Increasing phenotypic annotation improves the diagnostic rate of exome sequencing in a rare neuromuscular disorder

Thompson, Rachel; Papakonstantinou, Anastasios; Beltrán, Sergi; Töpf, Ana; Estephan, Eduardo de Paula; Polavarapu, Kiran; Hoen, Peter A C ‘t; Missier, Paolo; Lochmüller, Hanns

doi:10.1002/humu.23792

Cited by 22 publications

(14 citation statements)

References 23 publications

(28 reference statements)

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“…12,33,34 In variant prioritizing systems, the score of the top-ranked variant increases when patient symptoms more precisely match those caused by the responsible gene, and when the number of HPO terms of a patient increases. 35 The present study found no significant differences in the average numbers of HPO terms and organ types between patients in whom causative variants have and have not been identified. This finding was probably related to the wide range of phenotypes among our patients.…”

Section: Updated Information On Variants In Genome Databases Can Resucontrasting

confidence: 64%

Diagnostic yield and clinical utility of whole exome sequencing using an automated variant prioritization system, EVIDENCE

Seo¹,

Kim

Choi

et al. 2020

Clinical Genetics

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EVIDENCE, an automated variant prioritization system, has been developed to facilitate whole exome sequencing analyses. This study investigated the diagnostic yield of EVIDENCE in patients with suspected genetic disorders. DNA from 330 probands (age range, 0-68 years) with suspected genetic disorders were subjected to whole exome sequencing. Candidate variants were identified by EVIDENCE and confirmed by testing family members and/or clinical reassessments. EVIDENCE reported a total 228 variants in 200 (60.6%) of the 330 probands. The average number of organs involved per patient was 4.5 ± 5.0. After clinical reassessment and/or family member testing, 167 variants were identified in 141 probands (42.7%), including 105 novel variants. These variants were confirmed as being responsible for 121 genetic disorders. A total of 103 (61.7%) of the 167 variants in 95 patients were classified as pathogenic or probably to be pathogenic before, and 161 (96.4%) variants in 137 patients (41.5%) after, clinical assessment and/or family member testing. Factor associated with a variant being regarded as causative includes similar symptom Go Hun Seo, Taeho Kim, and In Hee Choi contributed equally to this work.

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Section: Updated Information On Variants In Genome Databases Can Resucontrasting

confidence: 64%

Diagnostic yield and clinical utility of whole exome sequencing using an automated variant prioritization system, EVIDENCE

Seo¹,

Kim

Choi

et al. 2020

Clinical Genetics

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“…[ 25 ]). This result is aligned with previous studies in the RD-Connect GPAP on a cohort of patients with rare neuromuscular disorders reporting the importance of deep and accurate phenotyping for variant prioritisation [ 26 ]. For cases remaining undiagnosed, it might be useful to keep updating the patient phenotypic descriptions with new observations, as this might help identify additional candidate pathogenic variants for the disease and increase specificity of the filtering step, thus lowering the time necessary for variant re-evaluation.…”

Section: Discussionsupporting

confidence: 89%

Solving patients with rare diseases through programmatic reanalysis of genome-phenome data

Matalonga

Hernández-Ferrer²,

Cuesta³

et al. 2021

Eur J Hum Genet

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Reanalysis of inconclusive exome/genome sequencing data increases the diagnosis yield of patients with rare diseases. However, the cost and efforts required for reanalysis prevent its routine implementation in research and clinical environments. The Solve-RD project aims to reveal the molecular causes underlying undiagnosed rare diseases. One of the goals is to implement innovative approaches to reanalyse the exomes and genomes from thousands of well-studied undiagnosed cases. The raw genomic data is submitted to Solve-RD through the RD-Connect Genome-Phenome Analysis Platform (GPAP) together with standardised phenotypic and pedigree data. We have developed a programmatic workflow to reanalyse genome-phenome data. It uses the RD-Connect GPAP’s Application Programming Interface (API) and relies on the big-data technologies upon which the system is built. We have applied the workflow to prioritise rare known pathogenic variants from 4411 undiagnosed cases. The queries returned an average of 1.45 variants per case, which first were evaluated in bulk by a panel of disease experts and afterwards specifically by the submitter of each case. A total of 120 index cases (21.2% of prioritised cases, 2.7% of all exome/genome-negative samples) have already been solved, with others being under investigation. The implementation of solutions as the one described here provide the technical framework to enable periodic case-level data re-evaluation in clinical settings, as recommended by the American College of Medical Genetics.

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“…GeneMatcher (42). Due to costs of manual reanalysis an automated reanalysis of VUS and LP variants incorporating genomic, phenotypic, and pedigree data could ideally prioritize the variants in established PID genes for clinicians to review, in line with what has been implemented for other disease groups (43)(44)(45)(46). Currently, new methods are being developed and implemented to improve automation of genetic reanalysis (8,10,47).…”

Section: Discussionmentioning

confidence: 99%

Added Value of Reanalysis of Whole Exome- and Whole Genome Sequencing Data From Patients Suspected of Primary Immune Deficiency Using an Extended Gene Panel and Structural Variation Calling

et al. 2022

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BackgroundKnowledge of the genetic variation underlying Primary Immune Deficiency (PID) is increasing. Reanalysis of genome-wide sequencing data from undiagnosed patients with suspected PID may improve the diagnostic rate.MethodsWe included patients monitored at the Department of Infectious Diseases or the Child and Adolescent Department, Rigshospitalet, Denmark, for a suspected PID, who had been analysed previously using a targeted PID gene panel (457 PID-related genes) on whole exome- (WES) or whole genome sequencing (WGS) data. A literature review was performed to extend the PID gene panel used for reanalysis of single nucleotide variation (SNV) and small indels. Structural variant (SV) calling was added on WGS data.ResultsGenetic data from 94 patients (86 adults) including 36 WES and 58 WGS was reanalysed a median of 23 months after the initial analysis. The extended gene panel included 208 additional PID-related genes. Genetic reanalysis led to a small increase in the proportion of patients with new suspicious PID related variants of uncertain significance (VUS). The proportion of patients with a causal genetic diagnosis was constant. In total, five patients (5%, including three WES and two WGS) had a new suspicious PID VUS identified due to reanalysis. Among these, two patients had a variant added due to the expansion of the PID gene panel, and three patients had a variant reclassified to a VUS in a gene included in the initial PID gene panel. The total proportion of patients with PID related VUS, likely pathogenic, and pathogenic variants increased from 43 (46%) to 47 (50%), as one patient had a VUS detected in both initial- and reanalysis. In addition, we detected new suspicious SNVs and SVs of uncertain significance in PID candidate genes with unknown inheritance and/or as heterozygous variants in genes with autosomal recessive inheritance in 8 patients.ConclusionThese data indicate a possible diagnostic gain of reassessing WES/WGS data from patients with suspected PID. Reasons for the possible gain included improved knowledge of genotype-phenotype correlation, expanding the gene panel, and adding SV analyses. Future studies of genotype-phenotype correlations may provide additional knowledge on the impact of the new suspicious VUSs.

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Increasing phenotypic annotation improves the diagnostic rate of exome sequencing in a rare neuromuscular disorder

Cited by 22 publications

References 23 publications

Diagnostic yield and clinical utility of whole exome sequencing using an automated variant prioritization system, EVIDENCE

Diagnostic yield and clinical utility of whole exome sequencing using an automated variant prioritization system, EVIDENCE

Solving patients with rare diseases through programmatic reanalysis of genome-phenome data

Added Value of Reanalysis of Whole Exome- and Whole Genome Sequencing Data From Patients Suspected of Primary Immune Deficiency Using an Extended Gene Panel and Structural Variation Calling

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