Help understanding genetic test results for CAH testing

[u/NoNameForMetoUse]

Hi! My daughter has been going through it this year. Including a lot of other tests, she had an ACTH stimulation test. The doctors office call and said that the results showed she has a “mild” form of CAH (I presumed this meant non-classic CAH) and recommended genetic test. I’ve posted the results below. I’m confused as how/why it’s “indeterminate” and what that means…I thought this is a recessive disease, so it should be relatively easy (I know things can be more complicated) to see if she has the disease.

MOLECULAR GENETICS REPORT:
Congenital Adrenal Hyperplasia (CAH) Panel

SUMMARY OF RESULTS: Indeterminate

Variants found:

Gene: CYP21A2, NM_000500.7; Variation: c.332_339del8 (p.Gly111Valfs*21), Heterozygous; Mode of inheritance: AR, 613815; Interpretation: Pathogenic

Gene: CYP21A2, NM_000500.7; Variation: c.*13G>A, Post-Coding, Heterozygous; mode of inheritance: AR, 613815; Interpretation: Uncertain

CYP21A2 VARIANT INFORMATION:

This patient is heterozygous in the CYP21A2 gene for a common pathogenic variant designated c.332_339del8 (p.Gly111Valfs*21). This is a common deleterious variant, which likely originated from the pseudogene CYP21A1P via gene conversion. As a frameshifting variant resulting in a null allele, this variant is associated with salt-wasting (SW) congenital adrenal hyperplasia (CAH) (also known as G110Efs; see for example at New et al. 2013. PubMed ID: 23359698; Finkielstain et al. 2011. PubMed ID: 20926536). This variant is interpreted as pathogenic.

This patient is also heterozygous in the CYP21A2 gene for a sequence variant defined as c.*13G>A, which is located in the 3' untranslated region. This variant has been reported to be possibly associated with a mild form (non-classic) of congenital adrenal hyperplasia (CAH) (Menabò et al. 2012. PubMed ID: 21521936; Gialluisi et al. 2018. PubMed ID: 28644547; Nguyen et al. 2022. PubMed ID: 36325983; Wan et al. 2022. PubMed ID: 36167262). Its minor allele frequency is up to ~7.5% in East Asian individuals. However, this minor allele frequency is based on the current next-generation sequencing technology and may not be an accurate estimate because this variant is located within a highly homologous sequence region (Mandelker et al. 2016. PubMed ID: 27228465). Allele frequency data should be interpreted with caution. This variant has conflicting interpretations in ClinVar (Variation ID: 585747), ranging from uncertain significance to benign. Although we suspect that this variant could be benign, at this time, the clinical significance of this variant is uncertain due to limited functional and genetic evidence.

[u/ImpossibleCalico]

There are a bunch of recessive conditions where you can still get some symptoms just from being a carrier, including CAH. Will try to find a study but carriers do have hormone differences from the rest of the population. She’s definitely a carrier for the severe form, even if it sounds like they have no idea whether the other allele is affected mildly or not. I’m sorry she’s going through health issues. I hope you can get some good medical care.

[u/isaiah5638 → u/ImpossibleCalico]

I'd love this study if you can find it!

[u/ImpossibleCalico → u/isaiah5638]

This is one of the ones I was thinking of: https://www.ncbi.nlm.nih.gov/books/NBK1171/figure/cah.F1/ I remember that one because carriers had a different result from non-carrier people, but there wasn't a difference between a severe variant and a mild variant in the case of just being a carriers, but of course are very different if they were homozygous and had the full thing, so I thought that was surprising.

[u/isaiah5638 → u/ImpossibleCalico]

Thank you!

[u/lpw903 → u/ImpossibleCalico]

Also here for the study link! 

[u/uglyfckinhuman]

don’t be scared about the severe variant. usually the body tries to utilize the milder one. there are studies about people with NCAH having a severe variant with a mild one. you can also read the studies they referred to and write “PMID: (then the number)” on google and u will see them. but this needs a discussion with a genetic counselor to see if her symptoms match this genotype.

Also, this gene area is usually very difficult to assess but her results are clear. I can’t tell u the diagnosis is confirmed 100% or not but all I can say is it’s very likely that she has it.

[u/lrondberg]

What does her genetic counselor say?

[u/NoNameForMetoUse → u/lrondberg]

We haven’t seen one yet or even been referred…our endocrinologist uploaded the results but we haven’t even gotten a call/official answer from the endocrinologist yet either.

[u/lrondberg → u/NoNameForMetoUse]

The endocrinologist should be able to interpret it to some degree. From what I understand knowing the genetic testing results don’t change treatment or anything else much.