r/ClinicalGenetics

Hi. I hope this is an appropriate question for the sub.

My wife and I have three kids. The oldest is a teenager and had a medical emergency recently. A genetic test was done looking for specific findings, but it came back negative. Because the medical emergency could happen again and is typically life ending, doctors are doing a genome sequencing analysis. Our teenager, my wife, and I will give blood and the test will be done on all of us. If there is a finding in our teenager, then they will look at my wife and I's test for the same thing, otherwise my wife and I's tests will not be looked at.

The doctor wants to know if we want secondary findings. At first this sounded like a great thing, but he mentioned that with some findings, it can prevent people from getting life insurance or disability insurance. I assume it can also make health insurance more expensive, but not prevent someone from getting health insurance. I have read some people will get secondary findings and wish they had not because there is nothing they can do about the findings. We are struggling to decide how to address secondary findings, especially since this will effect our teenager.

I'm hoping to hear from some people in this sub with experience on what the positives and negatives are for learning secondary findings.

I'm trying to understand the finer details of a human genetic report. I was promised full genome/exome sequencing with results based on search terms. This seems to be the best I can expect here, other than a handful of genes looked at at a time. I guess I got it, though it's not quite what I expected. Germany. Note: I'm not asking whether I have a condition or not. I'm merely asking about the quality of work and chosen methodology here.

Comments:

• upon receiving the result by phone I was told just one heterozygous mutation was found for which I'd need a second allele or another mutation in the same gene. This is also repeated in the clinical part of the letter. I was told nothing else in my whole genome was found that would explain my problems and to come back in 3-5 years.

• I asked whether potential mitochondrial mutations, nDNA or mtDNA were included and I was told it was. Seeing the 'Limitations' section of this report, it looks like mtDNA was not included in this analysis after all, and looking through the list of 66 selected genes, most are congenital myopathies, a few common metabolic myopathies, 8 mitochondrial myopathies, and a few others. About 16 and 10 (thus 26) of these were tested in this university hospital in the same department previously.

• I have the feeling this is far from complete. Given the rarity of my mutation (0,009347%) and no published papers, I wonder whether a heterozygous mutation together with a mutation on a different gene might cause milder, yet lifelong symptoms. I see references to TTN and MYH2, among a few others in relationship with OBSCN, especially where CA^+2 issues and core-like structure in muscle biopsy seem to play a role. None of which were included. No follow-up analysis on related genes was done after this one hit.

Questions: is this a standard methodology, doing a whole genome sequencing and only looking at a few genes? Is search depth and other methods used here normal for such work? Not following up with something that a) fits symptoms and findings and b) might work together with other genes on that part of the body?

The following is a translation, and I hope it makes sense as I used AI for it as this is totally not something I'd be confident translating (sorry!). Things in <> are comments by me

---

Analysis pipeline: megSAP 2025_10

Evaluation software: GSvar 2025_12-59-g062eb7ab

Phenotype

• HPO: HP:0003326 (Myalgia)
• <7 others>

Target region

The target region encompasses at minimum the CCDS ("consensus coding sequence") of the genes listed below ±20 bases of flanking intronic sequence, but may also include additional exons and/or flanking bases.

Name: <deleted as I guess this is confidential>

<list of 66 genes>

filter criteria

• Allele frequency ≤ 0.10%

• Allele frequency (sub-populations) ≤ 1.00%

• Count NGSD ≤ 20

• Impact HIGH, MODERATE, LOW

• Filter columns REMOVE: low_mappability, mosaic, off-target

• Annotated pathogenic KEEP: HGMD, ClinVar (also likely pathogenic)

• Classification NGSD REMOVE: 1, 2

• Classification NGSD KEEP: 3, 4, 5, M

• Variant quality qual≥0 depth≥0 mapq≥0 strand_bias≤-1 allele_balance≤-1 min_occurences≥1 min_af≥0.1 max_af≤1

Total SNVs/InDels found in target region: 646

Number of SNVs/InDels selected for report: 8

Number of CNVs/SVs/REs selected for report: 0

Where present, the following tables capture: pathogenic variants (Class 5) and likely pathogenic variants (Class 4), for which an association with the clinical question can be assumed, as well as variants of uncertain clinical significance (Class 3) for which, considering the literature and the patient's clinical presentation, a contribution to the symptomatology is conceivable and for which further classification of clinical relevance through follow-up investigations may be useful. In some cases — depending on the nature of the genetic change, the family history, and the clinical presentation of the patient — further investigations may result in a change of classification. An (uncommented) list of all detected variants can be requested if needed.

In the presence of specific differential diagnostic indications of a particular disease, further genetic investigations or diagnostic methods may be indicated. For information on the classification of variants, see general supplementary information.

Single nucleotide variants (SNVs) and insertions/deletions (InDels) following clinical interpretation in the context of the clinical question

Variant | Genotype | Gene(s) | Details | Class | Inheritance | gnomAD allele frequency (control cohort) | RNA

chr1:228371738 C>A | het | OBSCN (AR) | OBSCN:ENST00000680850.1:c.23831C>A:p.Ser7944Ter | | n/a | 0.005% | n/a OMIM ID: 608616 Details: GENE=OBSCN_PHENOS=[Rhabdomyolysis, susceptibility to, 1], 620235 (3), Autosomal recessive]

Copy number variants (CNV) and/or structural variants (SV) following clinical interpretation in the context of the clinical question

CNV/SV/RE | Position | Size | Copy number/Genotype | Gene(s) | Class | Inheritance | RNA

None

Coverage statistics target region

Average sequencing depth: 40.28

Average sequencing depth (chrMT): 101.77

<lots of information on the found mutation and classification>

Limitations of the method

• The sensitivity for detection of pathogenic variants in the analysed regions is approximately 95% using the applied methods.

• In homologous regions, the informative value of the analysis is limited.

• The applied methodology is not suitable for specific diagnosis of mosaics. In particular, mosaics with a variant allele fraction below 15% cannot be detected.

• The assessment of variants in the mitochondrial genome is not part of the accredited diagnostics.

Can somebody who knows something about genetics please tell me what the chances are of something related to chromosome 18 showing up on microarray when qf-pcr showed no evidence of trisomy 18? NIPT showed high risk t18 but qf-pcr ruled it out. Very confused.

Note: I posted this on Chronic Illness subreddit a few days ago, but felt you all may have some insight too.

I have been hyperaware and quietly suffering for over a decade. I displayed chronic illness behaviors (ie. fatigue/fine motor skill issues/delayed milestones) since I was born. Sooooo many medical professionals examined me over the years to piece together what is going on and lessen symptoms with varying success.

Recently, my latest surgery brought my “invisible” illness into the physical (total colectomy with an ileostomy). Essentially, lost one organ to extend the life of two other organs. People finally believe me when I am weak, pain, etc. because it is a physical presence. They cannot deny it anymore.

My medical personnel finally agreed that a genetic test could give us a direction. For YEARS, I have begged for this. I have a hypothesis about the underlying cause. In previous decades, if you did not have the severe version of genetic disorders, people overlooked your struggles or called you a hypochondriac. If you were not missing a limb, my family said suck it up. My theory would explain a majority of everything I have felt since birth...and why my body fails me in my 40s.

However, there is another greater fear nagging and eating me alive: no negative genetic abnormalities. So many routine tests showed nothing strange. One physician said, “We might have to reevaluation if your health declines farther.” Guess what!? I lost my colon waiting for the decline. Other organs are waiting in line for the next surgery. No children. No career. Poor and drowning in medical debt. Nothing to show but pain and anxiety. The waiting longevity analysis makes sense, but it feels like you cannot act. It is my personal limbo hellscape.

It took so long to get to this point. I had to lose a major organ to valid what I have always known. Yet modern medicine and genetic testing might not know my possible mutations. I might get a negative result, but must wait for medical research to find a correlation.

I am internally screaming and having nightmares of being told nothing is happening or "wrong" to me. That my dysautonomia and immunodeficiency have no explanation. I hate the word “idiopathic.” I know that is the nature of medicine, human physiology, and biology. I accepted that there is no cure. All I want is to be believed and treated like a person.

However, laying at home waiting for a stroke, another brain lesion, sickness after illness because the immune system is failing, or losing the rest of your GI tract...I live in my own bodily purgatory.

Man, I hope the test explains over ten years of wandering in the dark.

Thanks for reading my inability to wait six weeks for...something!

I’m based in the UK but can use online services from other countries too

The NHS won’t do genetic testing unless a genetic condition is clearly established, so I have to go private and self paid.

I’m no expert in this. I’m looking for a genetic test like whole genome sequencing that will show me every single gene and anything possibly wrong in them. Errors, mutations, etc. For example anything at all that can be a cause of a neurological disorder or any other illness. Anything that isn’t normal, is wrong or can cause something. I’m willing to do lots of research.

This must include showing all genes related to autism.
And even allow the possibility of finding new genetic errors like mutations or anything like that which aren’t discovered yet. So I can do my research from there.

Secondly I’m looking for a good reputable geneticist or genetic counsellor that I can speak with, get advice from and ask questions to.

Also is there a service or website which shows all known gene errors, conditions and things? To compare against my findings.

Backstory:
My symptoms may be related to autism, even if that’s the case I want to find associated genes.
However something is very wrong with me.
I am desperate to look into genes because I have explored so many other avenues.
I cannot live like this.

Undiagnosed and unexplained symptoms which are hard to explain. From about 5 years old something has been very wrong. I feel like I’m not in real life, vision is different. This has also, as a result caused severe anxiety, depression, neurological symptoms like stiffness and pain and overall suffering which can’t go on and am desperate to look into the cause. Yes I have explored so many GP options, mental health, etc etc. I can’t describe it with words but something is seriously wrong which I need to investigate.

I am interested in doing whole genome sequencing (WGS). Does anyone here have any experience, positive or negative, with current DTC providers?

Prior recommendations seem like they aren't a great idea. Nebula has a huge backlog and dubious financial position. Dante labs also seems to be collapsing. Sequencing.com uses Chinese labs currently blacklisted by the DOD. Invitae was bought by LabCorp and no longer DTC. Researcher providers like All of Us Research seem to have stopped providing people with their WGS results.

Some names that do come up that I am curious about: Psomagen, YSEQ, tellmeGen, SelfDecode, Nucleus Genomics, Sano Genetics.

Disclaimer: This is already in collaboration with my doctor. We are looking for some specific things and having them all go through clinical genomic testing is far more expensive than a DTC 30x WGS test. I do not need any assistance with data interpretation, just need reliable raw data. If a major health risk is flagged, I am prepared to do confirmatory clinical testing.

My son was born with VACTERL impacting his kidney, urinary system, and anus. We’ve decided to meet with genetic counselor and discuss genetic testing to determine if there’s anything else or if this is something he should consider for if/when he decides to have kids later in life. (He is 6 years old right now). I thought it’s better to know more so we can always get him the best help possible, however when they brought up the option to get secondary results my first thought was ‘yes, no doubt’. I would want to know just in case there’s anything we could possibly prevent or make lifestyle changes to. But now I don’t know… what if we learn he’s at a high risk for some type of cancer? I don’t think I could handle the anxiety if it’s something completely out of our control. But on the other hand I’d be so upset if we found something out down the road that I COULD have helped prevent. I just don’t know… please help. My heart hurts just thinking about it all. Are secondary findings few and far between?

I know that the obsurin gene is huge and controls various things. I wonder what is known so far on pathogenic mutations given that most papers seem to be very new. I had full genome/exome sequencing with search results based on symptoms. A heterocygotic mutation on something autosomal recessive in that gene came up as only thing. One month on I'm still waiting for the report to learn the name of this mutation. The phone call was a 3 minute affair, informing me that this mutation causes burning muscle pain, early fatigue, rhabdo and is related to how muscle cells function and that I need two copies of this mutation. Questions I sent by email after this call remained unanswered. I had just discussed with my neuromuscular specialist a few days before this call that for various reasons I feel my problem is related to how my muscles handle calcium, and here mainly in getting the muscles to relax again after doing anything, really. Based on what I find, parts of this gene seem to be responsible for pushing calcium out of cells and back into the endoplasmatic reticulum. The rest fits as well, even though I've not had rhabdo since childhood for unknown reason. Heck, my CK is always just above lower reference value in whatever situation.

Thus questions: How much is known on this gene and pathogenic mutations on it in general? Is there a possibility to be mildly symptomatic when only having a heterocygotic pathogenic mutation and especially the calcium part, should my mutation be part of that range? Is it possible that this testing was too superficial and there might be other mutations that work hand in hand with OBSCN (damn, love that abbreviation!) that require 'deeper' searching or different analysis to show up?

Way forward is now to get a muscle biopsy to extract mtDNA for further testing, but this will still take a few months to happen, and next appointment in neuromuscular department would be next year. Yeah, things are that slow. Main symptoms: cramps and stiff muscles for hours after doing anything, exercise intolerance, burning and early fatigue but normal strength and endurance building possible, distal muscles worst affected, repeated rhabdo as a child, lots of tests indicating some Mg and Ca issues and exercising on a low level possible if I supplement Mg ahead of it, exercise tests show very early switch to glucose/glycogen and no change despite years of training.

Is there any dark reality in this path? This is an international student asking. Grateful for that insight.

My partner and I are waiting to hear if we are positive for a specific gene variant that causes Noonan Syndrome. Reason for testing is our baby was found to have it through prenatal testing. We terminated the pregnancy due to the uncertainty of what her life would be like. It has been 4 weeks and the test turnaround time is 4-6 weeks. We have no telltale signs of this syndrome but I know a significant number of cases are inherited so I am worried sick about the results. I’ve heard that people with normal results get them back sooner. Is this true? TIA!

Can someone help break down cnv tags for me so I have a more clear idea of how to digest the information? Specifically the tags used in the sequencing.com CNV VCF file.

Included tags:

CN0

CN2

CN3

CN4

CN5

DUP

I presume “CN0 Copy number allele: 0 copies” means that the allele/sequence is deleted on just one chromosome strand, because there is no CN1 tag (which would just be the norm if it’s intended to represent the call on a single strand, whereas if CN0 meant homozygous double strand deletion I would expect CN1 to be a het del and CN2 to be the omitted tag).

However if CN1 is the expected call (and therefore omitted), then what is the difference between CN2 and DUP?

Can future genetic therapy remove existing melanin in the iris at large?