The Genetics oF CCHS

In March of 2003, it was established that a mutation of the PHOX2B gene was the primary cause of CCHS. This was a groundbreaking finding for researchers, clinicians, and most importantly, patients living without explanation of their extremely rare diagnosis. With the subsequent development of a mouse model, much is being learned about the genetic intricacies of CCHS.

Genetics 101

Your body is made up of trillions of cells. Cells are the basic units of life, allowing your very existence and survival. Within every cell, there is a structure called the nucleus where over 99% of your genes are found. Chromosomes are a component of the nucleus that organize and keep your ~20,000 genes packaged tightly together.

Genes explain your unique traits, meaning how your body looks, behaves, and functions. They also determine your predisposition to certain diseases. Genes are passed down from parent to child through chromosomes. You receive 23 chromosomes from your mother and 23 from your father, which are then formed into pairs and replicated in dividing cells. Keep in mind that as your cells divide and replicate, accidents (aka mutations) can occur and cause harmful effects depending on the gene involved.

Genes are small segments of larger molecules known as DNA. Most genes are responsible for producing “recipe cards” for making proteins. Proteins do the work of the cell and perform operations throughout the body. Each gene writes a code using sequences of DNA bases A (adenine), T (thymine), G (guanine), and C (cytosine) for development of a specific protein. DNA transfers these codes to RNA, which is then responsible for building the actual protein.

To summarize, your cells contain thousands and thousands of genes located within your DNA that are responsible for writing codes. These codes are then translated into proteins, which produce the expression of your personal biology.


The PHOX2B gene is located on chromosome 4. It plays a central role in development of the autonomic nervous system (ANS). The ANS is responsible for sending messages from the brain to various organs and glands in the body. It regulates involuntary and subconscious behaviors such as breathing, heart rate, blood glucose levels and body temperature. The PHOX2B gene has been identified as a “master control gene” because it regulates other genes. If the PHOX2B gene does not function properly, it will not activate the full list of genes needed for proper autonomic development, such as breathing. Researchers have identified several changes to the PHOX2B gene that can cause a genetic domino effect leading to CCHS.  As a reminder, you possess two copies of each gene inherited from your parents. CCHS is known as an autosomal dominant condition, meaning that it only requires one mutated PHOX2B gene to produce the disease.


PHOX2B mutations are classified as polyalanine repeat mutations (PARM) or non-polyalanine repeat mutations (NPARM). A PARM mutation occurs when alanines, a component of proteins, are overproduced by a faulty genetic code. A healthy PHOX2B protein will contain 20 alanines. With a mutated PHOX2B protein, you will have code for 20 alanines on one chromosome (the normal amount) and anywhere from 25 to 33 alanines in the other. Diagnosis of PARM CCHS will include a numerical mutation variant specifying the number of extra alanines (e.g. 20/25, 20/26, 20/27).

NPARM mutations occur when genetic changes are not the result of repeated alanines. These mutations occur in different regions of the PHOX2B gene and are much harder to detect. Laboratory experts must dissect every aspect of the gene until the abnormality is discovered. NPARM mutations are varied and the nomenclature of a mutation can be difficult to understand. For example, a known NPARM mutation is c.422G→A; this combination of letters, numbers and arrows means “coding DNA (c), at base 422, changed from a G base to an A base”.


Different PHOX2B mutations are thought to impact the symptoms and severity of CCHS. NPARMs are generally seen as more involved than PARMs. PARMs with a 20/27 expansion are known to carry a higher risk of CCHS related comorbidities as compared to those with a 20/25 expansion. While these theories are backed by science, they do not always hold true. Wide disparities can be seen within the same mutation. For example, some individuals with a 20/27 expansion may require ventilator support 24 hours a day while others are only sleep dependent. Researchers believe that these findings are a result of individual genetic strengths and vulnerabilities (you may hear these strengths and weaknesses referred to as epigenetics). It is imperative that both mutation type and individual presentation are considered by medical professionals for proper screening, treatment and discussions around quality of life.


Parents of a child diagnosed with CCHS often ask why, when, and how the PHOX2B gene mutated and if something may have caused it. The simple answer is that DNA can spontaneously mutate in all species. While some changes are harmful, others are beneficial and play a role in evolutionary advancements. For those with CCHS, the random mutation unfortunately occurred on a critical gene that controls breathing among other important functions. Parents should be reassured that their actions DID NOT cause CCHS. The when and how are more complicated discussions. The majority of PHOX2B mutations are considered “de novo”. This means that it is a single, new, and sporadic mutation that likely occurred when cells were dividing to form that specific egg within the mother or sperm within the father well before fertilization. For approximately 25% of cases, CCHS is inherited. Individuals diagnosed with CCHS have a 50% chance of passing the disease on to each biological child. Inheritance can also be from an unknowing “mosaic” parent that experienced DNA changes in some but not all of the body’s cells during their own fetal development. Because only a portion of their cells are affected, mosaic parents do not express symptoms of CCHS nor do they require treatment. If one of their eggs or sperm containing a PHOX2B mutated cell is used for fertilization, the child will develop CCHS. All parents of a child born with CCHS are strongly encouraged to undergo genetic testing to rule out mosaicism, or in very rare cases, undiagnosed CCHS.