Diagnostic Genomics and Clinical Bioinformatics

Haworth, Andrea; Savage, Helen; Lench, Nicholas

doi:10.1016/b978-0-12-420196-5.00004-6

Cited by 5 publications

(4 citation statements)

References 57 publications

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“…There are other ways to establish an etiological diagnosis, however. Three commonly used testing strategies (custom targeted next-generation sequencing panel-based testing, whole exome sequencing and whole genome sequencing) all have their own advantages and disadvantages, which we summarized in Table 3 [26][27][28][29][30][31]. Partly based on these evolutions, we recommend re-evaluating patients with unidentified hearing loss on a regular basis, in addition to the more frequent audiological follow-up.…”

Section: Discussionmentioning

confidence: 99%

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Negative Molecular Diagnostics in Non-Syndromic Hearing Loss: What Next?

Clabout

Maes

Acke

et al. 2022

Genes

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Congenital hearing loss has an impact on almost every facet of life. In more than 50% of cases, a genetic cause can be identified. Currently, extensive genetic testing is available, although the etiology of some patients with obvious familial hearing loss remains unknown. We selected a cohort of mutation-negative patients to optimize the diagnostic yield for genetic hearing impairment. In this retrospective study, 21 patients (17 families) with negative molecular diagnostics for non-syndromic hearing loss (gene panel analysis) were included based on a positive family history with a similar type of hearing loss. Additional genetic testing was performed using a whole exome sequencing panel (WESHL panel v2.0) in four families with the strongest likelihood of genetic hearing impairment. In this cohort (n = 21), the severity of hearing loss was most commonly moderate (52%). Additional genetic testing revealed pathogenic copy number variants in the STRC gene in two families. In summary, regular re-evaluation of hearing loss patients with presumably genetic etiology after negative molecular diagnostics is recommended, as we might miss newly discovered deafness genes. The switch from gene panel analysis to whole exome sequencing or whole genome sequencing for the testing of congenital hearing loss seems promising.

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Section: Discussionmentioning

confidence: 99%

“…The technique is very flexible because genes can easily be added to and removed from the panel when new genetic knowledge becomes available. Even a retrospective analysis of novel deafness genes is possible without new blood sampling, again stressing the importance of the regular re-evaluation of patients [26,28,29,32].…”

Section: Discussionmentioning

confidence: 99%

Negative Molecular Diagnostics in Non-Syndromic Hearing Loss: What Next?

Clabout

Maes

Acke

et al. 2022

Genes

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“…Genomic DNA is fragmented, assembled into a sequencing library, and then sequenced in a single run. By omitting the sequence capture step required in WES and targeted panel sequencing, a selection bias is avoided, enabling a more uniform coverage across sequences [Haworth et al, 2016]. Apart from its ability to identify additional types of mutations that are not typically detected by other approaches (e.g., large structural rearrangements, balanced translocations, and mosaicism), WGS can also detect sequence variants in the noncoding genome that may influence gene expression (e.g., in regulatory elements within promoters, introns, or enhancers) [Délot and Vilain, 2021].…”

Section: Whole Genome Sequencingmentioning

confidence: 99%

Targeting the Non-Coding Genome for the Diagnosis of Disorders of Sex Development

Atlas

Sreenivasan

Sinclair

2021

Sex Dev

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Disorders of sex development (DSD) are a complex group of conditions with highly variable clinical phenotypes, most often caused by failure of gonadal development. DSD are estimated to occur in around 1.7% of all live births. Whilst the understanding of genes involved in gonad development has increased exponentially, approximately 50% of patients with a DSD remain without a genetic diagnosis, possibly implicating non-coding genomic regions instead. Here, we review how variants in the non-coding genome of DSD patients can be identified using techniques such as array comparative genomic hybridization (CGH) to detect copy number variants (CNVs), and more recently, whole genome sequencing (WGS). Once a CNV in a patient’s non-coding genome is identified, putative regulatory elements such as enhancers need to be determined within these vast genomic regions. We will review the available online tools and databases that can be used to refine regions with potential enhancer activity based on chromosomal accessibility, histone modifications, transcription factor binding site analysis, chromatin conformation, and disease association. We will also review the current in vitro and in vivo techniques available to demonstrate the functionality of the identified enhancers. The review concludes with a clinical update on the enhancers linked to DSD.

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“…Whole genome sequencing (WGS) is a comprehensive genetic diagnostic test with broad sensitivity for most known single locus (Mendelian) disorders (4)(5)(6). WGS has a greater diagnostic yield compared to targeted gene panels and it can detect diagnostic results beyond the scope of whole exome sequencing, including intronic and extra-genic variants, and exonic single nucleotide variants (SNVs) missed due to poor sequencing read depth with exome capture (7,8).…”

Section: Introductionmentioning

confidence: 99%

Multi-center implementation of rapid whole genome sequencing provides additional evidence of its utility in the pediatric inpatient setting

Thompson,

Larson,

Salz

et al. 2024

Front. Pediatr.

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ObjectiveMulti-center implementation of rapid whole genome sequencing with assessment of the clinical utility of rapid whole genome sequencing (rWGS), including positive, negative and uncertain results, in admitted infants with a suspected genetic disease.Study designrWGS tests were ordered at eight hospitals between November 2017 and April 2020. Investigators completed a survey of demographic data, Human Phenotype Ontology (HPO) terms, test results and impacts of results on clinical care.ResultsA total of 188 patients, on general hospital floors and intensive care unit (ICU) settings, underwent rWGS testing. Racial and ethnic characteristics of the tested infants were broadly representative of births in the country at large. 35% of infants received a diagnostic result in a median of 6 days. The most common HPO terms for tested infants indicated an abnormality of the nervous system, followed by the cardiovascular system, the digestive system, the respiratory system and the head and neck. Providers indicated a major change in clinical management because of rWGS for 32% of infants tested overall and 70% of those with a diagnostic result. Also, 7% of infants with a negative rWGS result and 23% with a variant of unknown significance (VUS) had a major change in management due to testing.ConclusionsOur study demonstrates that the implementation of rWGS is feasible across diverse institutions, and provides additional evidence to support the clinical utility of rWGS in a demographically representative sample of admitted infants and includes assessment of the clinical impact of uncertain rWGS results in addition to both positive and negative results.

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Diagnostic Genomics and Clinical Bioinformatics

Cited by 5 publications

References 57 publications

Negative Molecular Diagnostics in Non-Syndromic Hearing Loss: What Next?

Negative Molecular Diagnostics in Non-Syndromic Hearing Loss: What Next?

Targeting the Non-Coding Genome for the Diagnosis of Disorders of Sex Development

Multi-center implementation of rapid whole genome sequencing provides additional evidence of its utility in the pediatric inpatient setting

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