Summary:

Turns out that I am also a carrier of the R457H variant that causes Antly-Bixler syndrome (ABS) in people that get two defective copies.

Common low-cost genotyping technologies:

So it looks like the genetic test you took is registered with the government here (https://www.ncbi.nlm.nih.gov/gtr/tests/528277/overview/). There isn’t anything particularly interesting there; I just think it’s notable that they have (voluntarily) become listed on this website, which keeps track of clinical genetic tests. On the other hand, 23andme is not listed on there, likely because they are direct-to-consumer and don’t try to go through the same processes (I’m assuming regulations) to really be considered a clinical genetic test.

The specific genetic test you took (CarrierMapGEN test from “Cooper Genomics” / “Recombine”) is very similar to the technology used by 23andme. Looking at the website, it says “CarrierMapGEN (genotyping) is built on Illumina’s proven genotyping platform”. Illumina is a company that specialized in offering a couple types of DNA sequencing / genotyping technologies; we actually use a different one of their products a lot in the our department / lab). The genotyping platform used by Cooper Genomics is apparently this chip (https://www.illumina.com/products/by-type/microarray-kits/infinium-iselect-custom-genotyping.html). 23andme also uses Illumina microarrays chips for genotyping. This youtube video here is pretty informative in describing how these chips work: (https://www.youtube.com/watch?v=lVG04dAAyvY). In short, there are certain positions in the genome where some small-to-moderate subset of the population has a different nucleotide than most of the rest of the population. Knowing this, these chips were printed to look at these nucleotide differences at tens of thousands of these positions. It’s not true DNA sequencing since it’s only looking at tens of thousands of possible nucleotide differences, rather than the 6 billion nucleotides that exist in each human cell, but it’s a more practical (fast and cost-effective) way to look at some major sites of genetic differences. Thus, the technology used by both services is likely very similar, though each company may customize / change exactly which DNA changes they’re looking for on their own versions of the chip.

The reason I bring this up, is that the single nucleotide polymorphism (change) you tested positive for is actually captured by 23andme; it’s just that they don’t report it, likely due to federal regulations / hoops they haven’t fully jumped through. The report from Cooper Genetics tells you the ABS carrier variation is in the POR gene, with the nucleotide at positions 1370, which is normally a G (guanine) instead being an A (adenine). This nucleotide change ends up changing the sequence of the protein encoded by the POR gene, where positions 457, which is normally an arginine, is now a histidine. In short, this variation is referred to as “R457H” at the protein level. These single nucleotide polymorphisms that exist at small-to-moderate subsets of the population (and thus are built into the genotyping chips supplied by Illumina) are listed in a government database, called dbSNP, and given a unique identifier name / number. In the case of this POR R457H variation, it’s listed here: (https://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?rs=rs28931608), and the associated unique identifier is “rs28931608”.

Importantly, if I (or you, for that matter) go to the 23andme webpage, hover over “tools” in the top menubar, and click on “Browse raw data” on the subsequent drop-down menu, it brings you to a page where you can enter the specific SNP id (so “rs28931608” in this case). It gave me a result that looked like this:

My results upon entering rs28931608 into 23andme

My results upon entering rs28931608 into 23andme

As the above image shows, it lists my genotype as being “A / G”, showing the nucleotide I have at this position, on each of my different copies of chromosome 7. One is the “G” found in the general population, encoding arginine at position 457 in that copy of the POR gene. On the other hand, the other version chromosome 7 I have encodes an “A”, resulting in histidine at position 457 in that second copy of POR gene. Thus, I seem to be a carrier as well. Based on my reseearch, it looks like this specific variant (R457H) is very rare, but still sporadically observed in some people of Japanese ancestry, suggesting that we likely inhereted it from mom. Dad’s 23andme result can likely shed some light on this.

So what is encoded by the POR gene, and what does this genetic change do?

While there are numerous useful resources online, I found this review article to be rather informative, so I uploaded here for you to see it without having to hit a paywall: (http://visualizedlife.com/wp-content/uploads/2017/10/Miller-et-al-2011-PMID-21070833.pdf). The POR gene encodes a moderately sized (not too big, but certainly not small) protein, which resides in the endoplasmic reticulum within just about every one of the cells of the human body. There are a certain group of important enzymes called cytochrome p450 enzymes, which are important for the synthesis and breakdown of a bunch of important small molecules, such as hormones (including estrogen and testosterone synthesis and metabolism), cholesterol synthesis, and vitamin D. Notably, these enzymes have to be powered to do their jobs, and the protein product of the POR gene, called cytochrome P450 Reductase or P450 oxidoreductase, is the protein responsible for powering these cytochrome P450 enzymes. Apparently, it uses NADPH, which is a molecule used to store energy for certain chemical reactions. POR helps to take some electrons from NADPH and pass them to an FAD (flavin adenine dinucleotide) molecule, and then onto an FMN (flavin mononucleotide) molecule, all the while changing shape to interact with the nearby cytochrome P450 enzymes. It then presses up against the nearby P450 enzymes and passes the electrons to the iron atom at the center of a heme molecule attached to the P450 enzymes, which is then used to perform its actual enzymatic function.