Genetic diseases are leading causes of childhood mortality. Whole-genome sequencing (WGS) and whole-exome sequencing (WES) are relatively new methods for diagnosing genetic diseases, whereas chromosomal microarray (CMA) is well established. Here we compared the diagnostic utility (rate of causative, pathogenic, or likely pathogenic genotypes in known disease genes) and clinical utility (proportion in whom medical or surgical management was changed by diagnosis) of WGS, WES, and CMA in children with suspected genetic diseases by systematic review of the literature (January 2011–August 2017) and meta-analysis, following MOOSE/PRISMA guidelines. In 37 studies, comprising 20,068 children, diagnostic utility of WGS (0.41, 95% CI 0.34–0.48, I2 = 44%) and WES (0.36, 95% CI 0.33–0.40, I2 = 83%) were qualitatively greater than CMA (0.10, 95% CI 0.08–0.12, I2 = 81%). Among studies published in 2017, the diagnostic utility of WGS was significantly greater than CMA (P < 0.0001, I2 = 13% and I2 = 40%, respectively). Among studies featuring within-cohort comparisons, the diagnostic utility of WES was significantly greater than CMA (P < 0.001, I2 = 36%). The diagnostic utility of WGS and WES were not significantly different. In studies featuring within-cohort comparisons of WGS/WES, the likelihood of diagnosis was significantly greater for trios than singletons (odds ratio 2.04, 95% CI 1.62–2.56, I2 = 12%; P < 0.0001). Diagnostic utility of WGS/WES with hospital-based interpretation (0.42, 95% CI 0.38–0.45, I2 = 48%) was qualitatively higher than that of reference laboratories (0.29, 95% CI 0.27–0.31, I2 = 49%); this difference was significant among studies published in 2017 (P < .0001, I2 = 22% and I2 = 26%, respectively). The clinical utility of WGS (0.27, 95% CI 0.17–0.40, I2 = 54%) and WES (0.17, 95% CI 0.12–0.24, I2 = 76%) were higher than CMA (0.06, 95% CI 0.05–0.07, I2 = 42%); this difference was significant for WGS vs CMA (P < 0.0001). In conclusion, in children with suspected genetic diseases, the diagnostic and clinical utility of WGS/WES were greater than CMA. Subgroups with higher WGS/WES diagnostic utility were trios and those receiving hospital-based interpretation. WGS/WES should be considered a first-line genomic test for children with suspected genetic diseases.

/pdf/meta-analysis-of-the-diagnostic-and-clinical-utility-of-3pyogbt4gv.pdf

Meta-analysis of the diagnostic and clinical utility of genome and exome sequencing and chromosomal microarray in children with suspected genetic diseases

Inherited retinal disease is a common cause of visual impairment and represents a highly heterogeneous group of conditions. Here, we present findings from a cohort of 722 individuals with inherited retinal disease, who have had whole-genome sequencing (n = 605), whole-exome sequencing (n = 72), or both (n = 45) performed, as part of the NIHR-BioResource Rare Diseases research study. We identified pathogenic variants (single-nucleotide variants, indels, or structural variants) for 404/722 (56%) individuals. Whole-genome sequencing gives unprecedented power to detect three categories of pathogenic variants in particular: structural variants, variants in GC-rich regions, which have significantly improved coverage compared to whole-exome sequencing, and variants in non-coding regulatory regions. In addition to previously reported pathogenic regulatory variants, we have identified a previously unreported pathogenic intronic variant in CHM in two males with choroideremia. We have also identified 19 genes not previously known to be associated with inherited retinal disease, which harbor biallelic predicted protein-truncating variants in unsolved cases. Whole-genome sequencing is an increasingly important comprehensive method with which to investigate the genetic causes of inherited retinal disease.

/pdf/comprehensive-rare-variant-analysis-via-whole-genome-df23u5eqgs.pdf

Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease

Inherited retinal degenerations (IRDs) represent a diverse group of progressive, visually debilitating diseases that can lead to blindness in which mutations in genes that are critical to retinal function lead to progressive photoreceptor cell death and associated vision loss. IRDs are genetically heterogeneous, with over 260 disease genes identified to date.1 The development of treatments and cures to modify the rate of disease progression has been limited to date, with some success of neurotrophic factor therapy and gene therapies reported from clinical trials.2–11 The best example of treatment success is gene augmentation therapy for IRD caused by mutations in the RPE65 gene, which recently received US Food and Drug Administration (FDA) approval, which in fact represented the first FDA-approved gene therapy (GT) for any genetically inherited disease.4–9 Recent developments in the IRD field have advanced understanding of the mechanisms responsible for vision loss, creating new opportunities to intervene in the course of disease by developing new therapeutic approaches. In 2013, a Delphi-style gathering of IRD experts led to the identification, by consensus, of top priorities to advance therapeutic efforts for IRDs, including the need for systematic genotyping, improved standardization of visual function testing, development of more rigorous and widespread data collection protocols, and increased data sharing.12 This document summarizes more recent advances in the IRD field and outlines specific knowledge gaps. These knowledge gaps present opportunities for further investigation to enable development of therapies that may slow down or prevent vision loss, or restore vision, in affected patients.

Atrophic age-related macular degeneration (AMD) is included among the target inherited retinal diseases of interest because first, understanding AMD may contribute to understanding of inherited macular diseases, and second, understanding of the genetics and mechanism of inherited macular degenerations may contribute to understanding of AMD.

/pdf/inherited-retinal-degenerations-current-landscape-and-15h6q0y3ee.pdf

Inherited Retinal Degenerations: Current Landscape and Knowledge Gaps.

Genetic disorders are a leading cause of morbidity and mortality in infants in neonatal and pediatric intensive care units (NICU/PICU). While genomic sequencing is useful for genetic disease diagnosis, results are usually reported too late to guide inpatient management. We performed an investigator-initiated, partially blinded, pragmatic, randomized, controlled trial to test the hypothesis that rapid whole-genome sequencing (rWGS) increased the proportion of NICU/PICU infants receiving a genetic diagnosis within 28 days. The participants were families with infants aged <4 months in a regional NICU and PICU, with illnesses of unknown etiology. The intervention was trio rWGS. Enrollment from October 2014 to June 2016, and follow-up until November 2016. Of all, 26 female infants, 37 male infants, and 2 infants of undetermined sex were randomized to receive rWGS plus standard genetic tests (n = 32, cases) or standard genetic tests alone (n = 33, controls). The study was terminated early due to loss of equipoise: 73% (24) controls received genomic sequencing as standard tests, and 15% (five) controls underwent compassionate cross-over to receive rWGS. Nevertheless, intention to treat analysis showed the rate of genetic diagnosis within 28 days of enrollment (the primary end-point) to be higher in cases (31%, 10 of 32) than controls (3%, 1 of 33; difference, 28% [95% CI, 10–46%]; p = 0.003). Among infants enrolled in the first 25 days of life, the rate of neonatal diagnosis was higher in cases (32%, 7 of 22) than controls (0%, 0 of 23; difference, 32% [95% CI, 11–53%];p = 0.004). Median age at diagnosis (25 days [range 14–90] in cases vs. 130 days [range 37–451] in controls) and median time to diagnosis (13 days [range 1–84] in cases, vs. 107 days [range 21–429] in controls) were significantly less in cases than controls (p = 0.04). In conclusion, rWGS increased the proportion of NICU/PICU infants who received timely diagnoses of genetic diseases. Genetic disorders in critically ill infants can be diagnosed in as little as 26 h by rapid whole genome sequencing (rWGS). A study led by Stephen F. Kingsmore at the Rady Children’s Institute for Genomic Medicine in San Diego and Children’s Mercy Hospital in Kansas City compared the time to genetic diagnosis in 65 infants with inherited diseases of unknown cause using rWGS, clinical confirmatory testing and standard genetic tests or standard genetic tests alone. They found that the addition of rWGS including confirmatory testing significantly decreased the time to diagnosis, which in newborns can mean the difference between life and death. Because of the increasing accessibility and decreasing costs of the technology and the critical need for timely and effective intervention in infants with suspected genetic diseases, the authors advocate the use of rWGS as a first-line diagnostic test.

/pdf/the-nsight1-randomized-controlled-trial-rapid-whole-genome-56a3q6b03c.pdf

The NSIGHT1-randomized controlled trial: rapid whole-genome sequencing for accelerated etiologic diagnosis in critically ill infants.

Background Inherited retinal diseases (IRDs) are a clinically and genetically heterogeneous set of disorders, for which diagnostic second-generation sequencing (next-generation sequencing, NGS) services have been developed worldwide. Methods We present the molecular findings of 537 individuals referred to a 105-gene diagnostic NGS test for IRDs. We assess the diagnostic yield, the spectrum of clinical referrals, the variant analysis burden and the genetic heterogeneity of IRD. We retrospectively analyse disease-causing variants, including an assessment of variant frequency in Exome Aggregation Consortium (ExAC). Results Individuals were referred from 10 clinically distinct classifications of IRD. Of the 4542 variants clinically analysed, we have reported 402 mutations as a cause or a potential cause of disease in 62 of the 105 genes surveyed. These variants account or likely account for the clinical diagnosis of IRD in 51% of the 537 referred individuals. 144 potentially disease-causing mutations were identified as novel at the time of clinical analysis, and we further demonstrate the segregation of known disease-causing variants among individuals with IRD. We show that clinically analysed variants indicated as rare in dbSNP and the Exome Variant Server remain rare in ExAC, and that genes discovered as a cause of IRD in the post-NGS era are rare causes of IRD in a population of clinically surveyed individuals. Conclusions Our findings illustrate the continued powerful utility of custom-gene panel diagnostic NGS tests for IRD in the clinic, but suggest clear future avenues for increasing diagnostic yields.

https://jmg.bmj.com/content/jmedgenet/53/11/761.full.pdf

Molecular findings from 537 individuals with inherited retinal disease

https://digital.library.adelaide.edu.au/dspace/bitstream/2440/107068/2/hdl_107068.pdf

Whole Genome Sequencing Increases Molecular Diagnostic Yield Compared with Current Diagnostic Testing for Inherited Retinal Disease

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Whole Genome Sequencing Increases Molecular Diagnostic Yield Compared with Current Diagnostic Testing for Inherited Retinal Disease