Sometimes a newborn or child is hospitalized with a severe illness that cannot be diagnosed with standard medical tests and imaging. In these rare cases, an answer that explains these puzzling symptoms might be buried in a person’s genes.

Your genes act as sentences in an instruction manual that tell the body how to function. Genes guide the production of molecules called proteins that are necessary for creating the body’s cells, tissues, and organs, as well as for maintaining their function and operation. 

Genes, however, only make up 1 to 2 percent of your entire “genome,” a term that refers to all of your DNA. This small portion of the genome that makes up actual genes with instructions for making proteins is called the “exome.” In the past decade, physicians and researchers have relied on whole exome sequencing (WES) to uncover new genetic mutations linked to diseases because the procedure was less expensive and required less storage space than sequencing a person’s entire genome.

However, as sequencing costs and data storage requirements have continued to drop, whole genome sequencing (WGS) has become more feasible, though it still is not a widely offered service. WGS translates all of the 3 billion DNA base pairs that make up an entire human genome into a file made up of letters. Doctors and researchers then use tools to scan and analyze these letters for mutations, or typos, in the genes.

At Yale Medicine, our team of physicians, geneticists, and researchers work together to solve complex medical problems that may have an underlying genetic component. Currently, WGS is only available to children hospitalized with severe illness.

WES and WGS both rely on sequencing machines that use a patient’s saliva or blood sample to translate biological information into a digital file of letters. The letters, which correspond to a patient’s DNA, can then be analyzed and examined using computational analysis and other methods to detect mutations. The difference between the two procedures is that WES sequences only 1 to 2 percent of a person’s genes, whereas WGS sequences the person’s entire genome.

There are two primary situations when WGS might be recommended over WES:

• When time is critical. Although everyone would like a diagnosis for their child as soon as possible, there are situations when a rapid diagnosis is crucial to determine potentially life-saving treatment, such as a particular medication or therapy that could not otherwise be known in the absence of a diagnosis.
• If WES results do not provide helpful insight. Your doctor may then suggest the more thorough method of WGS to search the whole genome for variants that may be linked to a condition and its symptoms.

Many known diseases can be diagnosed through the use of WGS. For children whose diseases have not been diagnosed, WGS may offer the opportunity to discover a new genetic cause.

Some unexplained conditions where WGS might uncover an underlying diagnosis include:

• Intellectual disability/severe learning problems
• Developmental issues, including delays in walking or talking
• Brain abnormalities
• Seizures
• Abnormalities of the head, neck, and face
• Hearing and vision problems
• Heart and lung problems
• Intestinal problems
• Short stature/severe skeletal abnormalities
• Limb (arms, legs, hands and feet) abnormalities
• Immune deficiencies or recurrent infections
• Recurrent or severe unexplained illnesses

A team of clinicians and laboratory genomics specialists from Pediatrics, Medical Genetics, and the Yale and Center Genome Analysis are working together to offer WGS. Currently, the service is available to the neonatal intensive care unit (NICU) and the pediatric intensive care unit (PICU) at Yale New Haven Children’s Hospital.

There are many potential benefits of WGS. If a child has a genetic diagnosis, then that information can be used to understand how a disease might progress and to help determine more personalized treatment approaches. Some patients and families feel an enormous relief in having an answer after a long time of uncertainty. WGS also allows the family to decide if more members would like to be tested.

Potential risks of WGS are mainly psychological and should be discussed with your child’s doctor and a genetic counselor. Because the entire genome will be sequenced, experts may discover what are called "secondary findings." This may uncover risk for a disease that was not originally suspected, or variants that may predispose you to other diseases, like cancer. In most cases, a patient can choose to opt out of learning about secondary findings.

"Rapid WGS results and their interpretation are available in under a week, which may prove extremely beneficial in situations where a rapid diagnosis is critical for patient management," says Yong-Hui Jiang, MD, PhD, chief of Medical Genetics.