CHERUBS Medical Expert Series: CDH & Genetics (Nov 4-11, 2013)

Julia Wynn, MS of DHREAMS Research Study (Congenital Diaphragmatic Hernia) will guest speak and answer your questions about genetics on CHERUBS CDH Family Forums during November 4th through the 11th.

DHREAMS (Diaphragmatic Hernia Research & Exploration; Advancing Molecular Science) study was created to improve the understanding of the molecular genetic basis of CDH. This National Institute of Health (NIH)-funded research team is composed of health care providers and researchers across the country, coordinated at Columbia University Medical Center. Multiple medical centers are enrolling individuals and families with CDH. The knowledge gained through this research will lead to improved diagnosis, treatment, and quality of life for individuals and families with CDH.

The DHREAMS study is an NIH funded multicenter national research study of congenital diaphragmatic hernia (CDH). The goal of our study is to improve the understanding of the causes of CDH. http://www.cdhgenetics.com/

All forum rules of courteous behavior apply and will be enforced if necessary.

I am here in the UK and have met and also spoken to Julia , no research takes place here in the UK specifically into CDH so it is wonderful to be able to participate in Dreams .

Hi Julia,

I have always been interested in genetics even prior to my being diagnosed with cdh. I was diagnosed when I was an adult. How close are geneticists at finding the genes responsibe to cdh. Do you think that there are more than one gene responsible. Why do you think that some cdh babies only have cdh and others have multiple congenital abnormalities?

Why are geneticists or other cdh physicians not producing studies of long term issues with cdh. Perhaps there is information to be learned from adult cdh patients that could lead to insight that could unravel the cdh mystery genes.

Thank you for participating in the cdh expert series.

Sandi

Sandi,

You pose some very interesting questions and I will do my best to answer them in text form
1) Genes associated with CDH - We and other studies have identified over 20 genes that are important for the development of the diaphragm and when there is a genetic mutation or a deletion of that gene a CDH can occur. We think though that it is just the tip of the ice berg and other studies into the development of the diaphragm suggest that there are at least 100 genes that play a role in the diaphragm
2) Babies with CDH and other birth defects? We know that 50-60% of babies with a CDH have a second birth defect. This can be for several reasons. Sometimes it is because the baby had a deletion of a portion of a chromosome and therefore is missing multiple genes that are important for many different aspects of development (for example heart, diaphragm, brain). Other children have a mutation in only one gene but that gene is important for the development of multiple organs. For example, we know that a gene called GATA4 is important in the development of the heart and the diaphragm so some babies with mutations in this gene have just a heart defect, some have just a diaphragm defect and some have both a heart and a diaphragm defect.
3) Research studies? DHREAMS is currently conduction long term follow up studies of children with a CDH. We are preparing a newsletter that discusses our finding of following over 40 children with a CDH until 2 years of age and we are now following these children and more to 5 years of age. Unfortunately research is expensive and not everyone has the funding to do the important studies that they want to do. We are always very grateful when organizations like Cherubs helps us to raise important research funds!

Thank you for your very insightful questions!

Julia will be joining us today. Please feel free to start posting your questions.

Please also remember that Julia cannot diagnose your cherub or give you medical advise. She can only share the work of DHREAMS and answer general genetic questions.

Hello Jullia,
does the 17th chromosomes having and extra piece show up a lot on CDH babies?

My question is the genes that you are finding through research that may be a cause of CDH, are they genes that are hereditary? Will my son who was born with CDH, have a higher probability of having CDH children (is the CDH gene going to be passed on)? As far as we know, my son's CDH was an isolated case, not linked to a genetic abnormality.

In the DREAMS research, if CDH has a genetic component, are you finding their may possibly be an environmental factor triggering the CDH in these genes?

Hi Julia,
My question would be since there are some families where more than one of their children have CDH is it likely that the parents genes are mutated. For instance ny husband had a minor heart attack at age 30 . Would it most likely be his genetic coding?

Hi , Julia!
I am a survivor & my grandfather was diagnosed at age 90 with CDH. Is it possible that it can skip a generation? So, my grandchildren may be at risk?
Also, I have observed that many of those affected are, for lack of a better term, wall-eyed (eyes turn outward). This is a trait found in my family as well (my grandfather included). Could there be a link or is it just another mid-line defect?

Hi Julia, after reading everyone's questions over mine have been covered. Just wanted to say thanks for all the great work you do and helping Cherubs and their families!

I'm going to go out on a limb here, but here goes...

Do we know if there could be 1 or more defective gene sub-component like a particular protein or RNA that could be present in most, if not all, of the chromosomes that be responsible for CDH showing up in so many different chromosomal locations?

Is it possible that CDH could wind up being another connective tissue disorder? After all defects in connective tissues can do some strange things... Maybe it could account for some the variations like eventrations & Late Presentation CDH (LP-CDH)???

*** Full Disclosure: Our CDH family is one of a 1/2 dozen families with Marfan syndrome, and there are several on the list with Ehlers–Danlos & Beals. ***

Shelly Moore

There are several different regions on chromosome 17 where we have seen extra or missing pieces in children with CDH. We are not yet sure what specific genes on chromosome 17 are the critical regions for CDH.

Our study is open to those who have a known chromosome deletion or duplication as well as those who have an unknown cause. Both types of cases are very informative to our study and will ultimately help us to better understand all of the different genetic causes of CDH.

Shelly,

You are not going out on a limb you are thinking like a scientist! We do think that while there are a lot of genes that are involved in the development of the CDH many of these genes are related - they interact with each other in development. For example there are two gene in the GATA family that have been identified to cause CDH. While they are two different genes, the proteins they make interact with each other and are both important in the development of the diaphragm.

With regards to your question about a connective tissue disorder. Yes I do think that a small proportion of individuals with a CDH have one because of a connective tissue disorder (your family and the others you listed might be examples). This is just one example of how diverse the genetic causes of CDH are.

All the best to your family!

Tracy,

Congratulations on your little boy.

You have a very thoughtful question about CDH and genetic causes.

There are several different ways that we think a genetic mutation occurs or is inherited to cause a CDH

1) A genetic mutation is not inherited from the mother or the father but rather happens new in the child at the time of conception when the egg and sperm come together. We know the new genetic changes occur in every pregnancy and we think that in children who are born with birth defects these new genetic changes disrupt important genes. These genetic changes happen by chance and there is nothing a parent does or doesn't do to cause them.

2) A child inherits a genetic change from the mother OR the father and this causes the child to have a CDH. The parent with the genetic change may have a very mild CDH and never know that they have it or they may have other protective genes that cause them not to have a CDH even though they have a genetic risk. We think this type of inheritance is much less common than the first type. We think of this type of inheritance when a family has a child affected with a CDH and a parent is affected or a more distant relative like a aunt, uncle or cousin is affected.

3) A child inherits a genetic change from the mother AND the father. This genetic change alone in the mother or the father does not cause a CDH but when the child has BOTH genetic changes this causes a CDH. We think this type of inheritance is most likely when a family has more than one child affected.


You asked about your child's risk to have a child with CDH. My hope is that we will have a much better understanding of the genetic causes of CDH by the time your child is having children because of families like yours that participate in genetic studies. The risk of an individual with a CDH having a child with a CDH (recurrence risk) is dependent on the specific genetic cause of their CDH. This risk can range from <1% to as great as 50%. I encourage everyone to see a geneticist or a genetic counselor prior to starting a family so that they can help to determine the recurrence risk based on that individuals family and medical history and possibly help them to pursue reproductive options to prevent their children from having a CDH if they wish to do this.

Casey,

Thank you for your question. I'm sorry to hear about your husband and hope he is well now.

For the most part we think that genetic risk for conditions is independent. We don't think having a child with CDH does not increase your risk for other genetic conditions that are not related to the CDH.

Best

Casey,


I'm sorry to hear about your husband I hope he is doing well. We think that genetic risk is independent. We do not think that having a child with a CDH increases a person risk for other genetic conditions that are NOT related to the CDH.

SORRY. I thought my previous reply didn't show up.

Julia,

We never really talked to our doctors that much about the reason why this happened. We met the genetesist and 2 hrs later had an amnio because she said there is sometimes CDH'ers who are stillborn or live only a month because of trisomy --. I can't remember the number but I'm wondering do you know how often that occurs? Also would the amnio have told them if there was a reason for her CDH? We always just assumed there was no chromosomal issues with our daughter because of the amnio.

Lizz,

Thank you for your interesting question. Typically the things that cause a CDH in a neonate are different than the things that cause a CDH in an adult. Sometimes adults can have a CDH if they had an accident or a surgery where their diaphragm was damaged. There is also a condition called a hiatal hernia where the stomach herniates through the hole in the diaphragm where the esophagus passes through. If neither of these situations describes your grandfather it is possible that his CDH is related to your CDH.

If all of your daughters are doing well, there is likely little screening that can be done at this time. You should always be careful to inform their doctors of the family history of the CDH.

Best

Hi Julia, my daughter is a rCDHer that is now 6 weeks old. I'm wondering if you have discovered any information regarding why right-sided cdh's happens instead of left and why its more rare. Also, it seems there's a much higher rate of unpredictability regarding right-siders and how they will react after being born and to surgery. Has there been any information discovered regarding why that happens? Basically I'd love to know anything being discovered about rcdh because I know there is currently very little information available. Thank you for all you do! We just recently began participating in the study and I hope it helps!

Julia,

I was born eighteen years ago with CDH on my left side. I am curious on whether or not it is hereditary. No one else in my family has CDH, but I am still curious on whether I could pass it on to my future children. Also, because of my birth genetics is my passion. Is there any advice on college majors/masters that will help me become a genetic counselor? I plan on finding out why CDH happens and how it can be prevented. Thank you.

Julia,

I am wondering if there are any new findings on the increased chances of having another CDH child. I know that the generally accepted probability goes up to 2% after your first child with CDH. But what about after you have 2 children with CDH. Does the probability increase even further with your 3rd child.

Thank you very much

Neil

Dear Julia,
Thank you for answer these questions! How does an older survivor get involved in these studies? I'm 23 and want to help learn more. The genetic aspect fascinates me because I'm still debating on having a child of my own. I've been told that my amniocentesis was "spot on" for no abnormalities. Has amniocentesis changed in anyway in the past 23 years? Are there more genes that get look at? (Ex: 23 years ago they looked at 300 gens but now they look at 500.)

Do you know any new information about the link to diaphragm and lung development (other than organs being in the way)? About ten years ago I was in Pittsburgh for consultation about a potential back surgery and while we were there we had the opportunity to talk to a surgeon with CDH experience. He talked about experiments they were doing with cats by inducing controlled CDH to see if its the diaphragm that stops forming first which causes the lung to stop, or vise versa. I haven't heard anything else since - I was turned down for the surgery and never visited that doctors again. I doubt my parents would remember his name.

Thank you again!
- Courtney

Neil,
I am pregnant with my third child, my other two children have CDH (one right, one left). We met with a genetic counselor at Minneapolis Children's Hospital, and were told we have between a 10-25% chance of having another baby born with CDH. If our children underwent genetic testing, depending on the results, the chance could increase our decrease.

I know you posted this to Julia, but I thought I'd add my info. Hope that's ok.

Also, I've been following Brody's journey on Facebook, I'm so glad he's doing well! What a fighter, and what a handsome little man!

Amanda

Thanks, Amanda. Interesting information....curious what Julia's response will be. And thanks regarding Brody...we'll keep him.

Hi Julia,

Our daughter passed away 4 months ago from CDH along with several VSD's and an interrupted aortic arch. We were pregnant with twins and lost one twin very early on. We are also part of your study and have several questions. First of all if you do find any genetic cause during the study how long does it usually take to get the results? Is CDH more common in twins? I know the risk of having another child with CDH is about 2% but does the risk increase if there was a heart defect as well? Thank you for taking the time to answer our questions. And thank you for trying to find a cause to this devastating birth defect.

Brooke

I have one more question I forgot to include. I read where you think it can be caused by a connective tissue disorder. I was diagnosed with a connective tissue disorder after I gave birth to my oldest daughter. If it is a connective tissue disorder are you able to determine that through the study and does that mean it was inherited from me?

Thanks again,
Brooke

Amanda,

I hope your daughter is doing well now. The amniocentesis you had during your pregnancy with Liz would have detected large genetic mistakes in the chromosomes - having an entire extra or missing chromosome- but there are smaller genetic mistakes that we are now able to detect that would not have been detected on the chromosome analysis. You can have you daughter evaluated by a geneticists who can explain the more expanded testing available. Approximately 15-20% of children with a CDH have a genetic cause that can be detected by available testing. Most of these children have second birth defect. We think that many other children have a genetic cause but it is too small to be detected by current available analysis. We are looking for these smaller genetic changes in our research study. I can discuss this more with you by phone if you are interested. 212 305 6987 or if you would like me to help you find a geneticist in your area.
Best,
Julia

Neil,

We cannot know the exact recurrence risk until we understand the specific genetic cause in your family. I have listed the two possible ways the CDH could have been inherited in your family. In scenario 1 the chance of it to happen again with each pregnancy is 1 in 4 (25%). In scenario 2 the chance of it happening again is less certain because the mutation does not always cause a CDH when it is inherited. In these cases we would say the chance may be as high at 50% because with each pregnancy there is a 1 in 2 chance (50%) to pass on the mutation but the child may not develop the CDH. If we know the exact molecular cause of the CDH in the family, there are reproductive options that family can pursue to prevent the CDH from happening again if they wish.


1) A child inherits a genetic change from the mother AND the father. This genetic change alone in the mother or the father does not cause a CDH but when the child has BOTH genetic changes this causes a CDH. We think this type of inheritance is most likely when a family has more than one child affected.

2) A child inherits a genetic change from the mother OR the father and this causes the child to have a CDH. The parent with the genetic change may have a very mild CDH and never know that they have it or they may have other protective genes that cause them not to have a CDH even though they have a genetic risk. We think this type of inheritance is much less common than the first type. We think of this type of inheritance when a family has a child affected with a CDH and a parent is affected or a more distant relative like a aunt, uncle or cousin is affected.

Brooke,

Thank you for your patience with the study. I know that so many people have participated in the study buy they have not yet received test results. We are working very hard on all of the samples to try to identify the genetic cause of the CDH. We have learned that the genetic causes of CDH are very complex and not always easy to identify. We know of over 100 different genetic causes!

We contact all families if and when we identify a genetic cause but we are not able to contact families each time we complete a genetic test on a sample. I encourage everyone to contact me by email jw2500@columbia.edu or by phone 212 305 6987 to ask specific questions about their family. I can tell you what analyses have been done and what this means about the risk that the CDH is genetic in the family.

I sent you a private email in response to the connective tissue disorder question. There are many different types of connective tissue disorders and only a few have been associated with CDH.

Best,
Julia

Courtney,

Thank you for your interest in our study. We enrolled individuals of all ages with a CDH.
The testing that can be done on an amniocentesis has changed quiet a bit in 23 years and I would encourage you to speak with a genetic counselor as you prepare to start a family of your own. I can refer you to someone close to you if you like.

There is still a lot of work on going with lung develop. Many of the studies are focused on trying to understand it so we then know how to treat it. Other studies are looking at trying to improve the lung development inutero while the fetus is growing. Presently there are no on going human studies of medications to improve lung growth in individuals with CDH but our hope is that through research studies and generous families we will better understand CDH and lung develop which will allow us to develop better treatment.

Please contact me by phone or email jw2500@columbia.edu or 212 305 6987 if you would like to discuss participating in the study.

Best,
Julia

Talked to Julia today and just can't believe how amazing she is! She took over half a hour of her time today to talk to me. Thanks Julia and thanks to Cherubs for giving me this opportunity!

Mandy,

I think I missed your question last week. I'm sorry for my late reply.

We have seen a region of chromosome 17 called 17q12 deleted (missing) in children with CDH. We have not seen this region duplicated (extra) in children with CDH. This region of chromosome 17 is one or the more common chromosome microdeletion (missing) or microdupliation (extra) we see in children. Most children with this region deleted or duplicated don't have a CDH. The more common symptoms are developmental delay and learning problems. Some individuals have no symptoms of the deletion.

This shows how complex genetics is and particularly this portion of chromosome 17.

Please feel free to email me with more specific question to jw2500@columbia.edu.

Best,
Julia

Jess,
Congratulations on your baby girl. I hope she is doing well.
You are correct that Right is less common than Left. We are not exactly sure why that is but we think it has to do with how the three sheets of muscle come together to form the diaphragm in early fetal development. This convergence of the muscles is more often disrupted on the left side.
We also have seen that children with a Right sided do not necessarily have a worse prognosis but may need more intervention than children with a Left sided hernia. In our follow up of 250 children with a CDH, we found that children with a Right sided CDH needed ECMO more often than L sided CDH but did not over all have a worse outcome than children with a Left sided CDH.

We have seen families with members with both Left sided and Right sided CDHs which leads us to believe that at least some of the genetic causes are the same but we also suspect that some genetic causes only cause a Right sided CDH and some only cause a Left sided CDH. We are working to answer all of these questions.

Best,
Julia