ReviewAmerican journal of human genetics2023
Beyond the exome: What's next in diagnostic testing for Mendelian conditions.
Review in American journal of human genetics, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 89 papers, 1 of them a synthesis that pooled it.
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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.
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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
89 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Diagnostic yield of long-read sequencing for rare diseases: a systematic review.Frontiers in genetics · 2026Pooled it
- Lessons from clinical and genetic characterization of intellectual disability.Developmental medicine and child neurology · 2026Article
- Caring for Rare Genetic Disease: A Vision for the Future.Journal of genetic counseling · 2026Article
- Optical genome mapping improves structural variant detection and characterization in syndromic and neurogenetic disorders.Human genetics · 2026Article
- Arriving at a diagnosis: Effective strategies used by the Undiagnosed Diseases Network.Genetics in medicine : official journal of the American College of Medical Genetics · 2026Article
- Cost-efficient long-read trio-barcoded adaptive sequencing improves rare disease diagnosis.Nature communications · 2026Article
- Genetic influences on haematopoiesis.Nature reviews. Genetics · 2026Review
- Functional Characterization of the VWF p.Cys2163Tyr Variant Reveals Impaired Secretion and Intracellular Processing.Biomolecules · 2026Article
- Sequential bilateral common carotid artery occlusion in protein C deficiency and patent foramen ovale: illustrative case.Journal of neurosurgery. Case lessons · 2026Article
- needLR: long-read structural variant annotation with population-scale frequency estimation.Bioinformatics (Oxford, England) · 2026Article
- Collaborative Genomics for Dystonia in Central and Eastern Europe: Successes Achieved, New Frontiers Ahead.Movement disorders : official journal of the Movement Disorder Society · 2026Article
- Transcription-based identification of uncharacterized genes in the human immune response.European journal of human genetics : EJHG · 2026Article
- Implementation of a medical genomics program for rare diseases in Uruguay.Orphanet journal of rare diseases · 2026Article
- Population-scale detection of methylation outliers from long-read genome sequencing.medRxiv : the preprint server for health sciences · 2026Article
- Low-level mosaic variants causing the pancreatic disease congenital hyperinsulinism can be detected from blood DNA.EBioMedicine · 2026Article
- Interpretable fine-tuned large language models facilitate making genetic test decisions for rare diseases.NPJ digital medicine · 2026Article
- Bridging the gap: an emerging link between tubulinopathies and ciliopathies.NPJ genomic medicine · 2026Review
- Pathogenicity prediction for noncanonical splice-altering variants based on multimodal feature fusion.Briefings in bioinformatics · 2026Article
- Review
- Identification of de novo variants from parent-proband duos via long-read sequencing.American journal of human genetics · 2026Article
29 more citing papers are in PubMed but not listed here.
Corrections and comments
- Update of
Authors and funding
23 authors.
Funding
Abstract
Despite advances in clinical genetic testing, including the introduction of exome sequencing (ES), more than 50% of individuals with a suspected Mendelian condition lack a precise molecular diagnosis. Clinical evaluation is increasingly undertaken by specialists outside of clinical genetics, often occurring in a tiered fashion and typically ending after ES. The current diagnostic rate reflects multiple factors, including technical limitations, incomplete understanding of variant pathogenicity, missing genotype-phenotype associations, complex gene-environment interactions, and reporting differences between clinical labs. Maintaining a clear understanding of the rapidly evolving landscape of diagnostic tests beyond ES, and their limitations, presents a challenge for non-genetics professionals. Newer tests, such as short-read genome or RNA sequencing, can be challenging to order, and emerging technologies, such as optical genome mapping and long-read DNA sequencing, are not available clinically. Furthermore, there is no clear guidance on the next best steps after inconclusive evaluation. Here, we review why a clinical genetic evaluation may be negative, discuss questions to be asked in this setting, and provide a framework for further investigation, including the advantages and disadvantages of new approaches that are nascent in the clinical sphere. We present a guide for the next best steps after inconclusive molecular testing based upon phenotype and prior evaluation, including when to consider referral to research consortia focused on elucidating the underlying cause of rare unsolved genetic disorders.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.