Updates on the work of the DHREAMS Study

Check out our NEW look!

Last year, we launched the CARE for Kids initiative. CARE for Kids was created with other studies of the genetic causes of birth defects, to help us engage with current and prospective research participants. As part of this change, we've created new logos for the study and have a brand new look! We also have a new website where information for all the CARE for Kids studies, including DHREAMS, can be found.

Continuing to Connect

Earlier this year, we held a series of online talks updating our community on our research; past, present, and future. Next year, we plan to continue reaching out to you to ensure that our research is answering the questions most important to you. Keep an eye on our Facebook page (www.facebook.com/CAREforKidsDHREAMS) or our new website (CAREforKidsGenetics.org) for updates. Have an idea for how we can better update you? Email us at CAREforKids@cumc.columbia.edu

Long Read Sequencing — Pilot Study Funding

DHREAMS was approved for a pilot project utilizing a new sequencing method called long-read whole genome sequencing. Traditional sequencing utilizing short-read techniques which is very effective at detecting small letter changes and really large DNA deletions or duplications. Long-read sequencing is useful for identifying more complex changes in the DNA, such as medium-size insertions of DNA, small variants in repetitive regions, repeat expansions, and complex structural variants. DHREAMS has received funding to allow us to test this new technique on ~200 samples. We believe that this type of research will help us to better understand the genetic causes of CDH as whole.

Third Grant for Genome Sequencing

DHREAMS received funding from the Gabriella Miller Kids First Pediatric Research Program (Kids First) for the third time!

With our first grant in 2015, we completed genome sequencing on 200 samples from 68 families. Our 2nd grant in 2016 allowed us to sequence 900 samples from over 300 families.

The new grant provides funding for sequencing of 1800 samples. Kids First (commonfund.nih.gov/kidsfirst) is a competitive grant from the National Institute of Health (NIH) that focuses on funding pediatric genetic research for children with cancer or birth defects.

The program recognizes the importance of having comprehensive clinical data on each child in the study including information about the medical and developmental outcomes and follow up care.

This was our 3rd submission and our 3rd time receiving funding from Kids First!

Our success in this area is due to the fact that we have a rich database for long term follow up care. Thank you to all our research participants for continuing to send us your updates and completing the follow up surveys via phone and email. Your continued participation is what makes this research possible.

If you have not heard from us regarding this update, we might not have your correct contact information.

Please make sure to update your contact information by emailing us at CAREforKids@cumc.columbia.edu

Deep Whole Genome Sequencing — The Genetics of CDH are Complex

This year, DHREAMS collaborators published a new study that performed a deep dive on the genetics of 4 children with CDH. This team looked at different types of genetic changes in blood, diaphragm tissue, and skin tissue. These genetic changes included those that are brand new in the child with CDH, changes that are inherited from healthy parents, and somatic changes (variants that are found in only some but not all of a person's cells).

This research revealed that there are some genetic changes found only in the diaphragm tissue. This finding will help researchers to better understand how defects in the diaphragm develop.

Thank you to all for your generous donations!

Donations $500 or greater

DHREAMS Centers

Over 1,000 families enrolled in DHREAMS!

Last year, DHREAMS, in collaboration with Massachusetts General Hospital (MGH) applied for a National Institute of Health (NIH) grant. We were recently awarded this grant allowing us to bring together two long-standing CDH genetics studies.

CDH review: from genes to mechanisms to therapies

DHREAMS researchers, in collaboration with other CDH experts, wrote a comprehensive overview of CDH. This review brought together recent research on our improved understanding of the development of the diaphragm and mechanisms causing diaphragm defects. These insights are helping to identify avenues that may lead to new therapies for CDH in the future. The development of the diaphragm is complex and includes many different genetic pathways. A gene pathway describes how multiple genes interact to produce changes such as movement of cells to form the diaphragm muscle. For example, several genes known to cause CDH are also found in gene pathways that influence the development of the lungs. Improved understanding of how these genes affect the development of the diaphragm and lungs may help us to better understand the risk for patients to develop clinical symptoms like pulmonary hypertension (PH).

Genes Involved in Heart Defects May Also Cause CDH

An analysis of DHREAMS participants and children with congenital heart defects enrolled in the International Congenital Heart Disease study identified the ROBO1 gene as a new genetic cause for CDH. ROBO1 is a part of the Slit-Robo pathway, and these findings confirm that this genetic pathway is part of both heart and diaphragm development. When the normal function of the ROBO1 gene is disrupted by a pathogenic mutation in the gene, it can cause a cardiac defect and/or CDH. This association was confirmed by creating a mouse model with a ROBO1 mutation that developed heart defects. Mice with mutations in SLIT3, a gene that makes a protein that binds to the ROBO1 protein, have CDH. Throughout development, there are genes that have multiple functions such as ROBO1, which is associated with both heart and diaphragm development. For this reason, children with genetic mutations may have multiple birth defects as well as developmental delays or growth problems. Mutations in the ROBO1 gene, like all genetic causes of CDH, are a rare cause of CDH and account for <1% of children with CDH.

International DHREAMS Families

This year we began working with CDH UK, a CDH Support Charity in the United Kingdom. We have applied for a grant from CDH UK to fund various parts of DHREAMS including enrolling more families, genetic sequencing and analysis to help us identify genetic causes of CDH, and additional studies to better understand the correlation between specific genetic changes and the clinical findings for children with CDH. We are excited to expand our international collaborations and hope that this new relationship will help us continue to learn more about CDH genetics with the goal of better treatment and support for CDH families.

Genomic Variation in Complex CDH is Different than in Isolated CDH

Variations in our genetic information are responsible for our unique characteristics, such as hair or eye color, but can also cause genetic diseases. All variants have different levels of severity and are usually classified according to a five- point scale that indicates the likelihood that any one variant is associated with human disease. Some variants do not impact the way the body works and are called benign, while those that cause disease are referred to as pathogenic mutations. A recent analysis of these variants in DHREAMS participants showed that children with a CDH plus an additional birth defect, such as a heart defect or a kidney malformation, have more genomic pathogenic or likely pathogenic variants than children with CDH and no additional birth defects. This suggests that the genetic causes of CDH are different in children with CDH with and without additional birth defects and may help point to treatments that are better geared toward each group.

DHREAMS Donations

DHREAMS is honored to receive both individual family donations as well as foundation donations. Several families hosted events in honor or memory of their children with CDH. The Williams family organized a 5K run and children's Fun Run in the Rockaways, NY in honor of their son, Ryan. The Zehr family hosted a paint party and silent auction in memory of their daughter, Ainsleigh. The Connery family started a foundation in memory of their son, Gavin, and hosted their first CDH event this past fall, Gavin's Flags. Attendees painted burlap garden flags to be hung every April for CDH awareness month. DHREAMS is humbled by the work of these families and their generous donations to the DHREAMS study. All donations, of any amount, are of great value to the DHREAMS study.

DHREAMS Donations

Donate online with a credit card or by pay pal at www.cdhgenetics.org/make-a-donation.cfm or by going to our website www.cdhgenetics.org and clicking on "make a donation." Mail a check made out to "Trustees of Columbia University" with “DHREAMS” in the memo line

Columbia University Medical Center
Dr. Wendy Chung
1150 St. Nicholas Avenue
Russ Berrie Pavilion 6th Floor Rm620
New York, NY 10032

How are Donations Used?

• $500 to enroll a family in the DHREAMS study
• $500 to complete a developmental assessment for a child in the study
• $2000 to complete comprehensive genetic analysis
• $10,000 to complete gene function studies
• $50,000 to make and study a mouse model of CDH

Each donation will be acknowledged with a personal thank you card and a receipt for tax purposes. Some families have asked for DHREAMS donations to celebrate birthdays or to commemorate an anniversary. These donations are extra special!

Thank you to all for your generous donations.
(Donations $500 or greater)

DHREAMS Centers

Happy New Years to all of the DHREAMS families and friends! We are excited to report that we now have over 2,500 people from over 900 families enrolled in DHREAMS.

Grant for Genome Sequencing

DHREAMS received its second Gabrielle Miller Kids First Research Grant for genome sequencing (www.commonfund.nih.gov/kidsfirst). With our first grant in 2015, we completed genome sequencing on 200 samples from 68 families. This new grant provides funding for sequencing 900 samples from over 300 families. The Gabrielle Miller Kids First Research Program is a competitive grant from the National Institute of Health (NIH) that focuses on funding pediatric genetic research for children with cancer and birth defects. The program recognizes the importance of having comprehensive clinical data on each child in the study including information about the medical and developmental outcomes and follow up care. DHREAMS collects over 500 pieces of clinical information on each child enrolled and followed the development of the child through 5 years of age for all children enrolled at birth. Genomic sequencing of the 3 billion genetic letters that make up all of our genetic information, which is called our genome, is more comprehensive than the previous exome sequencing we performed that included only ~ 1.5% of the genome. The genomic sequencing we are now doing is the most advanced genetic method of analysis possible and provides us with the opportunity to examine all the parts of the genes, including parts of the genes that have unknown functions.

New DHREAMS Collaborators Nationally and Internationally

DHREAMS has developed and strengthened our collaborations and partnerships in 2016. This past year, we had the opportunity to collaborate with Meriter-Unity Point Health in Madison, Wisconsin and Rush University Children's Hospital in Chicago, Illinois to help enroll families treated at these institutions. Internationally, in addition to our collaboration with Cairo University Hospital we are also collaborating with Dr. Przemyslaw Kosinski at the University of Poland, Warsaw. Dr. Kosinski is an obstetrician caring for pregnant women with babies with CDH. This past summer we attended the CHERUBS CDH Alliance Meeting in Paris France by video conference and connected with APEHDia, a French CDH support group (www.apehdia.org) and have been able to enroll several French families. To help enroll these families, two genetic counseling interns developed an instructional video with French subtitles on how to collect a saliva sample for our study.

Testing a New Protein Involved in CDH

DHREAMS and MGH Combine Forces

The DHREAMS collaboration with the CDH study at Massachusetts General Hospital (MGH) has grown, and we applied for a National Institute of Health (NIH) grant to provide funding for the DHREAMS and MGH studies. If funded, this grant will provide support to enroll additional families with CDH, genetic studies to identify new genetic causes of CDH, and studies to better understand how specific genetic mutations cause CDH and associated health problems. We hope the findings from this research will lead to better treatment, support, and prevention of CDH.

DHREAMS Donations

The DHREAMS study was awarded one of the four scientific grants from the Fore Hadley Foundation. The Fore Hadley Foundation (www.forehadley.com) was created by Ryan and Katie Bush after they lost their little girl Hadley to CDH. The Fore Hadley Foundation hosts an annual golf tournament in Atlanta, GA and is focused on raising funds to support the medical research community, hospitals caring for children affected with CDH, and families with children with CDH. In 2016 they raised over $60,000 which was distributed as Research Grants, Family Assistance Grants and Scholarships to CDH survivors and families affected by CDH.

Families in Omaha, Nebraska hosted the CDH & Child Infancy Loss Awareness Walk & Rally in Omaha, Nebraska this summer. The walk was organized to raise funds and awareness about CDH and sudden infant death. The DHREAMS study had the honor of working closely with the organizers to help facilitate a registration process that enabled the registration fee to be directly donated to DHREAMS and a study of genetic causes of sudden death. The walk raised over $2,500 from over 80 participants. The mayor of Omaha named April 19, 2016 Congenital Diaphragm Hernia Action Day.

DHREAMS is humbled by the generosity and work of the Fore Hadley Foundation and the CDH & Child Infancy Loss Awareness Walk and all of the families who have made generous donations to the DHREAMS study.

How to Donate?

Mail a check made out to "Trustees of Columbia University" and "DHREAMS" in the memo line:
Columbia University Medical Center
Dr. Wendy Chung
1150 St. Nicholas Avenue Russ Berrie Pavilion 6th Floor Rm620
New York, NY 10032

How are Donations Used?

• $500 to enroll a family in the DHREAMS study
• $500 to complete a developmental assessment for a child in the study
• $2000 to complete comprehensive genetic analysis
• $10,000 to complete gene function studies (see article above)
• $50,000 to make and study a mouse model of CDH

Each donation will be acknowledged with a personal thank you card and a receipt for tax purposes. Some families have asked for DHREAMS donations to celebrate birthdays or to commemorate an anniversary. These donations are extra special!

Thank you to all for your generous donations.
(Donations $500 or greater)

DHREAMS Centers

Happy New Year

We hope 2015 finds all of our DHREAMS families happy and healthy. We have had a productive year in the DHREAMS study with many new families, new participating centers, and new discoveries about CDH.

Thanks to our dedicated clinicians and families spreading the word about the DHREAMS study, we now have over 1700 DHREAMS participants composed of over 600 participating families from all across the nation and around the world.

DHREAMS Team at our annual meeting. Left to Right: Julia Wynn, MS; Wendy Chung, MD, PhD; Anthony Hesketh, MD,;Robert Cusick, MD; Tim Crombleholm, MS, MD; Foong-Yen Lim, MD; Ken Azarow, MD; Brad Warner, MD; George Mychaliska, MD; Amy Wagner, MD; David Schindel, MD

DHREAMS Goes International

MYH10 A New Genetic Cause of CDH

We recently identified a mutation in the MYH10 gene that causes congenital diaphragmatic hernia and other birth defects.

To understand how mutations in the MYH10 gene can cause CDH it is helpful to review information about our genes. We each have approximately 20,000 genes that are important in the development and function of our bodies. A complete set of our genes is located in nearly every single one of our cells. Genes are packaged onto chromosomes and are made up of DNA. The DNA "spells" our genes using the "letters" A, C, T, and G. Just like spelling mistakes can make a word unreadable, a mistake or a mutation can occur in the "spelling" of a gene making the gene unreadable. A gene that cannot be "read" does not function or does not function properly, and this can lead to a birth defect or genetic disease.

Most of our genes come in pairs, one copy we receive from our mother and one copy we receive from our father. Some genetic mutations are passed down or inherited from our parents and some genetic mutations occur new in the child and are not passed down from either parent. We encourage you to visit our website, www.cdhgenetics.org, where a more complete review of genes and genetic mutations can be found in the "genetic overview" tab.

We identified a mutation in the MYH10 gene in a child with a CDH, as well as many other birth defects including growth restriction during the pregnancy, a small head with cerebral and cerebellar atrophy, developmental delay, low weight and congenital bilateral hip dysplasia. The number of medical problems that this child has suggests that the MYH10 gene is important in the development of many parts of the body. The exact function of the MYH10 gene is not completely known. Studies in mice have shown that it plays an important role in the development of the heart, brain and hernia.

We examined the parents for the MYH10 gene mutation and both of them were negative. This confirms that that MYH10 gene mutation occurred new in the child and was not inherited from either parent.

This is important information for the family. When a mutation occurs that is new in a child, there is a less than 1% chance for the parents to have another child with the same genetic mutation. Additionally, the other family members are not at risk to have a child with the same genetic mutation.

This is the first time the mutations in the MYH10 gene have been identified in a human and more research is needed to fully understand the function of the MYH10 gene in diaphragm development. We are also in the process of screening the other children in our study with CDH and additional birth defects for mutations in the MYH10 gene.

ECMO and Pulmonary Hypertension are Associated with Low Weight in CDH Children

We recently analyzed the risk factors for low weight in children with CDH at 1 year of age. We followed 72 infants with CDH born at New York Presbyterian/Morgan Stanley Children’s Hospital for one year. At one year of age, 35% of the infants were less than the 5th percentile for weight. This means that at one year of age, 35% of the children weighed less than 95% of all other one year olds. Additionally, 18% of the children had difficulty eating enough calories by mouth and were receiving feeding assistance by a gastrostomy tube (G-tube) or nasogastric tube (NG-tube).

All of these children were also on medication for reflux. Examining the risk factors for low weight, we found that infants who required extracorporeal membrane oxygenations (ECMO) and/or had pulmonary hypertension in the neonatal period were at greater risk to have low weight at 1 year of age. This is important information that will be used to guide nutritional monitoring and counseling in CDH children. These findings were published in the October issue of the Journal of Pediatric Gastroenterology and Nutrition.

Undescended Testis Occurs Frequently in Males with CDH

Undescended testis (UDT) occurs when one or both testicles are not present in the scrotum at birth. The undescended testicle may move into the correct place but in some cases surgery is required to move the testis into the scrotum. UDT occurs in approximately 1-2% of all males in the general population. There have been several studies that suggested that UDT occurs more frequently in males with CDH.

We studied 65 males with CDH at two years of age. We found that 18% required surgical repair for UDT. Two males had both testes undescended and 10 had one testis undescended. Interestingly, all 10 of the boys with one testis undescended had it on the same side as their CDH. Our study confirmed that UDT is significantly more frequent in males with CDH than in the general population.

We also found that the side of the UDT correlates with the side of the CDH. One hypothesis for this correlation is that the absence or deficiency of diaphragm tissue may affect the normal descent of the testis when a baby is developing. Evaluation for UDTs is already part of the standard pediatric care for all males, but this research underlines the importance of this screening for males with CDH. Our study also demonstrates that more research is needed to understand why the side of the UDT correlates with the side of the CDH. These findings were presented at the 2014 Canadian Association of Pediatric Surgeons Meeting.

DHREAMS Events

The DHREAMS study group had an eventful year attending and virtually attending many different CDH events. Washington University Medical Center and St. Louis Children’s Hospital hosted a Family Meeting Day in April and DHREAMS was able to present information on the DHREAMS study. We attended the 2014 International CDH Conference in Washington, DC in July and the first meeting of the Alliance of Congenital Diaphragmatic Hernia in Dublin, Ireland in August.

On August 29, 2014 we rang the NY Stock Exchange Closing Bell with the Scelfo family and CHERUBS.

We especially enjoy these opportunities to update DHREAMS families on our research, meet new families and catch up with those already enrolled. Please contact us if you would like us to speak at your CDH event. We enjoy all opportunities to share information on CDH and the DHREAMS study.

Questions about the status of research for your family

We are very appreciative of each and every family that participates in our study and are dedicated to finding an answer for everyone. Unfortunately, we are not able to call everyone to provide individual updates. If your child was born at one of the DHREAMS hospitals, we encourage you to contact them for follow up information. If you enrolled directly in the DHREAMS study, we encourage you to contact us at (212) 305-6987 or jw2500@columbia.edu with any questions. We can update you on the studies that have been completed on your family and plans for future studies. We also want to learn about any updates in your family. More information will help us to better target possible genetic causes.

DHREAMS Funding

DHREAMS was funded for five years by a grant from the National Institute of Health (NIH), an agency of the U.S. Department of Health and Human Services that funds many different types of research. Due to budget cuts, NIH funding has been reduced across the board. As a result, many great research studies including the DHREAMS study did not continue to receive funding from the NIH. We will continue to apply for NIH funding and are hopeful that we will be successful in the future. We are fortunate to have alternate funds to help keep the DHREAMS active, but additional donations are critical. It costs approximately $150 to enroll a family in the study and $1000 to complete comprehensive genetic analysis on one individual. We are appreciative of all donations of all sizes.

If you are interested in making a donation to the DHREAMS study, please visit our donation page or contact us at (212) 305-6987.

Many thanks to everyone who makes the DHREAMS Research Possible!

DHREAMS Centers

Study Coordinator

If you have any questions about the information in this newsletter, please contact:
Julia Wynn, MS, CGC
212-305-6987 | jw2500@columbia.edu
www.cdhgenetics.org
Facebook: DHREAMS Research Study (Congenital Diaphragmatic Hernia)

Happy New Year

Happy New Year to all of the DHREAMS families! We now have over 500 participating families from all across the nation and the world. Thank you to all of you who educate the CDH community about our study. Nearly a quarter of the participating families find us through CDH support groups and/or other families who are enrolled in the study.

The DHREAMS study has had a busy year with some exciting findings.

Members of the DHREAMS team at the 2013 American Pediatric Surgery Association. L-R: Dr. David Bliss, University of California, San Diego; Julia Wynn and Dr. Wendy Chung, Columbia University; Sheila Horak, Nebraska Children’s Hospital; Dr. Samuel Soffer, North Shore University Hospital; Dr. Casey Calkins, Children’s Hospital of Wisconsin; Dr. Foong-Yen Lim, Cincinnati Children’s Hospital.

GATA6: A new genetic cause of CDH

We recently identified mutations in a gene called GATA6 that cause congenital diaphragmatic hernia. Some of the children with mutation in the GATA6 gene also had congenital heart defects.

Recall that genes are the blue print or instructions for how our body grows and develops. We have a complete copy of our genes in nearly all of our cells (Figure 1). We have two copies of most of our 20,000 genes in each cell, one copy comes from mom and one copy comes from dad. If a change occurs in the gene that affects the function, this is called a gene mutation. We encourage you to visit our website www.cdhgenetics.org, where a more complete review of genes and genetic mutations can be found in the “genetic overview” tab.

Each gene has a specific function but some genes work together. Just like members of a family work together to complete a task, there are genes that are part of a family that work together in the development of the body. Last year, we identified mutations in a gene called GATA4 that cause CDH. The genes GATA4 and GATA6 are part of a family of genes that are important in diaphragm and heart development. If one of the genes in this family has a mutation that causes it not to work, it can lead to problems with the development of different organs, leading to a birth defect.

We identified a mutation in the GATA6 gene in three different children. Two of the children were born with a left CDH and a congenital heart defect. Both of these children had a new GATA6 mutation that was not inherited their mother or their father (Figure 2). In the third family, the child was born with a left CDH and a heart defect. In this third family, the child inherited the GATA6 mutation from the mother, who also was born with a heart defect, but did not have a diaphragmatic hernia.

We looked for GATA6 mutations in over 100 other DHREAMS participants who had both a CDH and a heart defect and did not find any other children with a GATA6 mutation. This means that while GATA6 mutations are the cause of CDH in some individuals, it is not a very a common genetic cause.

Most genetic causes of CDH are not common and only a small percentage of all of the individuals with a CDH share the same genetic cause. This makes studying the genetic causes of CDH very complex and requires us to study many individuals with CDH before we can understand all of the genetic causes of CDH.

Now that we know of two genes in the GATA family that cause CDH, we will use this information to look for genetic mutations in genes that are related to the GATA6 and GATA4 family.

The results of this study were published in the American Journal of Medical Genetics.

Developmental outcomes in two-year-old children with CDH

Children born and enrolled in the DHREAMS study at the study sites have formal developmental assessment at two years of age. We recently published our findings on the development of 49 children with CDH in the Journal of Pediatric Surgery. Prior to our study, there was very little information known about the development of children with CDH.

All children in the study had a Bayley Scales of Infant Development III (BSID-III) evaluation. The BSID-III measures a child’s language, motor and cognitive skills through a series of games and questions with a developmental specialist. In the general population, the average score is 100 and development is considered normal with a score above 85 for each domain (language, motor, cognitive), borderline with a score of 70-85, and delayed if the score is below 70. In our study, we found that the majority of children scored within the normal range (figure 4). Overall, the average language, motor, and cognitive scores of the children we studied were 5-7 points below the normal score of 100.

We found that children who had more medical complications, including needing oxygen past 1 month of age, needing ECMO, needing feeding assistance through a tube in the nose or in the stomach after they went home from the hospital, tended to have more developmental challenges than children who did not need these interventions. Over half of the children received interventional therapies such as physical, occupation or speech therapy.

Our study of the developmental outcomes in children with CDH is ongoing and we are now assessing children at 5 years of age. We hope to learn about specific learning disabilities associated with CDH and the best therapies to treat and prevent developmental delays.

What about my family's research results?

We are hard at work trying to identify if there is a genetic cause of the CDH in all families enrolled in DHREAMS. Presently we have an answer for approximately 10% of the families participating in the study, and all of these families have been contacted with their results if they indicated at the time they enrolled in the study that they wanted to receive results. For the remaining 90% of families in our study, our genetic research has not yet been able to identify the cause. This could be due to several reasons: scientists do not yet know all of the genes involved in CDH, genetic analyses are not yet sensitive enough to detect all genetic causes, and the CDH in a particular family is not caused by a genetic mutation.

Sometimes we find a genetic change that we think might be the cause of the CDH in the family but we need to do further studies to better understand the genetic change. We may need to collect additional blood samples to complete these studies. We will contact your family if we need additional samples and explain why we need them.

When our study first began, some participants provided saliva samples for the study. Unfortunately, we have not been able to obtain the quality and amount of DNA we need from these samples to complete the sensitive genetic studies. If your family provided a saliva sample and you would like to now provide a blood sample, please contact us. We can arrange for a certified phlebotomist to come to your home to complete the blood draw at your convenience, free of charge.

We are very appreciative of each and every family that participates in our study and are dedicated to finding an answer for everyone. Unfortunately we are not able to call everyone to provide individual updates. We encourage you to contact us if you have questions. We can update you on the studies that have been completed on your family and plans for future studies. We also want to learn about any updates in your family. More information will help us to better target possible genetic causes.

CDH Events

The DHREAMS study group co-hosted CDH Awareness Day at New York Presbyterian Hospital with the New York Chapter of CHERUBS. We also attended The CHERUBS International CDH Conference in Boston and The Breath of Hopes CDH Summit in Cincinnati. We especially enjoy these opportunities to update DHREAMS families on our research, meet new families and catch up with those already enrolled. Please contact us if you would like us to speak at your CDH event.

Study Coordinator

If you have any questions about the information in this newsletter, please contact:
Julia Wynn, MS, CGC
212-305-6987 | jw2500@columbia.edu
www.cdhgenetics.org
facebook: DHREAMS Research Study (Congenital Diaphragmatic Hernia)

Happy New Year to the over 1200 DHREAMS participants from nearly every state and 7 countries

We hope the New Year finds our over 450 participating CDH families happy and healthy. We would like to begin by thanking all of you. Without your participation, this research would not be possible.

This was an exciting year with the discovery of new genetic causes of CDH and publications on the outcomes and development of CDH children.

GATA4: A New Genetic Cause of CDH

The GATA4 gene is part of the body’s instruction manual that tells it how to form the heart and diaphragm.

Like almost all of our genes, we have two copies of the GATA4 gene; one we get from our mother and one we get from our father. If a mutation occurs in one copy of the gene, this can cause a child to be born with a birth defect.

We found that GATA4 mutations cause a CDH with varying degrees of severity. We found a GATA4 mutation in an infant with an isolated CDH that required surgery shortly after birth.

We also found a GATA4 mutation in adult individuals with a very mild CDH that did not cause any symptoms and was only detected after an MRI was done to examine the diaphragm. These individuals never required surgery to fix the diaphragm. We also found a GATA4 mutation in an infant with a CDH and congenital heart defect. The identification of a GATA4 mutation in these individuals demonstrates that a GATA4 mutation affects individuals with different degrees of severity.

A GATA4 mutation may be inherited from one parent (the mother or the father) with no symptoms or it may occur new in a child at the time the egg and the sperm come together. If a GATA4 mutation is inherited from a parent, each time the parent has a child, there is a 50% chance the child will inherit the GATA4 mutation and be at risk to have a CDH and/or congenital heart defect. If the GATA4 mutation occurs new in the child, there is a very low chance that the parent will have another child with the GATA4 mutation. When the genetic cause of a CDH is known, a family can pursue reproductive options to prevent their children from inheriting the GATA4 mutation.

Current Neonatal Outcomes

We completed the largest prospective study of children with CDH. This study will be published in the Journal of Pediatrics.

We collected over 1000 pieces of information about the children’s hospital stay. We had an equal number of boys and girls in our study. 84% had a left sided CDH and 16% had a right sided CDH. Approximately 40% had another birth defect in addition to their CDH. The most common additional birth defect was a heart defect. 32% of the children in the study required extracorporeal membrane oxygenation (ECMO). Interestingly, we found that the side of the CDH (right or left) was NOT associated with survival. This is different than past studies that have found a higher mortality in children with right side CDH compared to children with a left sided CDH.

We also completed a detailed analysis of pulmonary hypertension in this group of children. Pulmonary hypertension is a common complication of CDH. Nearly 50% of the children in the study had pulmonary hypertension at 1 month of age while only 25% had pulmonary hypertension at 3 months of age.

Future studies will focus on understanding why pulmonary hypertension continues to be a complication in some children, but resolves or improves in other children.

Chromosome Microduplications and Microdeletions in CDH

We recently published one of the largest studies of the genetic causes of CDH in the Journal of Medical Genetics. We completed genetic analysis on 256 study participants and their parents. The specific genetic analysis we completed is called chromosome microarray analysis or CMA. A CMA examines all 23 pair of chromosomes for missing or extra pieces of genetic information called microdeletions and microduplications. Sixteen (6%) of the 256 study participants were found to have a large chromosome abnormality or a chromosome microdeletion or duplication that was determined to be the genetic cause of the CDH. All of these chromosomes abnormalities occurred new in the child and were not inherited from the mother or father.

Some of the microdeletions /duplications were the same as those previously found in other children with CDH, while others had never been identified before. We also found that children with a CDH and a second birth defect, such as a heart defect, were more likely to have a microdeletion /duplication than children with only a CDH. These children were also more likely to pass away than children who were not found to have a microdeletion /duplication.

The results of this study are very important for healthcare providers caring for families with CDH, as well as future studies of the genetic causes of CDH. Our next step is to examine the genes that are located in the microdeletions /duplications in more detail to try to identify other genetic causes of CDH.

Support Groups

We had the opportunity to attend several CDH patient support group meetings this summer where we saw old friends and met new families. We were also able to virtually attend several meetings by video conference.

If you would like DHREAMS to attend your support group, fund raiser or other CDH event, please contact our research coordinator Julia Wynn: jw2500@columbia.edu (212) 305-6987

In the laboratory, DHREAMS research is in the midst of intensive data analysis.  We have completed the microarray analysis on our subjects and hope to publish these results soon. We also have completed the preliminary exome sequencing on selected cases.  See the Summer 2010 for a more detailed discussion about exome sequencing.

DHREAMS has had a fantastic spring with a dramatic increase in our enrollment. We currently have over 150 participants in the study. Our increase in recruitment is owed in large part to the hard work of CDH family support groups and individual families who have worked to increase knowledge of the CDH research. We now have participants from over 30 different states and Canada.

Exome Sequencing

Long term development

In addition to DHREAMS’s focus on the genetic causes of CDH, we are one of the first studies to follow the long term development of children affected by CDH. All children who have been part of the DHREAMS study since birth have a formal developmental study, including the Bayley III and Vineland, at 2 years of age.

The Bayley III is a standardized assessment of motor, language, and cognitive development while the Vineland is a standardized assessment of personal and social skills. Through these assessments we will learn more about the long term development of children affected with CDH and the risk for developmental delays as related to underlying genetic causes. This information will provide parents and health care providers with the necessary tools to implement appropriate therapies and educational interventions.

Winter 2009

We currently have over 100 participants in our research study and have completed preliminary genetic analysis on 83 cases (approximately 50% female and 50% male).  Approximately 85% had a left CDH and 15% had a right CDH; 70% had an isolated CDH, while 30% had one or more additional congenital anomalies.

A total of four (4.8%) cases in our study population had identified chromosome anomalies. Two cases had chromosome anomalies that were detected by chromosome analysis and two cases had chromosome anomalies that were detected by DNA microarray; one case had a microduplication and one case had a microdeletion.  The specific microdeletion identified had not previously been identified in a CDH case.

All four cases with an identified chromosome anomaly had additional congenital anomalies that were diagnosed in the newborn period and three of the four cases passed away in the newborn period from complications of their anomalies. The fourth case has some degree of developmental delay and dysmorphic features at 18 months of age.

Future genetic analyses conducted by the DHREAMS research team will include genetic sequencing of specific genes suspected to be important in the formation of diaphragm.  It is likely, that some cases of CDH without an identified chromosome anomaly have a mutation in a single gene.

Because of the genetic heterogeneity (many different genetic causes) of CDH, one of the greatest challenges of identifying the genetic causes of CDH is the large number of CDH cases that must be included in a study. It is only through the generosity of families affected by CDH that we will reach our goal of understanding the genetics of CDH and improving diagnosis and treatment of CDH.