Systematic analysis of short tandem repeats in 38,095 exomes provides an additional diagnostic yield

Sanden, Bart van der; Corominas, Jordi; Groot, Michelle de; Pennings, Maartje; Meijer, Rowdy; Verbeek, Nienke E.; Warrenburg, Bart van de; Schouten, Meyke; Yntema, Helger G.; Vissers, Lisenka E L M; Kamsteeg, Erik‐Jan; Gilissen, Christian

doi:10.1038/s41436-021-01174-1

Cited by 32 publications

(20 citation statements)

References 23 publications

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“…WES combined TP PCR would be an innovative diagnostic algorithms for patients with HSPs-like phenotypes of unknown genetic cause. A large-scale assessment of the diagnostic potential of detecting short tandem repeats expansion from WES data showed that by applying ExpansionHunter with optimized manual curation is capable of detecting some dynamic mutation associated with movement disorders, some genes associated with SCAs were included, such as ATXN1, ATXN3, ATXN7 , and NOP56 ( 36 ). This suggests that WES might be a better diagnostic tool in patients clinically suspected of HSPs given the possibility to detect repeat expansion compared to target targeted gene panels in clinics.…”

Section: Discussionmentioning

confidence: 99%

Clinical Features and Genetic Spectrum of Patients With Clinically Suspected Hereditary Progressive Spastic Paraplegia

et al. 2022

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Background and PurposeA variety of hereditary diseases overlap with neurological phenotypes or even share genes with hereditary spastic paraplegia (HSP). The aim of this study was to determine the clinical features and genetic spectrum of patients with clinically suspected HSPs.MethodsA total of 52 patients with clinically suspected HSPs were enrolled in this study. All the patients underwent next-generation sequencing (NGS) and triplet repeat primed PCR to screen for the dynamic mutations typical of spinocerebellar ataxia (SCA). Multiplex ligation-dependent probe amplification (MLPA) was further conducted in patients with no causative genetic mutations detected to examine for large deletions and duplications in genes of SPAST, ATL1, REEP1, PGN, and SPG11. Clinical characteristics and findings of brain MRI were analyzed in patients with definite diagnoses.ResultsThe mean age of the patients studied was 36.90 ± 14.57 years. 75% (39/52) of patients manifested a phenotype of complex form of HSPs. A genetic diagnosis was made in 51.9% (27/52) of patients, of whom 40.3% (21/52) of patients had mutations in HSPs genes (SPG4/SPG6/SPG8/SPG11/SPG15/SPG78/SPG5A) and 11.5% (6/52) of patients had mutations in SCAs genes (SCA3/SCA17/SCA28). SPG4 and SPG11 were the most common cause of pure form of HSPs (5/6, 83.3%) and complex form of HSPs (5/15, 33.3%), respectively. Gait disturbance was the most common initial symptom in both the patients with HSPs (15/21) and in patients with SCAs (5/6). Dysarthria and cerebellar ataxia were detected in 28.5% (6/21) and 23.8% (5/21) of patients with HSPs, respectively, and were the most common symptoms in addition to progressive weakness and spasticity of the lower limbs. Cerebellar atrophy was seen on the brain MRI of patients with SPG5A, SCA3, and SCA28.ConclusionCausative genetic mutations were identified in 51.9% of patients with clinically suspected HSPs by NGS and triplet repeat primed PCR. A final diagnosis of HSPs or SCAs was made in 40.3% and 11.5% of patients, respectively. The clinical manifestations and neuroimaging findings overlapped between patients with HSPs and patients with SCAs. Dynamic mutations should be screened in patients with clinically suspected HSPs, especially in those with phenotypes of complex form of HSPs.

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Section: Discussionmentioning

confidence: 99%

Clinical Features and Genetic Spectrum of Patients With Clinically Suspected Hereditary Progressive Spastic Paraplegia

et al. 2022

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“…Second, as diagnostic data should comply with the FAIR Guiding Principles [39] (for Findable, Accessible, Interoperable, and Reusable), existing data could be reanalyzed. Initiation of such reanalysis can either be by a (time-driven) periodic system, for instance every 1 or 2 years, or by bioinformatic enhancements, such as the implementation of analysis tools [40]. Third, we have learned that there were additional benefits from using state-of-the-art technology.…”

Section: Towards a Future Sustainable Clinical Reanalysis Strategymentioning

confidence: 99%

Reanalysis of exome negative patients with rare disease: a pragmatic workflow for diagnostic applications

et al. 2022

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Background Approximately two third of patients with a rare genetic disease remain undiagnosed after exome sequencing (ES). As part of our post-test counseling procedures, patients without a conclusive diagnosis are advised to recontact their referring clinician to discuss new diagnostic opportunities in due time. We performed a systematic study of genetically undiagnosed patients 5 years after their initial negative ES report to determine the efficiency of diverse reanalysis strategies. Methods We revisited a cohort of 150 pediatric neurology patients originally enrolled at Radboud University Medical Center, of whom 103 initially remained genetically undiagnosed. We monitored uptake of physician-initiated routine clinical and/or genetic re-evaluation (ad hoc re-evaluation) and performed systematic reanalysis, including ES-based resequencing, of all genetically undiagnosed patients (systematic re-evaluation). Results Ad hoc re-evaluation was initiated for 45 of 103 patients and yielded 18 diagnoses (including 1 non-genetic). Subsequent systematic re-evaluation identified another 14 diagnoses, increasing the diagnostic yield in our cohort from 31% (47/150) to 53% (79/150). New genetic diagnoses were established by reclassification of previously identified variants (10%, 3/31), reanalysis with enhanced bioinformatic pipelines (19%, 6/31), improved coverage after resequencing (29%, 9/31), and new disease-gene associations (42%, 13/31). Crucially, our systematic study also showed that 11 of the 14 further conclusive genetic diagnoses were made in patients without a genetic diagnosis that did not recontact their referring clinician. Conclusions We find that upon re-evaluation of undiagnosed patients, both reanalysis of existing ES data as well as resequencing strategies are needed to identify additional genetic diagnoses. Importantly, not all patients are routinely re-evaluated in clinical care, prolonging their diagnostic trajectory, unless systematic reanalysis is facilitated. We have translated our observations into considerations for systematic and ad hoc reanalysis in routine genetic care.

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“…STR variants and mobile elements can also be detected by ES when specific bioinformatic tools are used, which are not yet standard in diagnostic settings. 117,118 STR expansions are often associated with neurologic disease, for example, Fragile X syndrome, Huntington's disease and several hereditary ataxias, and will likely be the underlying genetic pathomechanism in subgroups of unsolved patients (e.g., glutaminase deficiency 119 ). Another suitable new technique is optical genome mapping based on highresolution genome imaging instead of sequencing.…”

Section: Complex Dna Rearrangementsmentioning

confidence: 99%

How to proceed after “negative” exome: A review on genetic diagnostics, limitations, challenges, and emerging new multiomics techniques

Wortmann

Oud

Alders

et al. 2022

J of Inher Metab Disea

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Exome sequencing (ES) in the clinical setting of inborn metabolic diseases (IMDs) has created tremendous improvement in achieving an accurate and timely molecular diagnosis for a greater number of patients, but it still leaves the majority of patients without a diagnosis. In parallel, (personalized) treatment strategies are increasingly available, but this requires the availability of a molecular diagnosis. IMDs comprise an expanding field with the ongoing identification of novel disease genes and the recognition of multiple inheritance patterns, mosaicism, variable penetrance, and expressivity for known disease genes. The analysis of trio ES is preferred over singleton ES as information on the allelic origin (paternal, maternal, “de novo”) reduces the number of variants that require interpretation. All ES data and interpretation strategies should be exploited including CNV and mitochondrial DNA analysis. The constant advancements in available techniques and knowledge necessitate the close exchange of clinicians and molecular geneticists about genotypes and phenotypes, as well as knowledge of the challenges and pitfalls of ES to initiate proper further diagnostic steps. Functional analyses (transcriptomics, proteomics, and metabolomics) can be applied to characterize and validate the impact of identified variants, or to guide the genomic search for a diagnosis in unsolved cases. Future diagnostic techniques (genome sequencing [GS], optical genome mapping, long‐read sequencing, and epigenetic profiling) will further enhance the diagnostic yield. We provide an overview of the challenges and limitations inherent to ES followed by an outline of solutions and a clinical checklist, focused on establishing a diagnosis to eventually achieve (personalized) treatment.

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Systematic analysis of short tandem repeats in 38,095 exomes provides an additional diagnostic yield

Cited by 32 publications

References 23 publications

Clinical Features and Genetic Spectrum of Patients With Clinically Suspected Hereditary Progressive Spastic Paraplegia

Clinical Features and Genetic Spectrum of Patients With Clinically Suspected Hereditary Progressive Spastic Paraplegia

Reanalysis of exome negative patients with rare disease: a pragmatic workflow for diagnostic applications

How to proceed after “negative” exome: A review on genetic diagnostics, limitations, challenges, and emerging new multiomics techniques

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