Tandem repeats represent one of the most abundant class of variations in human genomes, which are polymorphic by nature and become highly unstable in a length-dependent manner. The expansion of repeat length across generations is a well-established process that results in human disorders mainly affecting the central nervous system. At least 50 disorders associated with expansion loci have been described to date, with half recognized only in the last ten years, as prior methodological difficulties limited their identification. These limitations still apply to the current widely used molecular diagnostic methods (exome or gene panels) and thus result in missed diagnosis detrimental to affected individuals and their families, especially for disorders that are very rare and/or clinically not recognizable. Most of these disorders have been identified through family-driven approaches and many others likely remain to be identified. The recent development of long-read technologies provides a unique opportunity to systematically investigate the contribution of tandem repeats and repeat expansions to the genetic architecture of human disorders. In this review, we summarize the current and most recent knowledge about the genetics of repeat expansion disorders and the diversity of their pathophysiological mechanisms and outline the perspectives of developing personalized treatments in the future.

30 years of repeat expansion disorders: What have we learned and what are the remaining challenges?

Purpose of reviewThis review aims at updating the clinical and genetic aspects of hereditary spastic paraplegias (HSPs) and hereditary cerebellar ataxias (HCAs), focusing on the concept of spastic-ataxia phenotypic spectrum and on newly identified clinical overlaps with other neurological and nonneu

Hereditary ataxias and paraparesias: clinical and genetic update.

Repeat expansion disorders affect about 1 in 3000 individuals and are clinically heterogeneous diseases caused by expansions of short tandem DNA repeats. Genetic testing is often locus-specific, resulting in underdiagnosis of people who have atypical clinical presentations, especially in paediatric patients without a previous positive family history. Whole genome sequencing is increasingly used as a first-line test for other rare genetic disorders, and we aimed to assess its performance in the diagnosis of patients with neurological repeat expansion disorders.We retrospectively assessed the diagnostic accuracy of whole genome sequencing to detect the most common repeat expansion loci associated with neurological outcomes (AR, ATN1, ATXN1, ATXN2, ATXN3, ATXN7, C9orf72, CACNA1A, DMPK, FMR1, FXN, HTT, and TBP) using samples obtained within the National Health Service in England from patients who were suspected of having neurological disorders; previous PCR test results were used as the reference standard. The clinical accuracy of whole genome sequencing to detect repeat expansions was prospectively examined in previously genetically tested and undiagnosed patients recruited in 2013-17 to the 100 000 Genomes Project in the UK, who were suspected of having a genetic neurological disorder (familial or early-onset forms of ataxia, neuropathy, spastic paraplegia, dementia, motor neuron disease, parkinsonian movement disorders, intellectual disability, or neuromuscular disorders). If a repeat expansion call was made using whole genome sequencing, PCR was used to confirm the result.The diagnostic accuracy of whole genome sequencing to detect repeat expansions was evaluated against 793 PCR tests previously performed within the NHS from 404 patients. Whole genome sequencing correctly classified 215 of 221 expanded alleles and 1316 of 1321 non-expanded alleles, showing 97·3% sensitivity (95% CI 94·2-99·0) and 99·6% specificity (99·1-99·9) across the 13 disease-associated loci when compared with PCR test results. In samples from 11 631 patients in the 100 000 Genomes Project, whole genome sequencing identified 81 repeat expansions, which were also tested by PCR: 68 were confirmed as repeat expansions in the full pathogenic range, 11 were non-pathogenic intermediate expansions or premutations, and two were non-expanded repeats (16% false discovery rate).In our study, whole genome sequencing for the detection of repeat expansions showed high sensitivity and specificity, and it led to identification of neurological repeat expansion disorders in previously undiagnosed patients. These findings support implementation of whole genome sequencing in clinical laboratories for diagnosis of patients who have a neurological presentation consistent with a repeat expansion disorder.Medical Research Council, Department of Health and Social Care, National Health Service England, National Institute for Health Research, and Illumina. 

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Whole genome sequencing for the diagnosis of neurological repeat expansion disorders in the UK: a retrospective diagnostic accuracy and prospective clinical validation study

http://www.thelancet.com/article/S1474442221004622/pdf

https://link.springer.com/content/pdf/10.1007/s13311-019-00778-5.pdf

Molecular Targets and Therapeutic Strategies in Spinocerebellar Ataxia Type 7

Progressive cerebellar ataxias are well-known hereditary neurological disorders. Among them, spinocerebellar ataxia type 7 (SCA7) is inherited as an autosomal dominant trait and is ascribed to the expansion of a CAG trinucleotide repeat within the ATXN7 gene. An anticipation phenomenon can occur during paternal transmission and sometimes is responsible for a severe infantile form. The specificity of SCA7 is the retinal involvement with retinitis pigmentosa and cone rod dystrophy. We describe a familial form with two siblings who died of a severe infantile form. Diagnosis was made in their father, who had a recent history of macular atrophy and presented with gait disturbance thereafter. Retrospectively, substantial triplet repeat expansion was confirmed in the two affected infants. These infantile forms are rare and difficult to diagnose in the absence of suggestive family symptoms.

R. Touraine

Papers

Lethal form of spinocerebellar ataxia type 7 with early onset in childhood