The Role of Next Generation Sequencing in Diagnosing Rare Genetic Disorders

Rare genetic disorders generally have no treatment and are poorly understood in most cases. The National Institutes of Health (NIH) defines a rare disease as one that affects fewer than 200,000 Americans, which includes about 7,000 diseases. However, a small number of these only affect a handful of individuals, making their diagnosis with traditional methods problematic. Fortunately, major advances like next generation sequencing have greatly improved the speed and precision of genetic tests, resulting in a dramatic reduction in their costs. This trend is radically changing the function of medical genetics clinics.


Next generation sequencing (NGS) was much more expensive a decade ago, making it a testing option of last resort. Today, it’s the preferred testing method for most genetic clinics. This technique can confirm suspected conditions that are well understood, but it can also diagnose extremely rare disorders with little known about them.

First-generation sequencing, also known as capillary or Sanger sequencing, is based on the electrophoretic separation of genetic products through individual sequencing reactions. Next generation sequencing, also known as massively parallel sequencing, is very different from Sanger sequencing because it includes multiple approaches to DNA sequencing that provide high throughput. The use of these technologies in scientific research originated between 1994 and 1998, although they weren’t commercially available until 2005.

NGS technologies use parallelized platforms that perform up to 43 billion short reads per instrument, which sequences about 400 base pairs. These platforms are all highly miniaturized, although they differ greatly in their approach to sequencing chemistry and engineering configurations. They also share the capability of massively parallel sequencing single DNA molecules or clonally amplified DNA templates.

Each platform that performs NGS uses its own strategy. This process typically begins by clonally amplifying a DNA sample in vitro through polymerase chain reaction (PCR), which generates the needed sequencing libraries. The next step is to sequence the DNA by synthesis, allowing the addition of nucleotides to the complementary strand to determine the sequence rather than chain-termination chemistry. The amplified DNA templates are then sequenced simultaneously in a massively parallel operation that doesn’t require physical separation of the templates.


Humans share the same genome, which consists of over 20,000 genes. These genes govern our physical traits, while variations in those genes determine our uniqueness. For example, all humans have genes that cause our bodies to make hair, but variants in those genes determine the color of that hair. However, some genetic variants change a trait so much that they’re considered diseases. The primary benefit of NGS is the speed with which it diagnoses such a condition.

Future Applications

NGS can also help us understand how a genetic variant causes the symptoms of a disease. Historically, this process requires years of effort by scientists and clinicians, especially in the case of rare diseases. In these cases, researchers must often piece together the complex puzzle of how a genetic difference manifests itself without the aid of a test subject.

A more complete picture of a rare disorder will begin to emerge over time, as the gene’s role in normal cells and more common disease becomes better understood. Researchers can then determine which functions aren’t working properly and develop possible therapies. These could include modifying a gene that isn’t functioning properly or completely replacing it. Other therapies for genetic diseases include infusing an enzyme that a patient’s body can’t make or requiring them to follow a specialized diet that excludes food the patient can’t properly digest. Clinicians may also use next generation sequencing to identify medication that can improve the symptoms of genetic disorders.

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