this paper is very good

Article Genetics of Congenital Adrenal Hyperplasia

Thank u sir

Dear Lavanya Ravichandran

Thank you for your interesting question.

The topic of compound heterozygous state and its clinical severity in autosomal recessive disorders is a bit complex. The type and site of mutation as well as other genetic / environmental factors all influence the clinical severity (phenotype).

Thus, some mutations (in homozygous states) produce a severe phenotype while others (in homozygous states) produce a less severe (moderate or even mild) phenotype.

In fact, i've worked on CAH mutations. We found in our cases few compound heterozygous patients, but all of them have similar-in-effect mutations (1 case has 3 mutations).

CAH is mainly caused by 21-OH enzyme deficiency. Enzyme level is determined by 2 alleles of Cyp21A2 gene (each is responsible for 50% of enzyme activity) in normal states. Sometimes other closely related genes interact with this gene.

If one allele carries a mutation that reduces enzyme activity to 10% (instead of the normal 50%) and the other carries a mutation that reduces the activity to 30%, the overall enzyme activity would be 40% or so, which is below the borderline or margin of safety level of 50% and shows disease manifestations. Thus ameliorating the severe deficiency caused by the more severe mutation and show milder manifestations closer to the less severe mutation. Although this is an oversimplification, but it might give you a hint on the answer.

If you have a specific situation with detailed data, we can discuss them.

Hope you find this answer helpful.

Regards

One of my patients is with congenital adrenal hyperplasia. The simple virilising male was positive for 3 pathogenic variants.. P30L, I2G and 8bp deletion... Previous literature suggests that in case of autosomal recessive disorder the phenotype is correlated with the mildest mutation retainin the maximum enzyme activity... I2g and 8bp del both results in 0% activity while p30L retains 30 to 60%. Also the first 2 are implicated in salt wasting type whereas p30l is associated with 20% of simple virilising.. In this case the simple virilising phenotype correlates with p30L which is the mildest form of mutation.... But i could not relate when 12g and 8bp del will lead to complete loss of enzyme function why is that the phenotype correlates to p30l

@lavanya Ravichandran

is it possible that one of your serious mutations is in a pseudogene so not expressed?

Dear Lavanya Ravichandran

Thank you for your rapid reply.

I have edited my first reply, so take notice.

What you stated in you case is true.

I agree that 8bp deletion causes SW in almost all cases, while I2 splice causes salt-wasting (SW) in some cases (mostly) but simple virilising (SV) type in others [see Amor et al., 1988 and Hsu etal., 1988b], and the P30 mutation causes SV type.

Classic CAH (SW-type) results from presence of 2 severe mutation types, while the non-classic (SV) results from 1 severe plus one mild or 2 mild types of mutations.

Thus, it seems that your case carries 2 mutations for SV type and 1 for SW type thus manifest as SV more than SW.

Other factors may also contribute to phenotype other than type of mutation. The pseudogene, the gene for 11-beta enzyme, etc.

See also, Speiser and New, 1987 and White and Speiser, 2000 for more details.

As for Paul Rutland

Obviously, the mutations occur in the CYP21A2 gene not the pseudogene.

Hope this was helpful.

Regards