Mendelian Inheritance of Primary Immunodeficiency

Question 1

What are the 3 characteristic manifestations of primary immune deficiency?

Answer 1

Question 2

True/false: SCID is more common in females than males.

Answer 2

False - more common in males

Question 3

What are the universal presenting features of SCID?

What are common presenting features of SCID?

What are less common presenting features of SCID?

Answer 3

Question 4

What are 2 main types of genetic mutations that cause SCID?

Answer 4

X-linked - IL2RG gene

• IL2RG gene encodes common gamma chain –> component of several different receptors involved in immune system function –> proteins attach to these receptors to trigger a series of chemical reactions inside the cell –> involved in lymphocyte development and maturation of T cells, B cells and NK cells

Question 5

Why are there no autosomal dominant mutations that cause SCID?

Answer 5

Because a normal copy of the gene on one chromosome is enough to compensate for the defective copy on the other chromosome

Question 6

Answer 6

X-linked

Question 7

Answer 7

If sex unknown: 25%

If sex is male: 50%

Question 8

Answer 8

Autosomal recessive

Question 9

Answer 9

2/3

Question 10

What is the best form of treatment available for SCID?

When should it be done?

Answer 10

Question 11

SICD is a very rare disease. So why do we screen all newborns for it in the US?

Answer 11

Question 12

If left untreated, how long can someone live with CGD?

Answer 12

Til 2nd or 3rd decade

Question 13

What is the pattern of inheritance of CGD?

Answer 13

Although it is a genetically heterogenous disease, the X-linked form is more common than all forms of autosomal recessive inheritance combined. All forms result from a mutation that results in defective or absent phagocyte NADPH oxidase.

Question 14

Allogenic hemotopoetic stem cell transplant is the best course of treatment both for SCID and CGD. However, it requires a “matched” donor. What does that mean?

Answer 14

HLA complex describes the genes that result in the MHC proteins in humans. MHC class 1 is on the surface of ALL nucleated cells in our body, so it is important that the donor’s HLA subtype match the patient’s to a certain degree so that the patient doesn’t mount a response agaisnt the donated cells seeing them as foreign (graft v host).

Question 15

True/False: HLA genes on one chromosome (either mom or dad) will be dominant.

True/False: the HLA gene complex undergoes rearrangement during crossing over in meiosis.

Answer 15

False - co-dominant expression

False - linked very closely together on chromosome, very unlikely to recombine.

Question 16

Who is the best match for a patient requiring HSCT?

Answer 16

Sibling

Question 17

Answer 17

P(unaffected) = 50%

P(match) = 25%

P(unaffected & match) = 0.5 * 0.25 = 0.125 or 12.5%

Question 18

What is Wiskott Aldrich Syndrome?

Answer 18

Question 19

What is the mechanism of disease in WAS?

Answer 19

X-linked inheritance of a mutated copy of the WAS gene, which provides instructions for making a protein called WASP. This protein is found in all blood cells. WASP is involved in relaying signals from the surface of blood cells to the actin cytoskeleton. WASP signaling triggers the cell to move and attach to other cells and tissues (adhesion). In white blood cells, this signaling allows the actin cytoskeleton to establish the interaction between cells and the foreign invaders that they target.

Question 20

• What is the prevalence of WAS?
• When does it present?
• How does it present?
• What is the lifespan?
• What is the treatment?
• When should treatment be given?

Answer 20

Question 21

Answer 21

Question 22

DiGeorge Syndrome

• Caused by?
• Incidence?
• Phenotype (as it relates to immune system)?
• X-linked? AD? AR?

Answer 22

Autosomal dominant inheritance