Exploring the Genetic Mysteries: Tandem Repeat Disorders and Whole Genome Sequencing

Exploring the Genetic Mysteries: Tandem Repeat Disorders and Whole Genome Sequencing

Tandem repeat disorders are a group of genetic disorders characterized by the expansion of specific sequences of DNA within a particular gene. These disorders result from abnormal repetitions of short DNA sequences, often three base pairs in length (trinucleotide repeat). The number of repeats can vary among patients, and when the repeat sequence expands beyond a certain threshold, it can lead to a range of health problems in affected individuals. Tandem repeat disorders can lead to neurological, musculoskeletal, cardiac, and respiratory issues in children and adults, with varying ages of onset depending on the specific condition and the size of the nucleotide repeat. Additionally, pediatric onset of repeat expansion disorders can manifest as multisystem syndromes lacking specific phenotypic hallmarks, and children affected by these disorders are more prone to underdiagnosis, particularly in cases where there is no family history. In some instances, expansions in different genes can yield similar phenotypes, making it difficult to arrive at a clinical diagnosis. Understanding the molecular basis of tandem repeat disorders is crucial for developing effective diagnostic and therapeutic approaches, especially in intensive care settings. A diagnostic tool that has transformed the field of genetics is whole genome sequencing, which is a comprehensive technique that rapidly analyzes a patient’s entire genome.

Syndromes Associated with Tandem Repeat Disorders

There are over 40 different genetic conditions linked to tandem repeat expansions¹. Trinucleotide repeat disorders (also called triplet repeat disorders) represent the most common type of tandem repeat disorder. While these syndromes primarily affect the nervous system, they can impact multiple organ systems. Three examples of trinucleotide repeat disorders relevant to the pediatric population are described below.

 Fragile X Syndrome (FXS): FXS is one of the most common inherited causes of intellectual disability and developmental delays. It is inherited in an X-linked manner and is characterized by the expansion of the CGG triplet, a specific sequence within the FMR1 gene. This expansion results in a deficiency of the FMRP protein which is essential for normal brain development and function. The number of repeats determines the severity of the syndrome. Individuals with 55 to 200 repeats are considered to have a “premutation”; while they do not have FXS, they could potentially develop other Fragile X-associated disorders. Moreover, those with a premutation can have children with either a premutation or a full mutation. Children with the full mutation have FXS and have an increased risk of developing seizures. Some children may have infrequent and mild seizures, while others may experience more frequent and severe episodes. A recent study found that around 12% of individuals with FXS experienced at least one seizure, with the mean age of onset being 6.4 years.

Huntington’s disease (HD): HD is caused by an abnormal expansion of the CAG (Cytosine, Adenine, Guanine) repeat within the HTT gene. This leads to the production of a modified huntingtin protein that accumulates in the brain and results in neurodegeneration². HD is inherited in an autosomal dominant manner, meaning that a child has a 50% chance of inheriting the mutated gene from a parent who carries it HD. Symptoms typically manifest in mid-adulthood, and include motor dysfunction, cognitive decline, and psychiatric symptoms. There is a less common form of the disease known as Juvenile Huntington’s disease (JHD) or Childhood-onset Huntington’s disease, in which symptoms occur before the age of 20. The proportion of JHD amongst all cases of HD varies by study methodology and country, but it is estimated to account for 5-10% of all cases. Childhood cases may present with seizures, muscle rigidity, and muscle weakness. In addition, JHD tends to progress more quickly than adult-onset HD, with more severe symptoms emerging over a shorter period. This can be particularly challenging for affected children and their families.

Myotonic dystrophy Type 1 (DM1): DM1 is caused by an expanded CTG repeat in the DMPK gene. DM1 is an autosomal dominant multisystem disorder affecting skeletal and smooth muscles, along with the eyes, heart, endocrine system, and central nervous system. Symptoms include muscle weakness, muscle stiffness (myotonia), delayed motor development, speech and swallowing difficulties, intellectual disabilities, and behavioral issues. Its clinical spectrum varies from mild to severe, and includes a congenital form called Congenital Myotonic Dystrophy (CDM). Infants born with CDM can have significant muscle weakness and respiratory problems from birth, and affected infants may also have difficulty feeding and experience developmental delays.

Hereditary Implications of Tandem Repeat Disorders

Adults with tandem repeat disorders can pass these conditions down to their children. When a parent carrying the expanded repeat sequence (but may not show severe symptoms) has children, there is a risk that the repeat sequence will expand further during the transmission of genetic material. This expansion occurs primarily during DNA replication, repair, or recombination processes.

One noticeable characteristic of tandem repeat disorders is that they can potentially intensify in severity when passed down from one generation to the next; leading to more critical symptoms in affected children. This phenomenon is often referred to as genetic anticipation.

Key considerations:

• Variable Inheritance: Tandem repeat disorders exhibit various inheritance patterns, including autosomal dominant, autosomal recessive, and X-linked. The inheritance pattern depends on the specific disorder and can be confounded by the expansion of repeat sequences across generations.
• Earlier Age of Onset: One of the consequences of repeat expansion is that it often leads to an earlier age of onset and more severe symptoms in the affected patient. As the number of repeats increases, the gene’s function is disrupted to a greater extent, resulting in more pronounced clinical manifestations³.
• Expansion Threshold: Tandem repeat disorders often exhibit a threshold effect. This means there are several repeats beyond which the symptoms become apparent or significantly worsen. In the initial generation, an affected patient may have a repeat length just above this threshold, leading to mild or late-onset symptoms. In subsequent generations, the repeat length may surpass the threshold more easily, leading to earlier and more severe symptoms.
• Variable Expression: Tandem repeat disorders can exhibit variable expressivity, meaning that the severity of symptoms can differ among affected individuals, even within the same family. This complexity underscores the importance of consulting with qualified healthcare providers to assess the risks accurately.
• Genetic Testing: Children can benefit from their parents being informed about tandem repeat disorders. Parents who know their genetic status can opt for whole genome sequencing and other genetic tests. This knowledge allows them to consult with healthcare providers to understand the risks and implications of potentially passing these mutations to their children, leading to more informed decision-making for their family’s health.

Whole Genome Sequencing

At-risk individuals (adults and children) can benefit from genetic testing to learn more about their specific condition and its implications for family members. This knowledge can facilitate informed decision-making and tailored clinical management.

Whole genome sequencing (WGS) has significantly improved the diagnosis and treatment of tandem repeat disorders. Unlike traditional genetic tests that target specific genes or regions, WGS sequences the entire genome, including areas with tandem repeats. This comprehensive approach allows for the detection of expanded repeats in known disease-associated genes and the identification of novel repeat expansions associated with previously undiagnosed disorders.

WGS has proven to be particularly valuable in the study of tandem repeat disorders for several reasons:

1. Detection of Repeat Expansions: WGS can detect repeat expansions with a high degree of sensitivity and specificity, removing the need for multiple genetic tests. This is crucial for establishing a specific molecular diagnosis in a timely manner. WGS can also detect mosaicism, where only a subset of cells in an individual’s body carries the repeat expansion, which can be missed by other testing methods. Moreover, WGS can aid in differential diagnosis, helping distinguish between different tandem repeat disorders that may present with similar clinical symptoms.
2. Duo-trio Testing: A key advantage of WGS is duo-trio testing, which enables the detection of rare and de novo mutations, identification of inheritance patterns, and reduction of false positives. This in turn contributes to our understanding of complex genetic traits in tandem repeat disorders.
3. Facilitating dual diagnosis: In cases where children (or adults) are suspected of having a repeat expansion disorder, it’s essential to consider the possibility of a different genetic condition with an overlapping phenotype. WGS can identify these additional variants⁴, providing a more comprehensive understanding of the genetic factors at play.
4. Research and Discovery: WGS has enabled researchers to discover novel tandem repeat disorders and expand our knowledge of existing conditions⁵. By studying more regions of the genome than before, researchers can pinpoint genetic changes responsible for rare and complex diseases.
5. Personalized Medicine: WGS can facilitate personalized medicine approaches by providing a comprehensive genetic profile for at-risk and affected individuals. As the utility of precision medicine expands, the information provided by WGS can guide clinical decisions, such as selecting the most appropriate therapeutic interventions and predicting disease progression. The potential for this concept to become reality has been discussed for several years, particularly with HD, and recent progress in the field has expanded to other conditions.⁶

A key advantage of WGS is duo-trio testing and its ability to detect rare and de novo mutations, including the identification of inheritance patterns, reducing false positives, and contributing to our understanding of complex genetic traits in tandem repeat disorders. In some cases, de novo mutations can be responsible for tandem repeat disorders, and WGS can identify these mutations with high sensitivity.

Moreover, WGS can aid in differential diagnosis, helping distinguish between different tandem repeat disorders that may present with similar clinical symptoms. This is critical for providing accurate prognoses and tailoring treatment strategies. For example, myotonic dystrophy type 1 (DM1) and myotonic dystrophy type 2 (DM2) share some clinical features, but their genetic underpinnings and management strategies differ. 

WGS in Intensive Care Units

Rapid Whole Genome Sequencing (rWGS) can be valuable in intensive care units (ICU) for the detection of tandem repeat disorders and other genetic conditions. While traditional diagnostic methods can be time-consuming and inconclusive, leading to delays in treatment, rWGS can expedite the diagnostic process for critically ill children with suspected genetic disorders. rWGS can pinpoint the underlying genetic cause within days, enabling healthcare providers to make informed decisions about treatment and care.

In addition, rWGS can potentially help prevent unnecessary medical interventions. Many patients in both pediatric and neonatal ICUs can undergo a series of tests and treatments without a clear diagnosis. rWGS reduces the need for such interventions, saving both time and resources while improving the overall quality of care. rWGS and its integration into clinical practice can significantly improve the outcomes and experiences of critically ill children and their families.

Baylor Genetics and rWGS

Baylor Genetics offers rapid whole genome sequencing (rWGS). This technique enables us to identify genetic variations, including single nucleotide changes and small insertions/deletions, which may be linked to a wide range of genetic disorders. Baylor Genetics excels in delivering fast results, a written report in five days, allowing for prompt diagnosis and personalized medical management. Our state-of-the-art sequencing technology and experienced geneticists ensure accuracy and reliability in identifying genetic mutations, aiding clinicians in the intensive care settings with making personalized, informed treatment decisions for young patients.

Conclusion

Tandem repeat disorders are a diverse group of genetic diseases characterized by the abnormal expansion of repetitive DNA sequences within coding regions of specific genes. These disorders can result in a wide range of debilitating symptoms and challenges in the children they affect. Whole genome sequencing has emerged as a valuable tool for diagnosing tandem repeat disorders in pediatric intensive care settings, allowing for the identification of repeat expansions and other disease-associated genetic variants.

When clinicians choose WGS for their patients, they are accessing the most comprehensive answers in clinical genomics. WGS provides a comprehensive view of an individual’s entire DNA, allowing for the identification of all genetic variants, including rare and novel ones, which may be missed by targeted genetic testing methods. It is important to choose a lab that offers a WGS that includes an analysis of a broad range of TRDs and because of the inheritance aspect where TRDs can be passed down through generations.

Comprehensive Portfolio of Genetic Tests

Our comprehensive genetic testing menu is a valuable resource for clinicians, genetic counselors, and patients seeking answers. Having more complete answers will allow for healthcare providers to improve treatment plans for the patients.

If you would like to get in touch with Baylor Genetics or want to learn more about our comprehensive portfolio of genetic tests, please click here: https://www.baylorgenetics.com/contact/

Scientific contributions from Arpita Neogi, CGC”

References

1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6485936/
2. https://medlineplus.gov/genetics/condition/huntingtons-disease/
3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6485936/
4. Chau, M. et al. (2023, November 1-5). Not just one: the utility of whole genome sequencing for making a dual molecular diagnosis [Conference presentation abstract]. American Society of Human Genetics Annual Meeting, Washington, DC, United States. https://www.ashg.org/wp-content/uploads/2023/10/ASHG2023-PosterAbstracts.pdf
5. Trost B, Engchuan W, Nguyen CM, Thiruvahindrapuram B, Dolzhenko E, Backstrom I, Mirceta M, Mojarad BA, Yin Y, Dov A, Chandrakumar I, Prasolava T, Shum N, Hamdan O, Pellecchia G, Howe JL, Whitney J, Klee EW, Baheti S, Amaral DG, Anagnostou E, Elsabbagh M, Fernandez BA, Hoang N, Lewis MES, Liu X, Sjaarda C, Smith IM, Szatmari P, Zwaigenbaum L, Glazer D, Hartley D, Stewart AK, Eberle MA, Sato N, Pearson CE, Scherer SW, Yuen RKC. Genome-wide detection of tandem DNA repeats that are expanded in autism. Nature. 2020 Oct;586(7827):80-86. doi: 10.1038/s41586-020-2579-z. Epub 2020 Jul 27. PMID: 32717741; PMCID: PMC9348607.
6. Depienne C, Mandel JL. 30 years of repeat expansion disorders: What have we learned and what are the remaining challenges? Am J Hum Genet. 2021 May 6;108(5):764-785. doi: 10.1016/j.ajhg.2021.03.011. Epub 2021 Apr 2. PMID: 33811808; PMCID: PMC8205997.