ReviewJournal of inherited metabolic disease2022
How to proceed after "negative" exome: A review on genetic diagnostics, limitations, challenges, and emerging new multiomics techniques.
Review in Journal of inherited metabolic disease, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers, 3 of them syntheses that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
36 citing papers in PubMed, 3 syntheses or guidelines pooled it.
- Portuguese Society of Ophthalmology and Portuguese Society of Human Genetics Joint Clinical Practice Guidelines for Genetic Testing in Inherited Retinal Dystrophies.Clinical genetics · 2025Guideline
- A Comprehensive Approach to the Diagnosis of Leigh Syndrome Spectrum.Diagnostics (Basel, Switzerland) · 2024Guideline
- Inherited metabolic disorders in adults: systematic review on patient characteristics and diagnostic yield of broad sequencing techniques (exome and genome sequencing).Frontiers in neurology · 2023Pooled it
- Genetic diagnosis of sibling cases initiated by identification of outlier gene expression using transcriptome analysis of urine-derived cells.Journal of human genetics · 2026Article
- Comparison of Whole Exome Sequencing Commercial Kits Performance Across Diverse Tissue Sources.International journal of molecular sciences · 2026Article
- The genotypic and phenotypic landscape of PDHA1-related pyruvate dehydrogenase complex deficiency.Brain : a journal of neurology · 2026Article
- Implementation of a medical genomics program for rare diseases in Uruguay.Orphanet journal of rare diseases · 2026Article
- NovelWorld journal of clinical pediatrics · 2026Article
- Radiogenomics of congenital brain malformations: Linking embryology, genetics, and imaging.Neuroradiology · 2026Review
- Heterogeneity of monogenic epilepsy in loci, phenotypes, and treatment approaches.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2026Review
- Biochemical Testing Promotes Interpretation of Variants of Uncertain Significance in Prenatal Genetic Disease Testing in Four Organic Acidurias.Clinical genetics · 2026Review
- Decoding rare inherited metabolic disorders: advancing precision in screening and diagnosis.Orphanet journal of rare diseases · 2026Review
- Phenylalanine-tyrosine-catecholamine axis disorders: pathways, molecular diagnosis, therapeutics, and emerging translational monitoring technologies.Frontiers in molecular biosciences · 2026Review
- Untargeted Metabolomics for Diagnosis, Monitoring, and Understanding the Pathophysiology of Inherited Metabolic Disorders.Journal of inherited metabolic disease · 2026Review
- The evolving genetic landscape of neuromuscular fetal akinesias.Journal of neuromuscular diseases · 2025Review
- The landscape of pediatric genetic white matter disorders at a tertiary referral hospital in Upper Egypt and the report of 31 novel variants.Italian journal of pediatrics · 2025Article
- Heterozygous deletion of 10q24.31-q24.33- a new syndrome associated with multiple congenital anomalies: case report and literature review.Neurological research and practice · 2025Article
- Genomic reanalysis of a pan-European rare-disease resource yields new diagnoses.Nature medicine · 2025Article
- Atypical free sialic acid storage disorder associated with tissue specific mosaicism of SLC17A5.Molecular genetics and metabolism · 2025Article
- Whole Exome Sequencing Facilitates Early Diagnosis of Lesch-Nyhan Syndrome: A Case Series.Diagnostics (Basel, Switzerland) · 2024Article
Corrections and comments
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Authors and funding
21 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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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