Inherited Disorders



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Happy viewing, The Patient Engagement Subcommittee

What is an Inherited Disorder?

An Inherited Disorder is a disease caused in whole or in part by a change in the DNA sequence that is different from the sequence observed in unaffected individuals. This is a difference between an individual's DNA and what we understand to be normal. These differences are called variants or mutations. These disorders can be caused by single mutations, multiple mutations, broad damage to DNA, or a combination of mutations and environmental factors.

During a patient's journey to diagnosis, multiple types of testing may be performed to determine whether they have an inherited disorder and/or which disorder it might be. This webpage has been created by experts in genetics and molecular pathology to provide information and offer additional resources that may help to understand the reports from lab testing the patient may receive during this process. A common type of laboratory testing a patient with an inherited disorder may encounter is DNA sequencing.

DNA sequencing is a procedure used by genetic laboratory professionals that include specialized machines and laboratory techniques to identify the A, C, G, and T bases of the DNA strand. Depending on the specific type of testing being performed (see Diagnostic Testing), either small specific sections of DNA can be sequenced or an entire genome. A specialist physician or doctoral scientist analyzes the data generated through sequencing and prepares a results report that includes the key findings, such as the detection of variants that are associated with an inherited disorder.


What is the difference between getting a gene sequenced and getting the whole genome sequenced?

A gene is a segment of DNA that encodes for a protein in our body that has a particular function. Humans have over 20,000 genes encoded by our DNA, but this only represents 1% of the information in our genome. When diagnostic laboratories use sequencing technology, they can sequence either part of a gene, a single gene, many genes (a “panel”), all or most of the genes in the body (the “exome”), or even the entire genome to make the best diagnosis for their patient. Learn more about the difference between "whole genome sequencing" (WGS) and "whole exome sequencing" (WES) below.


What is gene panel testing?

Gene panel testing is the analysis of multiple genes associated with a inherited disorder or group of disorders. Typically, gene panels are designed to include appropriate genes that can aid in diagnosis. For example, a panel test for an inherited disorder, such as epilepsy might contain over 100 genes that are known to be associated with different inherited disorders that include epilepsy as a symptom. A panel test allows for multiple different genes to be analyzed using a single patient sample.


What is next generation sequencing and why is it different?

Next generation sequencing, or NGS, is a powerful sequencing method that allows a clinical genetics laboratory to sequence an enormous amount of DNA, even an entire genome, at one time. Traditional sequencing (i.e. Sanger sequencing) usually requires multiple reactions to analyze a single gene. NGS technology allows laboratories to run millions of traditional sequencing-like reactions simultaneously. Software stitches the data together and identifies potential mutations. As a result, NGS as a technology has been responsible for the explosion of genetic information over the past decade.

What is “Germline testing”?

Germline Testing vs Genetic Testing for an Inherited Mutation

AMP would like to acknowledge the phrase “genetic testing for an inherited mutation” is the preferred terminology among patients in reference to germline testing. However, this webpage is built to introduce patients to the information found on their laboratory report and will use those terms to provide the clearest information.

The term ‘germline’ refers to the germ cells (eggs and sperm) which pass on genetic material from generation to generation. Germline testing, frequently referred to as “genetic testing”, detects genetic alterations that were inherited from germ cells and are therefore present throughout a person’s body. Germline testing is typically performed on blood or saliva, not cells or tissue.

A diagnostic germline test may be ordered for a patient with symptoms and/or a strong family history of a genetic disorder to determine the risk to the patient for developing a hereditary disorder. Sometimes a patient may have a diagnosis already, and, a diagnostic germline test is used to determine whether the disorder was inherited. Whether or not an individual has been diagnosed with an inherited disorder, a germline genetic test may provide information about how likely the person might be to pass the disorder on to their children.

Germline testing for inherited disorders is usually considered for three broad categories:

Diagnostic testing may detect or confirm the presence of a genetic disorder.

Carrier screening/testing provides information about the risk for having a child with a genetic disorder and may provide awareness and/or inform decisions about reproduction having children. Carrier screening is often performed for large groups of people (for example, all newborns), even if there is no other reason to be suspicious of the disorder. These tests are highly accurate, but they will sometimes produce an incorrect result. If a screening test is positive, it should always be confirmed with a diagnostic test (see below). If a screening test is negative, there is still some small risk ("residual risk") that the disorder is present.

Newborn screening is universal testing of healthy newborns for rare inherited disorders that can be treated or managed.

More information about diagnostic testing, carrier screening, and newborn screening can be found below in Screening Tests.

Diagnostic Testing 

Medical professionals administer diagnostic tests to identify a condition in a patient with symptoms or other reason for suspicion, such as close relatives with the condition. Diagnostic genetic testing is used when suspicion for the condition is high. Suspicion might be raised by the patient’s symptoms, their family history, or other laboratory tests. A positive result on a screening test should be confirmed with a diagnostic test. This testing may be done before birth, or after birth to help determine the genetic basis and course of a disorder as well as potential treatment(s).

Diagnostic testing is most often performed for patients with unexplained health problems, to understand the underlying cause, to possibly guide treatment, and support reproductive decisions when applicable. The signs and symptoms a patient experiences may be specific to a certain inherited disorder, in which case testing seeks to confirm the diagnosis. Alternatively, if the signs and symptoms are not specific to a single inherited disorder, testing for multiple disorders with similar features may be performed to determine which specific diagnosis is present. In diagnostic testing, a positive result confirms a specific diagnosis, paving the way for more specific treatment(s).

Types of Diagnostic Tests Chromosomal Structural Variants Methylation issues Copy number variants (CNV) Single Nucleotide Variants (SNV)




Fluorescent In Situ Hybridization(FISH)




Whole Genome Sequencing 


Multiplex Ligation-dependent probe amplification (MLPA)



Chromosomal Microarray (CMA)



Polymerase Chain Reaction (PCR)




Targeted Testing*

*The techniques that are used for targeted testing are diverse and depend on the size and type of variant(s) being tested


Why are there so many different tests?

The genetic changes that impact inherited disorders vary in size. For example, in some inherited disorders a whole chromosome may be lost or duplicated. Alternatively, a single base pair can be altered and may cause an inherited disorder. Loss of a whole chromosome can be seen with a microscope, but single base changes are too small, and require specific technologies to observe. There is a range of size and complexity of alterations to DNA, and different technologies are used to detect different types of changes.

Imagine you are looking at a newspaper. You would use a different strategy to see if the sports section was missing than you would to look for a typo. Similarly, different types of tests are designed and used to detect changes at different scales. A karyotype uses a light microscope to directly observe chromosome bands to identify “large” genetic changes. These changes are typically millions of base pairs in size. FISH testing uses fluorescent probes with special microscope filters to observe smaller, more specific genetic alterations, typically in the range of hundreds of thousands of base pairs. Microarray technologies (for example: CMA) can vary in identifying changes in DNA from tens of thousands to thousands of base pairs.

Gene sequencing, such as Sanger Sequencing, can identify the smallest changes to DNA, including alterations of a single base pair. They can identify a range of alteration sizes, but the most widely used sequencing technologies have difficulty identifying changes larger than a few hundred bases. Next-Generation Sequencing can be used to examine very large portions of the genome or even the whole genome as well as detect single base changes. Imagine using a microscope to read the newspaper, you would notice all the small typos. However, it would be inefficient to look for a missing sports section which can be identified by eye. 

Each technology has additional strengths and weaknesses. FISH, for example, is particularly good at confirming chromosomal rearrangements. Multiplexed Ligation-dependent Probe Amplification (MLPA) is useful for identifying small deletions or duplications.

Diagnostic Tests may be used alone or in different combinations to best diagnose or characterize a particular medical scenario. For example, if a patient has symptoms of trisomy 21 (Down’s Syndrome), karyotyping alone may confirm the diagnosis. On the other hand, if the patient has a nonspecific or unusual combination of symptoms,  Next Generation Sequencing of several genes may be performed to identify a genetic cause.

Screening Tests

Screening tests are designed to identify as many individuals as possible who are at risk for a particular disorder or condition. Often, the tests are applied to large groups of people who have no specific reason to suspect they have a disorder. These tests are designed for high sensitivity in order to identify the most people at risk for a potential disorder or condition as possible. On the other hand, diagnostic tests are designed to balance high sensitivity and specificity, to identify or confirm whether an individual has a particular disorder. These tests are often used when a disorder is already suspected. One example is if a person has already tested positive by a screening test. Individuals who test positive by a screening test should be confirmed using a diagnostic test that definitively determines whether the individual is at risk for or has the genetic change. Screening tests allow physicians to rule out people who do not have the disorder of interest. Diagnostic tests allow physicians to confirm suspected disorders. Examples of screening tests are newborn screening and Non-Invasive Prenatal Screening (NIPS, sometimes referred to as NIPT).

Accessed 1/25/2023 URL:

Image from "CTSA Resources Support Largest U.S. Newborn Screening Study for Fragile X Mutations" (, Last Accessed January 25, 2023)

My Test Results Showed a Variant of Uncertain Significance

Genetic laboratory tests are designed to identify differences in a patient's DNA which may be associated with diseases. These differences, sometimes called mutations, but often called variants, are evaluated by laboratory professionals using scientific literature, databases, and software tools. These experts look for associations with inherited (genetic) disorders. When the laboratory determines that a variant contributes to or causes a disorder, the variant is described as “pathogenic”. However, a variant is part of the normal human variation that simply makes people different from each other, it is described as “benign” and will not be mentioned in a laboratory report. A variant is described as a “Variant of Uncertain (or Unknown) Significance” (VUS or VOUS) when it cannot be classified with confidence as either pathogenic or benign.

Importantly, a VUS is just that, a variant of uncertain significance. Any decision, clinical or otherwise – which is based on a VUS finding should be approached with extreme caution. Since a VUS is dependent on existing medical understanding, its classification might change over time as more becomes known about a disorder or a rare genetic variant.

When testing is complete and variants detected have been classified using the best current knowledge, molecular professionals will send a report describing significant findings to the medical professional who ordered the test for the patient. For more complex testing like whole exome or genome sequencing, providers and genetics professionals will often consult as part of the patient’s care team to connect the genetic test results to what is being seen in the patient. For variants classified as a VUS, testing laboratories will often review the literature and clinical databases periodically to see if more evidence has been reported that can lead to a more helpful classification of the variant. Many laboratories have policies to reevaluate variants previously described as VUS. The policy may be described in the report, and questions should be directed to the laboratory. Ordering providers can also request the performing laboratory to re-review the results. Additionally, the report should provide enough information about the finding to support a second opinion by other health care provider(s). If a change in classification occurs, the laboratory may issue an amendment to the original report that explains the changes.

Overview of Types of Inherited Disorders


Additional Resources

AMP has many Molecular in My Pocket cards related to a number of inherited disorders, including: Hearing Loss, Cystic Fibrosis, Duchenne Muscular Dystrophy/Becker Muscular Dystrophy, Prothrombin-related Thrombophilia, Factor V Leiden, Sickle Cell Anemia, Trinucleotide Repeat Disorders, Prader-Willi and Angelman.

Access it here: Molecular in my Pocket 

Created: 3/2023