Clinically Responsive Genomic Analysis Pipelines

Sundercombe, Samantha; Berbic, Marina; Evans, Carey‐Anne; Cliffe, Corrina; Elakis, George; Temple, Suzanna E.L.; Selvanathan, Arthavan; Ewans, Lisa; Quayum, Nila; Nixon, Cheng-Yee; Dias, Kerith-Rae; Lang, Sarah; Richards, Anna; Goh, Shuxiang; Wilson, Meredith; Mowat, David; Sachdev, Rani; Sandaradura, Sarah A.; Walsh, Maie; Farrar, Michelle A.; Walsh, Rebecca; Fletcher, Janice M.; Kirk, Edwin P.; Teunisse, Guus M.; Schofield, Deborah; Buckley, Michael F.; Zhu, Ying; Roscioli, Tony

doi:10.1016/j.jmoldx.2021.04.007

Cited by 10 publications

(10 citation statements)

References 42 publications

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“…Original WES studies were performed at the Kinghorn Centre for Clinical Genomics (KCCG) and the NSW Health Pathology Randwick Genomics Laboratory (RGL), with one family sequenced at Radboud University Medical Centre Nijmegen (RUMC). 41% of the original KCCG and RGL WES cohort had diagnostic findings [ 12 , 13 ]. Following completion of WES analysis, individuals who remained undiagnosed were recruited for WGS, resulting in 38 families with 59 affected individuals and 41 unaffected first-degree relatives.…”

Section: Methodsmentioning

confidence: 99%

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Whole exome and genome sequencing in mendelian disorders: a diagnostic and health economic analysis

et al. 2022

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Whole genome sequencing (WGS) improves Mendelian disorder diagnosis over whole exome sequencing (WES); however, additional diagnostic yields and costs remain undefined. We investigated differences between diagnostic and cost outcomes of WGS and WES in a cohort with suspected Mendelian disorders. WGS was performed in 38 WES-negative families derived from a 64 family Mendelian cohort that previously underwent WES. For new WGS diagnoses, contemporary WES reanalysis determined whether variants were diagnosable by original WES or unique to WGS. Diagnostic rates were estimated for WES and WGS to simulate outcomes if both had been applied to the 64 families. Diagnostic costs were calculated for various genomic testing scenarios. WGS diagnosed 34% (13/38) of WES-negative families. However, contemporary WES reanalysis on average 2 years later would have diagnosed 18% (7/38 families) resulting in a WGS-specific diagnostic yield of 19% (6/31 remaining families). In WES-negative families, the incremental cost per additional diagnosis using WGS following WES reanalysis was AU$36,710 (£19,407;US$23,727) and WGS alone was AU$41,916 (£22,159;US$27,093) compared to WES-reanalysis. When we simulated the use of WGS alone as an initial genomic test, the incremental cost for each additional diagnosis was AU$29,708 (£15,705;US$19,201) whereas contemporary WES followed by WGS was AU$36,710 (£19,407;US$23,727) compared to contemporary WES. Our findings confirm that WGS is the optimal genomic test choice for maximal diagnosis in Mendelian disorders. However, accepting a small reduction in diagnostic yield, WES with subsequent reanalysis confers the lowest costs. Whether WES or WGS is utilised will depend on clinical scenario and local resourcing and availability.

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Section: Methodsmentioning

confidence: 99%

“…Family 12 had WES at RUMC on the SOLiD platform as described previously [ 14 ]. Accredited WES bioinformatics pipelines were utilised including GAIA at RGL [ 13 ], in-house methods at the RUMC, and Seave at KCCG [ 12 ]. CNV analysis was performed using Conifer [ 15 ] or XHMM [ 16 ].…”

Section: Methodsmentioning

confidence: 99%

Whole exome and genome sequencing in mendelian disorders: a diagnostic and health economic analysis

et al. 2022

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“…Library preparation was performed using an Agilent SureSelect XT Low Input Clinical Research Exome x 2 (Agilent CRE v2) kit, with libraries analyzed on an Illumina NovaSeq 6000 instrument. A NATA-approved in-house pipeline (GAIA) was used to annotate, filter and prioritize high-quality variants that differed from the reference sequence [11]. The following parameters where then analyzed in identified candidate variant: mutational class, zygosity/ inheritance patterns, population frequency, allele case frequency data (from disease-specific publications and ClinVar), conservation data, protein/domain structure databases, phenotype databases, pathogenicity predictions, functional/animal model studies, and mutation spectrum of the disease.…”

Section: Methods Massively Parallel Sequencing (Mps) Sanger Sequencingmentioning

confidence: 99%

Neonatal-lethal dilated cardiomyopathy due to a homozygous LMOD2 donor splice-site variant

et al. 2022

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Dilated cardiomyopathy (DCM) is characterized by cardiac enlargement and impaired ventricular contractility leading to heart failure. A single report identified variants in leiomodin-2 (LMOD2) as a cause of neonatally-lethal DCM. Here, we describe two siblings with DCM who died shortly after birth due to heart failure. Exome sequencing identified a homozygous LMOD2 variant in both siblings, (GRCh38)chr7:g.123656237G > A; NM_207163.2:c.273 + 1G > A, ablating the donor 5′ splice-site of intron-1. Pre-mRNA splicing studies and western blot analysis on cDNA derived from proband cardiac tissue, MyoD-transduced proband skin fibroblasts and HEK293 cells transfected with LMOD2 gene constructs established variant-associated absence of canonically spliced LMOD2 mRNA and full-length LMOD2 protein. Immunostaining of proband heart tissue unveiled abnormally short actin-thin filaments. Our data are consistent with LMOD2 c.273 + 1G > A abolishing/reducing LMOD2 transcript expression by: (1) variant-associated perturbation in initiation of transcription due to ablation of the intron-1 donor; and/or (2) degradation of aberrant LMOD2 transcripts (resulting from use of alternative transcription start-sites or cryptic splice-sites) by nonsense-mediated decay. LMOD2 expression is critical for life and the absence of LMOD2 is associated with thin filament shortening and severe cardiac contractile dysfunction. This study describes the first splice-site variant in LMOD2 and confirms the role of LMOD2 variants in DCM.

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“…(Sundercombe et al, 2021), especially given ethnic differences, which we have shown examples of in our dataset of Emirati variants. As we have outlined, CTGA contains variant data along with phenotypic data, a feature many other genomic databases lack.…”

Section: Discussionmentioning

confidence: 72%

“…The clinical significance (CS) of a gene variant is one of the main components of the diagnostic pipeline for genetic disorders (Sundercombe et al, 2021). On CTGA, we report CS according to Clinvar, where available, as well as CTGA CS.…”

Section: Resultsmentioning

confidence: 99%

Spectrum of Genetic Disorders and Gene Variants in the United Arab Emirates National Population: Insights from the CTGA Database

Bizzari

Nair

Hana

et al. 2023

Preprint

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Like many other Arab countries, the United Arab Emirates (UAE) has a relatively high prevalence of genetic disorders. Here we present the first review and analysis of all genetic disorders and gene variants reported in Emirati nationals and hosted on the Catalogue for Transmission Genetics in Arabs (CTGA), an open-access database hosting bibliographic data on human gene variants associated with inherited or heritable phenotypes in Arabs. To date, CTGA hosts 665 distinct genetic conditions that have been described in Emiratis, 621 of which follow a clear Mendelian inheritance. Strikingly, over half of these are extremely rare according to global prevalence rates, predominantly with an autosomal recessive mode of inheritance. This is likely due to the relatively high consanguinity rates within the Emirati population. The 665 conditions include disorders that are unique to the Emirati population, as well as clearly monogenic disorders that have not yet been mapped to a causal genetic locus. We also describe 1,365 gene variants reported in Emiratis, most of which are substitutions and over half are classified as likely pathogenic or pathogenic. Of these, 235 had not been reported on the international databases dbSNP and Clinvar, as of December 2022. Further analysis of this Emirati variant dataset allows a comparison of clinical significance as reported by Clinvar and CTGA, where the latter is derived from the study cited. A total of 306 pathogenic/likely pathogenic variants from CTGA's Emirati dataset, were classified as benign, variants of uncertain significance, or were missing a clinical significance or had not been reported by Clinvar. In conclusion, we present here the spectrum of genetic disorders and gene variants reported in Emiratis. This review emphasizes the importance of ethnic databases such as CTGA in addressing the underrepresentation of Arab variant data in international databases and documenting population-specific discrepancies in variant interpretation, reiterating the value of such repositories for clinicians and researchers, especially when dealing with rare disorders.

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Clinically Responsive Genomic Analysis Pipelines

Cited by 10 publications

References 42 publications

Whole exome and genome sequencing in mendelian disorders: a diagnostic and health economic analysis

Whole exome and genome sequencing in mendelian disorders: a diagnostic and health economic analysis

Neonatal-lethal dilated cardiomyopathy due to a homozygous LMOD2 donor splice-site variant

Spectrum of Genetic Disorders and Gene Variants in the United Arab Emirates National Population: Insights from the CTGA Database

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