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Rare Disease Genetics

How Many People Really have a Rare Disease?

Colloquially, many diseases are referred to as a “rare disease,” simply because they are uncommon. And while it may seem that the impact of rare disease is small, it is estimated that approximately 30 million people are living with a rare disease within the U.S. alone, and more than half of those individuals affected by rare disease are infants or children. That is approximately 1 in 10 Americans, according to the National Organization for Rare Diseases (NORD). Currently, there are approximately 7,000 rare diseases, but many individuals living with a rare disease are often  misdiagnosed or go undiagnosed. Rare diseases are individually rare—but collectively common!

What is Whole Exome Sequencing?

Most genetic tests are focused on careful analysis of specific genes, depending on which possible genetic diagnoses are suspected. When there are complex medical issues that are not well understood, however, a broader approach to diagnostic testing is often helpful. 

Approximately 1% of a person’s genome contains sequences that actually code for proteins. These sequences are called exons. All of the exons in a person’s DNA are collectively referred to as the exome. Whole Exome Sequencing (WES) refers to the process of sequencing just those coding regions of the DNA to look for any changes. This testing produces a large amount of data for a laboratory to sort through and evaluate. Variations in our exome are perfectly normal, and labs are faced with the challenge of filtering out which variations may be uncommon but not significant, so they can focus on the genetic changes that may lead to a diagnosis.

WES is most useful when samples of DNA from family members are also taken for comparison (ex. a sample from a child and both biological parents). This is referred to as a trio analysis

A trio analysis provides context for understanding genetic changes that may not be common in the general population but that are also present in healthy family members and so unlikely to be a good place for a laboratory to focus its energy. With trio analysis, a laboratory can filter out a lot of noise and instead  focus on findings that may be important and could aid in finding a diagnosis. In fact, the use of WES has an estimated 30% positive rate of diagnosis, with the positive rate of diagnosis going as high as 37% for families that perform a trio analysis. 

However, a diagnosis is not guaranteed with WES. Limitations of WES include conditions that may be caused by genes that are not well understood or documented in literature, or conditions that are caused by genomic imprinting (i.e. Prader-Willi Syndrome).

When is Whole Exome Sequencing the Best Option?

  • When a patient has an undiagnosed disease or condition and there is a strong indication that the cause may be genetic
  • When the clinical features of a disease/condition do not suggest a known genetic condition
  • When the clinical features suggest multiple genetic disease/conditions that are not included on any multi-gene panels
  • When the clinical features in a patient and family history suggested an inherited condition that can not be diagnosed by their presenting symptoms alone.
  • When an infant or child is very sick and the cause is not known (ex. In the NICU or PICU). WES may help with a diagnosis that will assist acute and long-term clinical decisions. 

You can read more about applications of Whole Exome Sequencing here

What is Whole Genome Sequencing? 

While Whole Exome Sequencing (WES) sequences only the coding regions of the DNA (about 1% of DNA), Whole Genome Sequencing (WGS) on the other hand sequences 100% of the genetic material in an individual’s DNA (the genome). Once considered to be “junk DNA”, the non-coding regions of DNA are now understood to play a regulatory role in how genes are expressed and how they can affect different processes in the body. However, WGS produces even more data than WES, and most of this data is not clinically useful at this point.  As such, WGS rather than WES is increasingly performed in a research setting but is not typically offered in a clinical setting. 
You can read more about the applications of WGS here.

When should I see a genetic counselor? 

If you think that you or your family members may have a rare genetic condition, we highly recommend that you speak with a genetic counselor before having any testing done. Working with a genetic counselor can ensure that you have a good understanding of your options and can also help with cost savings since a genetic counselor can help guide you toward the best, high quality test that makes the most sense for you, often avoiding the need to do additional testing at an additional cost down the road. For those who have a hereditary condition in the family and have questions about how that might impact your children, Grey Genetics offers prenatal counseling, as well as counseling for IVF and PGD. Or, perhaps you’re interested in WES or WGS, a genetic counselor can help to provide you with the best information on how those forms of testing may be effective for you and your family.

A Pediatric Genetic Counseling session includes a review of your child’s and your family health history. If you already have a diagnosis, a genetic counselor can provide you with more information regarding what that diagnosis means for your child, for you, and for family members. If your child does not have a diagnosis, and you are concerned about missed milestones, a genetic counselor can discuss your child’s health history and talk you through the best possible testing options for a diagnosis. Depending on your location, our genetic counselors may be able to connect you with other local resources. 

If you suspect that you or your child may have a rare genetic condition but aren’t sure if you should see geneticist, scheduling a Healthy Genetics Consult is a great option to get those questions answered. During a Healthy Genetics Consult a genetic counselor will review your child’s or your family health history and discuss and potential indications for genetic testing. They will also assist in creating a personal plan of care, and determine if you or your child may benefit from further evaluation by a physician or geneticist. 

You can schedule a Pediatric Genetic Counseling session or a Healthy Genetics Consult here.

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