance

Question 1

What type of mutations are autosomal recessive?

Answer 1

All loss-of-function mutations

Question 2

What are the pedigree characteristics of autosomal recessive mutations?

Answer 2

1. Only individuals in a sibship in one generation are affected
2. Other relatives are typically not affected, except in consangunity
3. In small sibships, the condition may appear sporadic or isolated
4. Males + females are equally likely
5. If it’s a very rare condition, parents may be related by blood (consanguinity)

Question 3

What is the exception of the two phenotype rule for autosomal recessive conditions?

Answer 3

In some genetic conditions, i.e. ataxia-telangectasia, carriers are at in increased risk for cancer (different phenotype)

Question 4

What is meant by recurrence risk?

Answer 4

If the parents of an affected child have another child, what are the chances that their next child will have the condition again?

Question 5

What is the definition of consanguinity? Why is this an issue?

Answer 5

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

Question 6

What is a genetic isolate?

Answer 6

Group which separates from larger population for a number of factors, including geographical, religious, or linguistic

One example is an ethnic group

Question 7

Why are ethnic groups more susceptible to autosomal recessive disease?

Answer 7

They mate within their own genetic isolate. These isolates have many mutant heterozygous alleles.

These matings are NOT consanguinous

Question 8

What are Ashkenazi Jews, and what diseases do they have the highest incidence of?

Answer 8

Jews from Central and Eastern Europe - highest incidence of Tay-Sachs disease and Gaucher disease, as well as autosomal recessive congenital deafness

Question 9

What disease do Africans have the highest incidence of?

Answer 9

Sickle cell disease

Question 10

What disease do North Europeans have the highest incidence of?

Answer 10

Cystic fibrosis

Question 11

What is the normal function of alpha-1 antitrypsin (AAT)?

Answer 11

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

Question 12

What is protease inhibitor (PI) typing, and what are the three alleles?

Answer 12

Three alleles for deficiency of AAT
M - normal allele
S - moderate deficiency
Z - worst deficiency

Question 13

What are the four PI types and their clinical manifestations?

Answer 13

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

Question 14

What are the clinical findings of AAT deficiency (AATD)?

Answer 14

COPD, including emphysema and asthma, chronic bronchitis. AAT can also become trapped in liver and cause liver damage.

Symptoms are worse in smokers.

Question 15

How is diagnosis of AATD confirmed?

Answer 15

Low plasma AAT, and AAT protein variant (PI typing) or molecular testing for SERPINA1 (Gene encoding AAT)

Question 16

What are the treatment options for AATD?

Answer 16

Inhaled purified AAT, abstaining from smoking / pollutants which may trigger neutrophils, lung / liver transplant

Question 17

What can you not rule out when assessing the parents of someone affected with AATD?

Answer 17

They could also be homozygous affected, since it is so common.

Question 18

What is DFNB1? What is the most common birth defect in the developed world?

Answer 18

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

Question 19

What mutations are involved in DFNB1?

Answer 19

GJB2 - protein encoding connexin 26
GJB6 - protein encoding connexin 30

They are both gap junctions proteins important in recycling of K+ back into endolymph

Question 20

What is a compound heterozygote and how does it relate to DFNB1?

Answer 20

Two different mutant alleles at the same locus, can cause an autosomal recessive condition at that locus, as in two different mutations of GJB2

Question 21

How does double heterozygosity play into DFNB1 and what is inheritance of an autosomal recessive mutation via this way cold?

Answer 21

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

Question 22

What are the best treatments for DFNB1?

Answer 22

Cochlear implants or hearing aids

Question 23

What is spinal muscular atrophy (SMA)?

Answer 23

Progressive muscle weakness resulting from degeneration and loss of anterior horn cells (LMN) in spinal cord and brainstem nuclei.

Question 24

What are common clinical manifestations of SMA?

Answer 24

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

Question 25

What genes are involved in SMA?

Answer 25

1. Survival motor neuron 1 (SMN1) - primary gene to produce SMN protein. Critical to survival of motor neurons, otherwise cells shrink and die
2. 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

Question 26

How many copies of SMN1 and SMN2 will normal individuals have?

Answer 26

SMN1 = 1 on each chromosome
SMN2 = 0-5 on each chromosome

Question 27

What is one complication with carrier testing of SMA?

Answer 27

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

Question 28

For someone with only one functioning copy of SMN1, what percentage of normal protein do they make? When does it become a problem?

Answer 28

Carriers make 45-55% of normal protein. Becomes a problem at <23% of normal amounts (double gene knockout, autosomal recessive)

Question 29

How does each type of SMA scale with protein levels?

Answer 29

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

Question 30

What is the function of SMN2 in SMA outcomes?

Answer 30

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

Question 31

What is the genetic etiology of SMA?

Answer 31

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).