Presently, only a fraction of the genetic causes of CDH are known.  In order to understand what is known about the genetic causes of CDH it is helpful to review information about our chromosomes and our genes.  

Our bodies are composed of millions of cells. Within the center of each cell are rod-like structures known as chromosomes.  Typically, there are 46 chromosomes in each cell. They are grouped into 23 pairs, one member of each pair coming from our mother and the other from our father at the time of conception. The first 22 pairs of chromosomes are the same in both men and women and are number 1 through 22. The last two determine our sex and are called X and Y.  Women have two X chromosomes and men have one X chromosome and one Y chromosome. 

Our chromosomes carry our genes, which are the instructions that tell our body how to grow and develop. Each pair of chromosomes is unique and contains a unique set of genes.  There are approximately 30,000 genes that influence our growth and development.  Each gene occupies a specific location on a chromosome. With the exception of the X and Y chromosomes, there are two copies of each chromosome and therefore two copies of each gene. When there is an entire extra or missing chromosome or a portion of a chromosome deleted or duplicated, there is too much or too little genetic information and this can lead to a genetic disease.

Our genes are composed of DNA, and DNA is made up of four chemical bases which are represented by letters: adenine (A), guanine (G), cytosine (C), and thymine (T).  These base pairs are strung to together in specific combinations and lengths to spell our genes.  When the DNA code is altered, and this can lead to a genetic disease.

A chromosome analysis or karyotype is the most basic genetic analysis. The analysis is able to visualize each individual chromosome and is able to detect missing or extra chromosomes.  A chromosome analysis is also able to detect large chromosome abnormalities including large deletions or duplications of chromosomes. A chromosome an

alysis cannot detect small chromosome abnormalities or single gene abnormalities.

Approximately 10 to 20% of all cases of CDH have a chromosome anomaly that can be detected by a chromosome analysis .  There are many different chromosome anomalies that have been identified in cases of CDH, in fact a chromosome anomaly of almost every chromosome has been identified in at least one case of CDH.  The identification of many different types of chromosome anomalies confirms that CDH is genetically heterogeneous, or there are many different genetic causes and not all cases of CDH have the same genetic cause.  

A certain number of cases of CDH are caused by a microdeletion or microduplication of a chromosome that can only be detected by DNA microarray analysis.  Many different types of microdeletions and microduplications have been identified in cases of CDH but there are certain abnormalities that have been identified more frequently including microdeletions on chromosome 8,  microduplication on chromosome 11, microdeletions on chromosome 15, and microduplications on chromosome 22.  

There are many different genes that have been proposed to be important in the formation of the diaphragm and therefore a mutation in one of these genes may result in a CDH.  Many of these genes are located in the regions of the chromosomes listed above.

Almost all cases of CDH that have a chromosome anomalies detected by a chromosome analysis and many cases of CDH that have a microduplication or microdeletion detected by DNA microarray have one or more additional anomalies such as a congenital heart defect, dysmorphic features, genitourinary anomalies, musculoskeletal anomalies, gastrointestinal anomalies, and  neurological anomalies . The prognosis for cases of CDH with an identified chromosome anomaly is poorer than that of cases without an identified chromosome anomaly.  

Unfortunately, many of these cases do not survive infancy and those that do may have long term complications including developmental delay and mental retardation.  

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 peri

od 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.  One of the goals of our collaboration with Global CDH is to educated the CDH community about the DHREAMS study and invite families to enroll.   We hope that our collaboration will untimely lead to a better understanding of the genetics of CDH which will in turn improve diagnosis and treatment of CDH.

DHREAMS Official website: www.cdhgenetics.com