r/ClinicalGenetics

Hi everyone,
I'm trying to understand our next steps with our baby's long bones and if we should move forward with whole exome sequencing. 

At 20 weeks:
-BPD: 31%
-HC: 13%
AC: 37%
Femur: 4%
Humerus: 7%
-FL/AC: 19.4%
-EFW:12%

At 24 weeks:
-BPD: 34%
-HC: 17%
-AC: 60%
-Femur: <3%
-Humerus: 10%
-Radius, ulna, tibia, and fibula all ~<3%
-FL/AC: 19.2%
-EFW: 23%

normal mineralization
no fractures
no bowing
no bell-shaped thorax
no major skeletal abnormalities elsewhere

Testing so far:
-Normal NT scan at 13w
-Low risk Vistara
-Normal microarray
-Waiting for karyotype testing

I am strongly considering going forward with WES. Has anyone been in a similar situation? Did you do WES testing? What did it find, if anything?

\*\*I’m writing this post feeling completely heartbroken and desperate to find anyone who has been through something similar. 🙏\*\*

I am currently \*\*29 weeks pregnant\*\*. Following a detailed ultrasound, our baby girl was found to have \*\*short long bones measuring approximately 2 weeks behind\*\*, which led us to undergo whole exome sequencing (WES).

The WES identified a \*\*pathogenic variant in the NOTCH2 gene: c.6007C>T (p.Arg2003\*)\*\*, detected in approximately \*\*24% of sequencing reads (VAF)\*\*. We were told that this is consistent with \*\*mosaicism of approximately 50% of the cells\*\*.

We were told that the main concern is \*\*Alagille syndrome\*\*, particularly the possibility of \*\*liver and bile duct involvement and cholestasis\*\*. According to our genetic counselor, the long-bone shortening that initially led us to the exome may not necessarily be related to the NOTCH2 finding.

We had a genetic consultation with a professor who explained that \*\*NOTCH2-related Alagille syndrome is relatively rare\*\*, and that he has not personally encountered mosaicism in this gene. Because of this, it is very difficult to predict \*\*whether or how the variant will manifest in our baby, and how severe it might be\*\*.

We have been advised to have a targeted ultrasound focusing on the \*\*liver and gallbladder\*\*, but we were also told that a normal prenatal ultrasound \*\*cannot rule out liver disease or cholestasis developing after birth\*\*.

This has put us in an incredibly difficult position. We are trying to make decisions about the pregnancy while having so much uncertainty about the potential severity of the condition.

\*\*I would be incredibly grateful for any information, personal experience, medical experience, or research that anyone may have regarding:\*\*

\* \*\*NOTCH2-related Alagille syndrome\*\*
\* \*\*NOTCH2 mosaicism\*\*
\* The specific variant \*\*NOTCH2 c.6007C>T (p.Arg2003\*)\*\*
\* Prenatal diagnosis of NOTCH2/Alagille
\* Anyone who had a similar mosaic result and can share what happened after birth

\*\*We are truly looking for any information that could help us understand what this finding might mean for our baby.\*\* 🙏

I’m looking for anyone who has had a similar experience with isochromosome 21 / mosaic trisomy 21 on CVS followed by mostly normal amniocentesis results, particularly anyone who was ultimately diagnosed with confined placental mosaicism (CPM).

This has been an incredibly stressful and confusing pregnancy, and we’re currently waiting on the final microarray while trying to understand what the results so far actually mean.

Here is our timeline:

12w5d ultrasound
NT was 3.56 mm
Nasal bone present
No other abnormalities noted

NIPT
Low risk for trisomy 21
Because of the slightly increased NT, we proceeded with CVS.

CVS FISH
Normal female result
Normal copy number for chromosomes X, 13, 18 and 21
Initially tested 100 nuclei, and I was later told the CVS FISH was re run on approximately 500 cells
No trisomy 21 detected

Then came the unexpected result:
CVS karyotype
46,XX,i(21)(q10)[15]/46,XX[5]
So 15/20 cells showed an isochromosome 21 and 5/20 were normal.
The report interpreted this as mosaicism for an isochromosome 21, resulting in trisomy of the long arm of chromosome 21.

We subsequently had CVS genome sequencing, which also detected i(21) mosaicism at approximately 20–21%.

At that point we were obviously very concerned about mosaic Down syndrome, but we were told that because CVS samples the placenta, this could potentially represent confined placental mosaicism (CPM) and that amniocentesis would be needed to better assess the fetus.

Amniocentesis
The amnio FISH came back NORMAL.
The report showed a normal female result with normal copy numbers for X, 13, 18 and 21 in all tested nuclei.

We were hopeful, but then the full karyotype came back:
46,XX,i(21)(q10)[1]/46,XX[104]
So:
104/105 metaphases were normal female cells
1/105 metaphases contained i(21)
The lab notes that two trisomy-21 cells were actually identified within the same colony from one culture
The other cultures/colonies were normal
No other consistent chromosome abnormalities were found
The lab specifically commented that because i(21) had previously been identified on the CVS, the amniotic-fluid finding should be carefully correlated with the CVS.

So this is where we are now.
The discrepancy is huge:
CVS:
15/20 abnormal by karyotype
~20–21% mosaicism by genome sequencing
Amnio:
Normal FISH
104/105 normal metaphases
Only one abnormal metaphase, with the two abnormal cells confined to one colony from one culture
Our fetal imaging has also been reassuring:
Nuchal fold at ~16 weeks: 3 mm
No other soft markers on the anatomy scan
Growth measurements have been generally appropriate
Fetal echocardiogram was normal
We are currently waiting for the GeneDx microarray on the amniotic-fluid specimen.

What I’m trying to understand
Has anyone experienced something similar where:
CVS showed significant mosaic i(21)/T21 → amnio FISH was normal → amnio karyotype found only one/few abnormal cells, particularly confined to one colony → ultimately diagnosed with CPM or had a healthy baby.

My MFM and genetic counselors have been great, but have limited experience in this situation. I’m pursuing a second opinion at Columbia at the moment. Mo

Hi everyone. I’m a pediatric genetic counselor and have been in the field for over 5 years now, but I seem to have hit the point where I don’t know what comes next for my career.

I’ve had my share of woes with the genetic counseling field, both personal experiences and the evolution of the career as a whole. I’ve realized that I’ve outgrown my current position at this point (a senior GC job, but not much more room for growth beyond that) so I’m looking for something else, but not sure what that actually looks like.

The GC field is growing exponentially, both students and the job market- this may not be evident right now, but I predict in the next year we will see an explosion of lab GC positions (for example, GeneDx will need more GCs for virtual counseling now that they’ve basically started doing direct to consumer testing (sigh)). In an age where technology continues to evolve, we’ll move towards never seeing patients face to face and, eventually, maybe AI will just replace us entirely, who knows. There’s also the fact that non-genetics providers now order their own testing and can basically just hire a GC to explain whatever they order and not have to worry about it themselves (worried about this evolution too, see next paragraph). Personally, I don’t find myself fitting into either type of role.

I’ve been told by numerous people, including doctors, that I should consider going to medical school to become a geneticist. I thought about it and even bought the MCAT books to get started, but I forgot there are other science topics besides genetics (what is physics) and quickly lost interest. There’s several unappealing things about being a doctor, both the education I’d need to go through and the job itself. I also genuinely think the field is shrinking and will eventually collapse, especially now that non-geneticist MDs are ordering their own testing and hiring GCs to advise on the results. There was a time when no one ordered genetic testing besides genetics clinics, and now look how the tables have turned. Soon, they’ll just learn how to refer out and not even need geneticists for the syndromic stuff, eradicating the field entirely (perhaps dramatic, but that’s my prediction). All things considered, I don’t think this avenue is a good idea.

I briefly contemplated NP or PA school, but I don’t feel motivated for either of those paths, especially not ones with “assistant” in the name in a field as cutthroat as medicine (no offense to PAs).

Anyway, I’m not sure what I’m trying to get at here, but my partner recommended finding a mentor to go through all of this. But Reddit is faster and easier! Open to thoughts and recommendations, if any. TIA!

Posting because I searched this exact combination at 2am for weeks and only found panic. Here's our story, short version.

Wife is 30, third pregnancy, two prior losses at ~8 weeks. Full workup before trying again — both karyotypes normal, APLA negative.

12wk NT scan: Growth and heartbeat perfect, but NT 2.9mm (95th centile) + bilateral distended jugular sacs, plus a positive pre-eclampsia (PIH) screen. The words "screen positive" wrecked us.

Second opinion, fetal medicine specialist (14wk): Better machine — NT re-measured at 3.0mm (98th centile), sacs confirmed, Down risk 1 in 116. He named the real concern: markers of aneuploidy AND RASopathy (Noonan). Recommended CVS with microarray + whole exome — not NIPT, because NIPT can't detect Noonan. Silver lining: the PIH screen was now negative.

What actually helped me:

- NT itself doesn't harm the baby — it's just a statistical marker.

- Risk scales steeply with thickness. At 3.0mm you're at the BOTTOM of the "raised" range. Scary online stats are mostly NT ≥3.5mm.

- Severe cases usually come with cystic hygroma/hydrops/heart defect. We had none — normal heart, normal nasal bone, normal ductus venosus, normal growth.

- The jugular sacs are the same lymphatic finding as the NT — expected at 3mm, not a separate disaster.

CVS results, as they came:

- QF-PCR: no aneuploidy (Down/Edwards/Patau/Turner all clear).

- Microarray: normal, no microdeletions.

- Whole Exome Sequencing: no pathogenic variants, no Noonan/RASopathy, no VUS. Clean.

Every concern got asked directly — every answer came back normal. Our OB confirmed everything is normal.

If you're terrified right now:

1. NT 3mm with normal anatomy is the FAVOURABLE end. Don't anchor to ≥3.5mm stats.

2. Get a second opinion at a real fetal-medicine centre — NT is operator-dependent.

3. Know what each test detects. NIPT ≠ CVS + exome.

4. A screening flag is a reason to test, not a verdict.

To my wife, who carried the pregnancy and the fear at once after everything we'd lost — you're braver than I can say. Ask us anything.

Does anyone know much about the full panel (single-gene disorders and micro deletions)? A genetic counsellor I spoke with said this is a fairly new offering, and didn’t have any information other than a single basic printout about the test, so I’d love to hear anyone’s experience with it. In particular, if you know of any true (or false) positive results, and what sort of technology it uses and how that differs from other tests (is it potentially better and more accurate?).

Also, I’m wondering if it’s slang when talking to patients to call Mb ‘megabytes’, or if she is mistaken? Because it really put me off and I couldn’t concentrate on the conversation afterwards, thinking surely she must know it’s mega bases? I’ve had a previous appointment where the same thing happened (same counsellor) so it wasn’t a once off.

After several losses, my doctor wanted me to go to the hematologist just to make sure we weren’t missing any bleeding or clotting disorders. Of course I ended up getting pregnant before that and ended up going to the hematologist around nine weeks pregnant. All of that has just resulted now, and one of the things that she tested me for genetic cancer risk screening through natera. I have a heterozygous likely pathogenic variant on the LZTR1 gene I know now that this gene is directly correlated with noonan syndrome in some cases. I’m a nurse so I have a pretty basic understanding and for my knowledge my husband would also have to be a carrier if it was an autosomal recessive however, I know sometimes it can be autosomal dominant. & that this is a very understudied gene variant. I have my nuchal translucency test on Monday as I’m 12 weeks today. I’m just so stressed after all these losses that I could be passing down noonan syndrome. I have called the genetic counselor at my doctors, but would love to hear if anyone else has also tested positive for this variant in their experience.

Can anyone provide some enlightenment on this? We are to have very important genetic testing coming up and we were told we could order from either one but from what I understand LabCorp owns a part of Invitae now? Yet they still lists all their tests as separate entities. So its still a labcorp panel does x, y, z and then Invitae does a, b, c.

Who has a better track record of reporting?

Is there a distinctive difference in testing accuracy and reliability?

embryo is a **boy (XY)** with:
**Low mosaic trisomy 14**
**High mosaic partial monosomy 9p24.3–p23 (11 Mb)**
Has anyone transferred an embryo with a similar **+14 / -9p complex mosaic** result?
If so, how did it turn out—implantation, pregnancy, amnio/NIPT, and ultimately baby?
I’d really appreciate hearing any experiences, good or bad. ❤️

Hi all,

I’m interested in learning more about this balanced translocation:

46, XY, t (11; 18) (p15. 3;p11. 2)

My husband and I have two healthy children. Third pregnancy genetic testing prompted parental genetic testing which revealed BT in my husband.

Curious for more information.

Looking for anyone who has been through something similar. I’m 24 weeks pregnant and trying not to Google myself into oblivion.

At our 20-week anatomy scan, baby was growing overall normally (EFW 12th percentile), but the femurs and humeri were short:

• Femur: 28.1 mm, 4th percentile (~18w4d)
• Humerus: 28.1 mm, 7th percentile (~19w)
• FL/AC: 19.4%
• Bilateral pyelectasis (7.1 mm left, 5.7 mm right)
• Otherwise anatomy was normal.

We repeated the scan at 24 weeks, and the long bones are still short, but they did grow appropriately over the 4 weeks and are following their own curve:

• EFW: 23rd percentile
• AC: 60th percentile
• Femurs: <3rd percentile, measuring ~22w2–22w3d
• Humeri: ~9–10th percentile, measuring ~23w3d
• Ulnae/radii also <3rd percentile
• Tibiae ~4th percentile, fibulae ~9th
• Feet are normal size (~36–47th percentile)
• FL/AC: 19.2%
• Pyelectasis is stable at ~7 mm

The reassuring part is that everything else looks good: normal bone mineralization, no bowing or fractures, normal skull/profile, normal hands/feet, no bell-shaped thorax, no hydrops, normal fluid, and appropriate overall growth.

MFM specifically said they have low suspicion for a lethal skeletal dysplasia, but skeletal dysplasia is still on the differential because the long bones remain so short.

Our testing so far:

• Low-risk QNatal NIPT (T21/18/13, sex chromosomes, microdeletions)
• Normal NT
• Normal AFP
• Negative Vistara, including achondroplasia, hypochondroplasia, and thanatophoric dysplasia
• We are now considering amniocentesis with CMA + exome sequencing

Our OB/genetic counselor seem to think the two biggest possibilities are constitutional short long bones vs. a mild skeletal dysplasia.

My husband and I are both 5'8".

Has anyone had persistent femurs/long bones <3rd percentile that continued to grow along their own curve, with otherwise reassuring anatomy?

Did your baby eventually catch up? Was it constitutional? Did you have amnio and did it find anything?

I ask because I came across anecdotal evidence of an autosomal recessive condition exhibiting symptoms despite 1 allele. It was eds. Now could something more serious like a POLG variant do the same?

I hope this is the right place to post this.

We have been on a journey for what started as seeking a diagnosis for my daughter. It slowly turned to realizing it spans across multiple maternal generations.

High on our list was a mitochondrial disease type of issue. I have a maternal nephew that passed from Leigh’s Syndrome so their focus has been there for the last few months.

My WES and WGS both show that I am a carrier for chr14:32319298 T>C. The issue is, my daughter is not and we share a very similar phenotype.

With that being said, it’s still something I’d like to explore since my sister, mother and I all have adult onset decline. I’m reading that it’s possible to have adult onset symptoms with certain mutations.

Has anyone been diagnosed after only being a carrier and not fully homozygous for something considered an autosomal recessive disease?

Hello! Does anyone have experience with Variantyx and the quality of their reports? Any comments would be helpful especially for whole genome sequencing in a prenatal context. Thank you!

my 1 month old daughter was just diagnosed with this deletion. they don’t know the exact genomes until the final report comes back. she was in the nicu up until today with breathing issues which turned into issues eating but she’s off oxygen and taking bottle like a champ. can anyone tell me what this diagnosis might mean for her?

she has some heart issues, a rotated kidney which is fully functioning and a slight head lag that has already gotten better. just look for any sort of information.