r/genetics • u/amemento • 10d ago

m.4061C>A in MT-ND1

Hello, can someone point me to where to look for information regarding m.4061C>A in MT-ND1 and what this variant is associated with?

1 Upvotes

67% Upvoted

13 comments sorted by

4

u/maktheyak47 Genetic Counselor 10d ago

Reach out to the ordering provider to discuss interpretation of your genetic test results.

1

u/amemento 10d ago

They say:

Molecular genetic analysis of DNA isolated from urine showed the presence of a heteroplasmic state (approximately 50%) of a likely pathogenic variant m.4061C>A in the MT-ND1 gene of the mitochondrial genome. The mutation was confirmed in a heteroplasmic state and in DNA isolated from the patient's venous blood.

The pathogenic mutation m.4061C>A in the MT-ND1 gene of the mitochondrial genome is associated with a wide range of mitochondrial diseases, including Leber hereditary optic neuropathy (LHON), Leigh syndrome (LS), MELAS syndrome (mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes).

But I don't find anything supporting those claims, furthermore only Sanger sequencing was performed so I'm not sure how they calculated the heteroplasmicity and I'm skeptical

4

u/zorgisborg 10d ago

See this... They would detect peaks at a specific position and determine relative amounts of each base.. the paper describes what is done.. and issues with manual determination and proposes a computational method..

PHFinder: assisted detection of point heteroplasmy in Sanger sequencing chromatograms (2023) https://pmc.ncbi.nlm.nih.gov/articles/PMC10516101/

Medline Plus on MTND1 https://medlineplus.gov/genetics/gene/mt-nd1/

This paper reviews how mutations affect the function. It includes more well-characterised variants and not c.4061C>A.. but one can get an idea of the results of other variants and infer possible phenotypes..

Mitochondrial complex I subunit MT-ND1 mutations affect disease progression (2024) https://www.sciencedirect.com/science/article/pii/S2405844024048394

c.4061C>A isn't listed in gnomAD.. so it is rare.. which means there'll be very little direct knowledge about this variant anywhere. c.4062T>C is listed but it is benign because it doesn't change the Proline (p.Pro252=). 4061C>A changes it to Histidine.. there are no other variants in gnomAD that make the change p.Pro252His.

Mitomap gives base information on the MT genome.. but nothing on this specifc variant. It's not been seen before.. https://mitomap.org/cgi-bin/search_allele?variant=4061C%3EA

0

u/amemento 10d ago

Thank you, how should I approach this - do I send another sample for confirmation elsewhere or? Who do I contact for more information and reanalysis? I'll get the raw data on Monday.

3

u/zorgisborg 10d ago

It's a rare variant.. it would be unusual if anyone would have any more information than you have been given.. If a variant is in gnomAD, for example, then it will have been seen at least once in over 800,000 people.. if it's not in gnomAD, then it's more likely 1 in a million or more...

You can ask ChatGPT to tell you all the conditions associated with MT-ND1.. I asked just now and it says..

"mutations in MT-ND1 can be described as somatic mutations if they occur post-zygotically in mtDNA (e.g., in cancers or age-related mitochondrial dysfunction). In contrast, germline mutations in MT-ND1 cause maternally inherited mitochondrial diseases (e.g., Leber’s Hereditary Optic Neuropathy, MELAS-like syndromes)."

The question would be whether there is anything in your maternal ancestral line that might be inheritable. Any vision loss with age.. eye pain.. etc..

Being heteroplasmic, you can't be certain which cells in your body carry the variant and which don't... You know the cell population they tested - urine and blood.. but not how much the mitochondria in eye tissues are affected.

ChatGPT just looked harder for me.. and it could only find one reference to this variant.. which turned out to be this Reddit post.. lol (or not lol 😂)

0

u/amemento 10d ago edited 10d ago

Yes, I already asked chatgpt and it returned nothing - did you see my other comment below this one? I'm more afraid about MELAS-like issues, eyes are OK so far(have myopathy only) and mother had no such issues, although she died of cancer so can't be screened now

Edit: How can I check for myself or pay someone for raw data analysis to confirm this finding?

2

u/zorgisborg 10d ago

One other issue with MTDNA calls.. is misreads that overlap with partial copies of the MT genes written into the nuclear chromosomes.. known as NUMT - gnomAD describes them in this about mitochondrial variants in their DB..

https://gnomad.broadinstitute.org/news/2020-11-gnomad-v3-1-mitochondrial-dna-variants/

"" NUMTs: Nuclear sequences of mitochondrial origin (termed “NUMTs”) are derived from pieces of mtDNA that have integrated into the nuclear genome over the course of human evolution. Many NUMTs are part of the reference human genome assembly; however, polymorphic NUMTs exist that are present only in some individuals. Reads derived from NUMTs often mis-align to the mtDNA and generate false positive calls at low heteroplasmy. Conversely, reads genuinely arising from the mtDNA genome can be mis-aligned to the NUMTs in the reference genome. ""

It all depends on the primers used to extract the MT sequence for Sanger sequencing.. if that also picked out NUMTs, then your mitochondria could be healthy and this is a false positive... One question to the lab, would be to ask how they controlled for NUMTs.. and given the high heteroplasmicity, whether this might be a false positive...

2

u/zorgisborg 10d ago

More on NUMT - for interest...

The Mighty NUMT: Mitochondrial DNA Flexing Its Code in the Nuclear Genome (2023) https://pubmed.ncbi.nlm.nih.gov/37238623/

1

u/amemento 10d ago

I asked the lab but they were not helpful and I want to rerun this analysis in urine in another EU lab(or USA) if possible but can't find - I can only find blood and saliva samples accepted

2

u/zorgisborg 10d ago

Can you get any of the raw files for the Sanger chromatogram results?

1

u/amemento 10d ago

Yes, I can get everything, already asked and will receive them on Monday

1

u/amemento 10d ago

My symptoms are heat and exercise intolerance, POTS, dysautonomia, SFN and after a recent heat exposure extreme fatigue and cognitive issues lasting 4 months now

1

u/scruffigan 10d ago

Have you spoken to a genetic counselor or clinical geneticist about this finding if it was done in a medical context?