a-Thalessemia practice question...stumped.

[IDoIt4Love]

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I'm stumped on a practice question about alpha thalessemia:

An Asian man has a-thalessemia trait (2 gene deletions). His brother died at birth with hydrops fetalis (all 4 gene deletions). His uncle has HbH disease (3 gene deletions). His wife is genotypically normal.

The question is, what are the odds that this man's kid will also have a-thalessemia trait (2 deletions)?

I didn't think I had enough info to answer this question. From my understanding, you could have one of two genotypes to have the a-thalessemia trait: "aa/--" or "a-/a-". The kid's odds of inheriting both of dad's deletions depends on which genotype the father is...if he's aa/-- the kid has a 50% chance of having a-thal trait, whereas if dad was a-/a- the kid would have no chance (he would just be a silent carrier, with only one deletion).

Am I missing something here?

EDIT: mystery solved. Asians with a-thalessemia trait are usually aa/-- (cis), whereas African Americans with the trait are usually a-/a- (trans). Indeed, assuming the father to be aa/-- should lead you to the correct answer: 50%. I was confused because the explanation to the question made no mention of this fact, but it is mentioned in Pathoma. Thanks guys!

 

[MrBeauregard]

What was the correct answer said to be?

 

[johndoe3344]

Yeah I have no idea. Lol... wtf

 

[Phloston]

50%. You've gotta know that Asians vs Blacks are typically cis- vs trans-mutations, respectively. The Asian guy's going to give "--" or "aa" to his offspring.

Don't ask me why I know that.

 

[mdeast]

I'm stumped on a practice question about alpha thalessemia:

An Asian man has a-thalessemia trait (2 gene deletions). His brother died at birth with hydrops fetalis (all 4 gene deletions). His uncle has HbH disease (3 gene deletions). His wife is genotypically normal.

The question is, what are the odds that this man's kid will also have a-thalessemia trait (2 deletions)?

I didn't think I had enough info to answer this question. From my understanding, you could have one of two genotypes to have the a-thalessemia trait: "aa/--" or "a-/a-". The kid's odds of inheriting both of dad's deletions depends on which genotype the father is...if he's aa/-- the kid has a 50% chance of having a-thal trait, whereas if dad was a-/a- the kid would have no chance (he would just be a silent carrier, with only one deletion).

Am I missing something here?

When I went to think about....he has to be a-/a-. His parents had to have been both --/a-. It's the only way they could produce children with all those different conditions (i.e. 2,3 and 4 gene deletions) assuming none of the mutations are happening germ-line.

So assuming that his wife is aa/aa there is a 0% chance that his kids will get it.

Edit: Wait....didn't realize it was an uncle and not another brother. Woops. Forget that.

 

[Phloston]

I would also say that his uncle's genotype of HbH is a distractor. He may have had a grandparent who was Black, but that's not relevant here.

 

[johndoe3344]

50%. You've gotta know that Asians vs Blacks are typically cis- vs trans-mutations, respectively. The Asian guy's going to give "--" or "aa" to his offspring.

Don't ask me why I know that.

Ugh. That was straight out of pathoma too :/

 

[IDoIt4Love]

I just checked...so it IS in Pathoma! The Asian father is most likely aa/-- because that's the mutation usually seen in Asians, whereas the a-/a- genotype is usually seen in African-Americans with the trait. Mystery solved; thanks!

The correct answer was indeed 50%, also consistent with a paternal genotype of aa/--. However, the explanation made no mention of the above fact, hence my confusion.

 

[Morsetlis]

Thalassemias are found near the sea (Greek, Asians, Africans). They reduce the half life of RBCs so confer resistance against blood-born parasites.

a-/a- cannot pass a cis mutation! aa/-- x a-/a- will create a-/aa or a-/-- (HbH). Most likely both parents were aa/-- x aa/--, giving possibility of Hb Bart or cis-del. Uncle most likely resulted from grandparents with a-/-- x aa/--, and then also passing -- to his dad.

Trans-del CANNOT create hydrops fetalis. No need to know obscure Asian secrets here.

 

[IDoIt4Love]

Thalassemias are found near the sea (Greek, Asians, Africans). They reduce the half life of RBCs so confer resistance against blood-born parasites.

a-/a- cannot pass a cis mutation! aa/-- x a-/a- will create a-/aa or a-/-- (HbH). Most likely both parents were aa/-- x aa/--, giving possibility of Hb Bart or cis-del. Uncle most likely resulted from grandparents with a-/-- x aa/--, and then also passing -- to his dad.

Trans-del CANNOT create hydrops fetalis. No need to know obscure Asian secrets here.

Obscure Asian secrets...lol!

Well, technically the Asian man's parents could have both been a-/--, accounting for both the child with hydrops fetalis AND the one with a-thal trait. If they were both a-/--, their son (the father-to-be in the question stem) could have been a-/a- genotype. The question stem did not explicitly comment on the man's parents' health, and I couldn't assume how many deletions each parent had without being given their clinical presentations.

Unfortunately it looks like the only way I could have fairly assumed that the man's genotype was aa/-- and not a-/a- was by knowing the obscure Asian secret 🙁

 

[johndoe3344]

Well, technically the Asian man's parents could have both been a-/--, accounting for both the child with hydrops fetalis AND the one with a-thal trait. If they were both a-/--, their son (the father-to-be in the question stem) could have been a-/a- genotype. The question stem did not explicitly comment on the man's parents' health, so I didn't know if I could assume that they were asymptomatic.

Agreed. This question was definitely testing on Asian vs African, cis vs trans. Blah. Why do I only know where the answer to a question comes from after I get it wrong?? Happens all the time with UW too.

 

[Morsetlis]

Obscure Asian secrets...lol!

Well, technically the Asian man's parents could have both been a-/--, accounting for both the child with hydrops fetalis AND the one with a-thal trait. If they were both a-/--, their son (the father-to-be in the question stem) could have been a-/a- genotype. The question stem did not explicitly comment on the man's parents' health, and I couldn't assume how many deletions each parent had without being given their clinical presentations.

Unfortunately it looks like the only way I could have fairly assumed that the man's genotype was aa/-- and not a-/a- was by knowing the obscure Asian secret 🙁

In patients with HbH disease (--/-&#945😉, the degree of anemia varies, and morbidity and mortality are largely related to the degree. As a result of multiple blood transfusions, consequences of iron overload on the heart, liver, and other organs may be present; these can contribute to morbidity and mortality. Patients with HbH disease may develop hypersplenism, gallstones, leg ulcers, frequent infections, and various forms of venous thrombosis.

Ok it doesn't sound to me like people who are like this tend to marry other individuals who are like this, but at least now we all know the obscure Asian secret...

 

[VisionaryTics]

I didn't know the Asian/Black cis/trans thing, but I just reasoned it out from the stem.

If his brother died at birth (aa/aa), that means that both of his parents must be aa/--. That's the clincher of the question. The parents have to be homozygous at one of the loci for the kid to be homozygous at both loci.

So the proband must be aa/-- (didn't die at birth, but still alpha thal trait). With a normal wife (--/--), his risk of passing on the trait is 50%.

 

[Phloston]

I just thought I should throw out there that I encountered an alpha-thalassaemia question today in FA Q&A, and they specifically wanted you to know that hydrops fetalis is due to the accumulation of FOUR GAMMA chains within the fetal RBCs, with an obvious hyper-left-shifted Hb-O2 curve.

 

[IDoIt4Love]

I just thought I should throw out there that I encountered an alpha-thalassaemia question today in FA Q&A, and they specifically wanted you to know that hydrops fetalis is due to the accumulation of FOUR GAMMA chains within the fetal RBCs, with an obvious hyper-left-shifted Hb-O2 curve.

Makes sense b/c fetal hemoglobin is alpha2gamma2 instead of alpha2beta2. If you can't make alpha chains at all (like in hydrops fetalis), all you can really make are gamma chains.