u/AdventurousTravel882

I'm trying to understand something about how genetic variant interpretation works and would love input from people who understand this better than I do.

A proband had whole exome sequencing.
Two heterozygous variants of uncertain significance were found in the same gene. The proband's clinical features somewhat overlap with the published phenotype for that syndrome. Parental testing has not been done yet.

I have a few questions about the genetics reasoning here, not asking anyone to interpret specific results:

Question 1:

What are the odds that two VUS variants land in the same gene purely by coincidence during exome sequencing? Is finding two variants in the same gene more meaningful than finding one, statistically speaking?

Question 2:
Before parental testing is done, what is the starting probability that two VUS in that gene actually represent a true genetic finding, versus just being noise? Do geneticists have a way of thinking through this?

Question 3:
How much weight do clinical geneticists give to the fact that the person's clinical features overlap with the published phenotype for that gene? Does a strong phenotype match move the needle on how seriously to take a VUS in that gene?

Thanks in advance.

It’s been a fucking nightmare. I always wanted kids but was always hesitant about having them because my mind immediately went to what if something goes wrong. And I firmly believed that I’m becoming parents you have to be willing to accept the possibility of having a child with a disability. Deep down I would tell myself that it would never happen to me.

Well whootidoo. I had an unplanned pregnancy, and I felt like I could prepare myself to be a mom.

Well none of my prenatal visits showed that anything was wrong other than the fact I had extra fluid towards the end. I had my baby 6 months ago, and I have had only one worry free day with her. It’s been constant hospital admissions since then. Three months, 5 days, 2 weeks and now admitted again. The Drs here can’t tell me what the overall diagnosis is other than the current illnesses she has. Two genetic tests later and still no answers. I’ve been pushing for further genetic testing but it’s not available in this hellhole of a country and I need a Dr to order the kit from the company who offers it overseas but it seems no one wants to do it.

I am unhappy and exhausted. I feel like I’ve already gone through so much. I was so hoping to improve my life after so much loss. Don’t get me wrong I love my baby, but I feel like I’m living my worst nightmare everyday. Everyday feels like walking on egg shells because I’m waiting for the worst. I hate people with their perfect healthy children. I’m trying my best and it hurts my best is just not enough. I resent my husband for getting me pregnant and I hate myself for not being more careful.

My baby girl has a complex, undiagnosed condition that has left her doctors searching for answers. She has already had mitochondrial testing and testing for inborn errors of metabolism, and both came back negative.
Please note I don’t live in the US but in a small developing island nation. Back in May, I asked her doctors to proceed with whole exome sequencing, but things are moving very slowly, and I’m worried it could take months before the test is actually ordered.
The company that performed her previous genetic testing is based in the United States. The testing kit was sent to my daughter’s physician, and I collected and shipped the samples back to the lab myself.

I tried checking online to see if the company would allow me to order whole exome sequencing directly, but it appears they only accept orders from a medical professional.

I’m the type of person who likes to move things forward rather than wait months, especially when we’re trying to find answers for our daughter. I’m not looking for medical advice or opinions on my daughter’s condition. I’m simply trying to understand the logistics of obtaining clinical whole exome sequencing?
Is there a reputable company that allows parents to arrange whole exome sequencing directly?

I (29F) have been married to my husband for two years, and we’ve been together for five in total. He moved in with me and my mom.

Now to the issue at hand. I’m not the neatest person on earth, in fact I’m most to in my own way but I absolutely cannot stand other people’s mess. My husband is annoyingly messy. Think clothes on the floor, receipts and bills scattered everywhere, dishes left where he ate, and a car full of trash (which especially irritates me because he’s driving my car). I handle the majority of the household responsibilities, though I would usually hire someone to deep clean once a month.

We recently had a baby who had a very rough start to life. She spent three months in the hospital before we were finally able to bring her home. The adjustment has been overwhelming, to say the least. Our baby requires more care than the average infant, and I currently handle about 80% of that care because my husband’s business keeps him away from home most of the day. Since our baby is home, he went back to well. He’s usually gone from around 9 a.m. to 10 p.m. I’m still on maternity leave (even though I still work on my side gigs) so I try to cut him some slack. He does usually give me a break between 3- 7 a.m., so we are both exhausted.

Now to the current issue. We’ve been dealing with a roach problem. The house is by no means filthy or cluttered, but we have small roaches in the kitchen and it genuinely stresses me out. We already had the house fumigated, but it didn’t completely solve the problem.

Today, I spent over three hours deep cleaning the kitchen. I scrubbed and wiped down everything from top to bottom while also taking care of the baby. When my husband came home tonight at around 9, he made himself something to eat. He has a habit of leaving dishes in the sink overnight because he usually falls asleep after eating. I was raised to always keep the kitchen clean especially at nights and never to leave dishes in the sink overnight.

I repeatedly asked him to please wash up after himself. I told him how hard I worked at cleaning the kitchen today. We were laughing and joking, as we usually do. I reminded him several times over the course of more than an hour to please wash up. I said it lightheartedly , I said it sternly. I could see his eyelids drooping and I reminded him again. He then got a call that requires him to go back out again ( work related stuff) and he still left the dishes in the sink anyway. I texted him expressing how upset I am and asked him to sleep at his parents house tonight.

At this point, I genuinely don’t know if I’m overreacting or if I’m justified in being upset.