Achieving a Diagnosis

Achieving a Diagnosis

For many people living with a rare disease, getting a diagnosis can be a long, stressful experience that can take years. Navigating the healthcare system for months or years in search of a diagnosis can leave a person feeling frustrated and exhausted from a seemingly never-ending quest for answers.

There are several reasons why a rare disease can be difficult to diagnose. Many primary care physicians, and even some specialists, are often unfamiliar with the variety of symptoms that can be associated with rare diseases. Also, some rare diseases have nonspecific symptoms, such as weakness, pain, or dizziness. These symptoms can be misdiagnosed as more common conditions.

Also, because more than 80% of rare diseases have a genetic cause, genetic testing is often the only way a definite diagnosis can be made. However, if a physician does not include genetic testing as part of the diagnostic process, the diagnosis may be missed.

Achieving an accurate diagnosis is the first step in finding the right treatment and improving care for people with rare diseases and their families. However, delays in diagnosis can lead to inappropriate management of a rare disease and disease progression. Also, a misdiagnosis can lead to interventions that are not appropriate for the underlying disease or condition.

A correct diagnosis ensures that people with rare diseases receive the clinical care and counseling appropriate for their disease. Also, a diagnosis removes a significant psychological weight from those who have been struggling with a long diagnostic odyssey. It also gives people and families affected by a rare disease the chance to connect with a rare disease community. Improving the diagnostic journey for people with rare diseases is an important area of focus for rare disease patient advocacy organizations.

Finding a Clinic or Diagnostic Program

Help and resources are available for people who are currently searching for a diagnosis.

Some simply have not been referred to the correct specialist, while others have a disease that is either unknown to the medical community or does not yet have a known test.

Finding a clinic or diagnostic program that specializes in undiagnosed patients is an important way to connect with specialists who have expertise in diagnosing rare disorders.

The Undiagnosed Diseases Network (UDN)

The UDN comprises 12 clinical sites across the United States including a coordinating center, a sequencing core, a metabolomics core, two model organism screening centers, and a central biorepository.

The Undiagnosed Diseases Program (UDP) at the University of Alabama at Birmingham

Undiagnosed patients in Alabama also have access to the Undiagnosed Diseases Program (UDP) at the University of Alabama at Birmingham (UAB). This leading-edge program addresses the needs of patients with severe chronic medical conditions for whom a diagnosis has not been made despite extensive efforts by the referring physician.

The UDP strives to meet the needs of patients of all ages. The program serves those with rare diseases, those with conditions not previously known to exist, and those with atypical presentations of common diseases.

The UDP is led by a multidisciplinary team of experienced UAB clinicians that includes:

– Bruce R. Korf, MD, PhD
– Martin Rodriguez, MD
– Anna Hurst, MD

The team also includes certified genetic counselor Kirstin Smith, MS, CGC, and certified registered nurse practitioners Tammi Skelton, MSN, CRNP, NP-C, and Kaitlin Callaway, MSN, CRNP, NP-C.

The program benefits from the expertise of clinicians and investigators from UAB Medicine, Children’s of Alabama, and HudsonAlpha Institute for Biotechnology. These experienced professionals work together in using medical expertise and testing, as well as genetic and genomic technologies, to uncover a diagnosis and determine an effective treatment. For an evaluation, patients need a physician referral and must also meet essential criteria.

Smith Family Clinic for Genomic Medicine

The Smith Family Clinic for Genomic Medicine is the first clinic in the world designed to provide diagnoses to patients with undiagnosed diseases by using whole genome sequencing data when other genetic technologies are unable to reach a diagnosis.

Led by Medical Director David Bick, MD, the Clinic is unique in sequencing the whole genome, rather than part of the genome, in the diagnostic process. The Clinic is located on the campus of the HudsonAlpha Institute for Biotechnology in Huntsville.

The Undiagnosed Disease Registry

The National Organization for Rare Disorders (NORD) is the leading patient advocacy organization dedicated to improving the lives of individuals and families living with rare diseases.

NORD has launched the Undiagnosed Rare Disease Registry to support research on rare diseases and how they progress over time. The online registry securely collects and stores data for medical research. The goal of the study is to limit the diagnostic odyssey for people with undiagnosed rare diseases by building a rare disease community. Other goals include collecting relevant demographic and symptom-related data and informing researchers, clinicians, and regulatory agencies.

Role of Genetic Testing and Genome Sequencing

Because a high percentage of rare diseases have a genetic component, most undiagnosed patients benefit from evaluation at a clinical genetics center where they can receive genetic testing (for a search tool to locate clinical genetics centers in the U.S., please visit the American College of Medical Genetics and Genomics website at:

Genetic testing involves examining a person’s DNA, the structure in cells that carries the genetic code. This testing can reveal variants, or changes, in genes that can help to diagnose some rare diseases.

Genetic tests can be performed on samples of blood, skin, saliva, or other tissue. These tests can help to confirm a rare disease diagnosis and identify treatment options, including clinical trials. Most genetic tests focus on examining one gene at a time, based on a clinician’s judgement of the most likely cause for a person’s condition.

Although genetic testing often provides a diagnosis, it may be difficult to predict which of the approximately 22,000 genes in the human genome is the cause of a person’s condition.

Genome Sequencing

It is now possible to examine most or all of these genes in a single test called genome sequencing.

Genome sequencing comes in two forms: whole exome sequencing (WES) and whole genome sequencing (WGS). WES focuses just on that part of the genome that encodes for proteins. This is where most genetic variants that cause disease are located. WGS looks at the entire genome, including regions that do not encode protein.

Currently, most clinical laboratories that do genome sequencing offer WES, which is much less expensive and easier to interpret than WGS. WGS is offered on a clinical or research basis in some settings; it may be able to detect a larger number of genetic variants associated with disease, but it is also considerably more expensive to perform.

Genome sequencing identifies a genetic explanation for rare disease in 25-50% of cases. The diagnostic rate depends in part on how much information there is to support a genetic cause for a person’s rare disease in the first place. The genetic variant that is identified may be a unique one that has never been seen before.

Sometimes this results in discoveries of new genetic conditions, especially if more than one person is found with a change in the same gene. Laboratories can share information on a confidential basis to try to find similar cases that help to validate these new findings. However, sometimes genome sequencing results in finding a genetic variant that cannot be definitively concluded to be the cause of a person’s condition, though it may have features that suggest it is possibly related. Geneticists call these “variants of unknown significance,” or VUSs.

It’s important to note that a VUS is not the definitive cause of a person’s condition. Some VUSs are eventually determined to be the cause, while others are eventually found not to cause disease. Therefore, clinical decisions, such as starting treatment, should not be based on the finding of a VUS.

Even with advances in genome sequencing technology, we are still not able to detect all possible genetic changes that cause disease. Because of this, a negative result from genome sequencing does not mean that there is no genetic cause of a person’s condition. For this reason, one should not assume that genetic transmission of the condition will not occur if the sequencing was not informative.

In some cases, re-analysis of a genome sequence a year or two after the initial test reveals a variant that was not initially appreciated. This is usually because more information has been gained to help interpret variants. Genome sequencing is gradually being improved to detect specific kinds of genetic variants. If genome sequencing does not result in a diagnosis, it can be useful to maintain contact with a genetics physician to periodically explore whether there are new approaches that may shed light on the underlying diagnosis.

Alabama Genomic Health Initiative

Undiagnosed patients in Alabama may benefit from participation in the Alabama Genomic Health Initiative (AGHI). This program is one of the first statewide efforts in the nation to use the power of genomic analysis (genome sequencing) in helping to identify those who are at risk for disease and genomic abnormalities.

AGHI includes members from UAB, HudsonAlpha Institute for Biotechnology, and Tuskegee University, all of which are nationally recognized institutions and leaders in bioethics and genomic medicine.

The program includes a component of testing adults for several rare genetic conditions. These mostly include conditions that increase risk of cancer or some kinds of heart disease. The program also offers WGS for individuals with rare undiagnosed diseases.

Genetics Professionals

Most clinical genetics centers and diagnostic programs offer teams of experienced physician medical geneticists and genetic counselors who can help families learn more about genetic testing and provide support to assist in adjusting to a new diagnosis.

This genetics professional team can help families determine whether genetic testing is appropriate and provide information about interpretation of a genetic test. Services can include:

  • Providing information about how a genetic disease can be passed through families and determining your risk of having children with the disease
  • Explaining the testing options available and discussing the benefits and limits of genetic testing
  • Providing information about specific tests that are available for prenatal and preimplantation genetic diagnosis
  • Interpreting and explaining the results of genetic testing
  • Implementing a management plan based on a genetic diagnosis
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