How Next-Generation Sequencing modified medical practice: the example of Neurology

Marcondes França Jr.

In the past 5 to 10 years, we witnessed a revolution in medical practice with the development of Next-Generation Sequencing (NGS). The identification of many new disease-related genes and the recognition of novel phenotypes associated with a given gene are two nice examples of what became possible with this groundbreaking technology. The impact was felt in all medical areas, but for some of them – such as clinical neurology – it was remarkable. In the coming sections, we will give you insights into the changes imposed to neurological practice in this new era.

Why such an impact in neurology?

We have approximately 20,000 genes and at least one third of them are actively expressed in the brain. This is much higher than any other organ in the body. A straightforward consequence is that many genetic diseases have neurological manifestations. When one takes into account only the field of neuromuscular diseases, for instance, there are approximately 800 distinct diseases related to more than 400 specific genes. Then, it is not difficult to understand why NGS changed so much neurological practice…

Finding new disease-related genes

The cause of many neurological diseases remains elusive, which is an obvious limitation in the search for effective therapies. We now know that some of these ‘idiopathic’ neurologic disorders actually have a genetic etiology! This is indeed the case for motor neuron diseases (MND). These are characterized by progressive muscle weakness and atrophy that eventually lead to death.

Nowadays, it is clear that approximately 10% of all cases have an underlying genetic abnormality and many genes have already been implicated. Lately, English researchers found that some patients with MND have mutations in two new genes that interfere with the intestinal absorption of vitamin B2 (riboflavin). Although quite rare, these individuals are readily treatable with oral supplementation of high doses of vitamin B2. So, in the appropriate setting, pursuing genetic testing makes a huge difference.

New diseases x old genes

Ataxia is a disabling neurological syndrome characterized by unsteadiness and loss of motor coordination. There many causes for ataxia, either genetic and non-genetic. Despite that, no cause can be found in up to 40% of all cases. After the availability of NGS, it is becoming clear that a significant proportion of these “mysterious” cases indeed have a genetic cause. At UNICAMP, we recently evaluated using whole exome sequencing a group of 60 patients with ataxia, some of them with more than 10 years of disease duration, but unclear cause. We proceeded the analyses using the Varstation platform and were able to discover the cause of the disease in 1/3 of the subjects. Surprisingly, many patients (6/60) had abnormalities in genes related to other completely unrelated neurological conditions! The message: some genes can cause more than one neurological disease. If we did not use NGS, these would be easily missed…

New therapies

Many genetic diseases previously deemed incurable have now effective therapies. There are now molecules – such as antisense oligonucleotides – able to modulate the expression of defective genes, which result in clinical benefit. In the neurology field, these achievements are most noticeable for neuromuscular diseases. There are now approved treatments for severe and life-threatening conditions such as Duchenne muscular dystrophy (DMD) and Spinal muscular atrophy. Interestingly, some of these treatments for DMD are designed to correct the genetic abnormality and are considered mutation-specific.  They are intended to treat only patients harboring specific types of mutations in the DMD gene.

So, one needs to perform detailed genetic testing before prescribing these medicines. The DMD gene is incredibly large, so comprehensive sequencing of all exons is only possible with NGS. Our group has recently coordinated a multicentric study that uncovered the genetic profile of Brazilian patients with DMD. In our country, it seems that fewer than 15% of all patients would be eligible for these new treatments.

These are a few examples of how NGS changed neurological practice. The impact is much larger and extends to apparently “non-genetic” neurological diseases (eg, identification of risk alleles for stroke and polymorphisms that interfere with the metabolism of drugs for epilepsy). 

Due to the advances in genetic testing, the care for neurological patients has dramatically changed and will change even more… for better.

About the Author:

Marcondes França Jr is the associate professor (Neuromuscular and Neurogenetic diseases) of the department of Neurology, School of Medical Sciences – UNICAMP

References:

[1] https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Genes-Work-Brain. Consulted on March 26, 2020.   

[2] Norwood FL, Harling C, Chinnery PF, Eagle M, Bushby K, Straub V. Prevalence of genetic muscle disease in Northern England: in-depth analysis of a muscle clinic population. Brain 2009;132(Pt 11):3175-86.

[3] Johnson JO, Gibbs JR, Megarbane A, Urtizberea JA, Hernandez DG, Foley AR, Arepalli S, Pandraud A, Simón-Sánchez J, Clayton P, Reilly MM, Muntoni F, Abramzon Y, Houlden H, Singleton AB. Exome sequencing reveals riboflavin transporter mutations as a cause of motor neuron disease. Brain 2012;135(Pt 9):2875-82.

[4] de Almeida PAD, Machado-Costa MC, Manzoli GN, Ferreira LS, Rodrigues MCS, Bueno LSM, Saute JAM, Pinto Vairo F, Matte US, Siebert M, Cossio SL, Macedo GS, Winckler PB, Becker MM, Magalhães LVB, Gonçalves MVM, Marrone CD, Nucci A, França MC Jr.Genetic profile of Brazilian patients with dystrophinopathies. Clin Genet 2017;92(2):199-203.

[5] Neurogenética na prática clínica. José Luis Pedroso, Marcondes C França Jr, Fernando Kok, Orlando G Póvoas Barsottini, Sarah T Camargos. 1ª edição, 2019, Atheneu, São Paulo.

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