FMRP translational regulator 1

For example, if we have a phenotype of, let's say, Beckwith-Wiedemann syndrome, right, we order a specific test, which would be methylation-sensitive MLPA.

If we have a Fragile X phenotype, we would order FMR1 repeat expansion analysis.

But when the phenotype becomes more broader, does not point us towards any specific diagnosis, then our testing becomes broader.

We move towards array exome sequencing, genome sequencing, so to say.

Okay.

So just because it's not the full expression, having a fragile X condition still puts the patient at risk for for fragile X-associated tremor and ataxia, and if they are a woman, for FMR1-related premature ovarian failure.

Okay, so even though they don't have the full fragile X expression as a syndrome, those pre-mutations have issues.

Guys, we're dropping clinical pearls in the intro.

It was very important to study a very large cohort, and you can see here 375 cohort patients with POI.

No cause was identified, normal karyotype, normal FMR1 gene, so we performed next-generation sequencing.

And what we observed with this next-generation sequencing panel, as you can see, a very high genetic diagnosis, almost 30% of unexplained POI that had a diagnosis with Spanner.

And the proportion was even higher in familial or consanguineous POI, or in syndromic form, it means with another organ defect.

So what three genes specifically are we talking about?

The three genes are CFTR, FMR1, and SMN1, and the conditions are cystic fibrosis, fragile X syndrome, and spinal muscular atrophy.

Okay.

And kind of obvious question from the microbiologist, why have we chosen those three?

Um, but then they also create other problems, like the repetitive sequence, like GC-rich and, and GA-rich just wreak havoc on polymerases.

So anything that requires the polymerase, you might find a polymerase that's okay for fragile X, that FMR1 repeat, but struggles with the RFC repeat.

Um, and so it's really difficult to, to manage that.

There's, um, you know, there's mosaicism in the read length that's difficult to interpret and understand.

Um, but you, you know, w- you are already, 'cause fragile X is a very common test, you are already applying using this in the clinic, right? So, so talk to us about, uh, your, your overall thoughts on this, what, what you're bringing to this challenge, Simon.

Simon.Um, well, I think, yeah, Alex's point was really, really important before around the single gene nature of the testing that's been done.

So, you know, previously, um, VCGS has a, um, a long history of testing for, um, FMR1 expansions and other expansions, but the critical piece-

Yeah, th-this is, um, this is where you work, VCGS, Victorian-

Yeah, okay.

So to go into a genetic sort of, um, background, it's carried on the FMR1 gene on the X chromosome.

Okay.

So that's been passed down, um, obviously through the genes.

Yeah

...

FMR1 gene is if you think of your makeup has got all your genes, right? So then if you think of 100 fluoro lights, so your fluorescent tubes, some will stay on permanently, some are just switched off, they'll be black, and then when they need to change, you know, they flicker.

Yep, yep.

So Fragile X syndrome is a disorder, a genetic disorder.

It's caused by a FMR1 gene mutation in the chromosome X.

So it's linked to chromosome X.

So it affects both genders, males and females, but more severely in males.

There is others in the same clinical stage, but different in mechanification.

Is it easy to diagnose?

The diagnosis is quite direct in the sense that there is a genetic test showing this FMR1 gene unusual repeat of some bases.

So there is quite a straightforward genetic component.