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Genetic Basis of Neuromuscular Disorders
Published in Maher Kurdi, Neuromuscular Pathology Made Easy, 2021
WGS is a technique where the complete human genome is sequenced, and mutations are identified whether they are single nucleotide variants, deletions, or duplications. Furthermore, WGS has the potential to identify trinucleotide repeat expansion, the majority of which are located in non-coding regions and therefore missed in WES. The WES technique is a very useful prelude to WGS as it provides a significant opportunity to identify the pathogenic variant with reduced cost, faster turn-around time, and easier interpretation compared to WGS. The starting material for both WGS and WES is genomic DNA typically extracted from mononucleated cells in the patient's peripheral blood. The genomic DNA is fragmented and processed into barcoded “libraries,” which are then sequenced on specialized platforms; the selection of which depends on throughput needs and application (Table 8.1).
Predictive genetic testing
Published in Angus Clarke, Alex Murray, Julian Sampson, Harper's Practical Genetic Counselling, 2019
Gene sequencing techniques have proved particularly valuable in the analysis of dominantly inherited disorders, especially those where the genes involved are small or the mechanism of disease is a trinucleotide repeat expansion, since they are usually able to detect or exclude an abnormality even when this may not be known from a previous family member. It can be assumed that mutation detection is at least potentially feasible for any dominantly inherited disorder where the responsible gene has been identified. Genetic testing within a known family is generally much more satisfactory if the family's mutation has been determined unambiguously in an affected individual. If that is not the case, the feasibility of molecular testing in unaffected family members will depend on the particular family circumstances as well as the range of mutations in the gene, whether there is genetic heterogeneity and, if linked markers rather than mutation analysis are being used, the structure of the particular family pedigree.
Examine the face
Published in Hani TS Benamer, Neurology for MRCP PACES, 2019
Q: How would you confirm the diagnosis? Send for DNA analysis, looking for the trinucleotide repeat expansion (CTG or CCTG).EMG.
Recent and Evolving Therapies in the Management of Endothelial Diseases
Published in Seminars in Ophthalmology, 2023
Shalini Singh, Sunita Chaurasia
In the past couple of decades, there have been rapid advances in understanding trinucleotide repeat expansion disorders, especially in the field of neuromuscular degenerative condition like spinocerebellar ataxia, myotonic dystrophy and Huntington's disease.81 Recently, it has been known that a significant proportion of FECD has trinucleotide repeat disease (TCF4 gene), thus making gene therapies theoretically an option for FECD. Human genome project has led to significant knowledge and techniques for the treatment of both systemic and ophthalmologic diseases. In the recent times, the development of molecular scissors specifically cleaved the diseased targets so that defective genes can be deleted, replaced or repaired in situ. Clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated 9 (Cas9) nucleases are the most interesting innovations in the field of human biomedicine by removing the abnormal DNA segments directly.70 mRNA transcription can be inhibited by designing ssRNA oligonucleotides, which directly attach to the promoter sequences.82
Molecular diagnostics of disorders of sexual development: an Indian survey and systems biology perspective
Published in Systems Biology in Reproductive Medicine, 2019
MR Nagaraja, Satya Prakash Gubbala, C. R. Wilma Delphine Silvia, Ramars Amanchy
Currently, 32 different mutations in AR coding sequences have been documented amongst Indian ethnics (Table 1), of which most were in LBD (14 mutations) and the least in Hinge region (2 mutations). Previous reports have shown that Hinge region mutations like p.A645D (MacLean et al. 2004; Werner et al. 2006) and p.R629W (Deeb 2008) have led to AIS. In contrast to the above, AR defects were scored in cases of ovarian failure (Panda et al. 2011) and congenital adrenal hyperplasia (CAH) (Sharma et al. 2014a), thus expanding the role of AR in 46,XX DSD too. Exon deletion or addition of a premature termination codon of AR has led to varying degree of AIS, while variants of splicing mutations can result in diverse phenotypes and a cause of human infertility diseases (including AIS and polycystic ovary syndrome (Wang F et al. 2015). Trinucleotide repeat expansion (CAG and GGN repeats in exon 1 of AR) has been indicated as a risk for hypospadias (Adamovic and Nordenskjold 2012) but was not observed in the current survey. Hitherto, of 20 AR splice mutations (as per literature survey) accounting for AIS only one novel splicing donor site mutation in XY sex reversed female from southern India has been documented (Vasu et al. 2012).
Macular degeneration as a common cause of visual loss in spinocerebellar ataxia type 1 (SCA1) patients
Published in Ophthalmic Genetics, 2019
Koji M. Nishiguchi, Masashi Aoki, Toru Nakazawa, Toshiaki Abe
Two types of autosomal dominant spinocerebellar degeneration (ADSCD) caused by pathogenic trinucleotide repeat expansion in the defective gene (i.e., spinocerebellar ataxia type 1 (SCA1) and SCA7) are associated with reduced visual acuity and ocular pathology. Visual loss in SCA7 patients is caused by retinal degeneration and macular degeneration (1,2), whereas loss in SCA1 has been initially associated with optic atrophy (3). Recently, macular degeneration has been reported as an alternative cause of visual loss in SCA1 patients (4–6), in addition to retinal degeneration with diffuse retinal involvement (6,7). However, the significance of the macular pathology remains elusive as only a few case reports have been published and other studies have found contradictory results regarding the structural integrity of the macula in SCA1 patients, by optical coherence tomography (OCT) (8,9) Namely, one study found thinning of the macula in patients with SCA1 (9) and the other did not (8). Herein, we report the results of structural and functional assessment of the macula in five unrelated patients with SCA1 with preceding neurological symptoms.