Question

Why can't Next Generation Sequencing (NGS) detect expansion repeat disorders (trinucleotide repeats) such as Huntington's, and does GC rich sections on exons have anything to do with it?

Answer 1

Answer and Explaination-

Trinucleotide repeat represents repetitive stretches of three base-pair motifs in DNA sequences. For example, the DNA sequence “CAGCAGCAGCAGCAG” contains five CAG repeats. Trinucleotide repeat can be located in coding and non-coding regions of the genome and is a common type of microsatellite repeats. The expansion of microsatellites, especially trinucleotide repeat expansion (TRE), has been implicated in more than 40 neurological disorder.

Polyglutamine diseases-

Several CAG repeat diseases are also known as polyglutamine diseases, where extensive repeats of the CAG codon result in multiple consecutive glutamines in the protein sequence. Currently, there are at least nine polyglutamine diseases, including Huntington’s disease.

Spinocerebellar ataxia-

where the repeat thresholds for pathogenicity vary in these disorders. In addition, trinucleotide expansion may also cause other types of disorders, including fragile X syndrome , Friedreich’s ataxia, myotonic dystrophy, and fragile XE mental retardation. All these genetic diseases caused by excessive expansion of trinucleotide repeats .are collectively referred to as trinucleotide repeat disorders (TRDs).

To better understand the genotype-phenotype correlation of TRDs, it is important to detect repeat sizes accurately on personal genomes. Repeat size is critically associated with the severity of TRDs and the age of onset of TRDs symptoms. Usually, when repeat count is higher than a certain threshold, the higher the repeat count, the more severe the disorder and the earlier the onset of symptoms. The severity of TRDs may also increase from an affected ancestor generation to each successive offspring generation, demonstrating the property of genetic anticipation . Therefore, precise determination of repeat counts of trinucleotide repeats will lead to an improved understanding of TRDs and the molecular mechanisms involved, and is also crucial for diagnosis, risk assessment, and prognosis of TRDs.

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