ArticleGenetics in medicine : official journal of the American College of Medical Genetics2018
Looking beyond the exome: a phenotype-first approach to molecular diagnostic resolution in rare and undiagnosed diseases.
Article in Genetics in medicine : official journal of the American College of Medical Genetics, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT02450851 (Clinical and Genetic Evaluation of Patients With Undiagnosed Disorders Through the Undiagnosed Diseases Network), which is not on this map. Cited by 26 papers.
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.
Clinical and Genetic Evaluation of Patients With Undiagnosed Disorders Through the Undiagnosed Diseases Network
Who cites it
26 citing papers in PubMed, 52 citations in OpenAlex.
- A review of multiple diagnostic approaches in the undiagnosed diseases network to identify inherited metabolic diseases.Orphanet journal of rare diseases · 2024Review
- VUS next in rare diseases? Deciphering genetic determinants of biomolecular condensation.Orphanet journal of rare diseases · 2024Review
- The Approach to a Child with Dysmorphic Features: What the Pediatrician Should Know.Children (Basel, Switzerland) · 2024Review
- Beyond the exome: utility of long-read whole genome sequencing in exome-negative autosomal recessive diseases.Genome medicine · 2023Article
- Article
- The diagnostic yield, candidate genes, and pitfalls for a genetic study of intellectual disability in 118 middle eastern families.Scientific reports · 2022Article
- Review
- What Has the Undiagnosed Diseases Network Taught Us About the Clinical Applications of Genomic Testing?Annual review of medicine · 2022Review
- Deep clinicopathological phenotyping identifies a previously unrecognized pathogenic EMD splice variant.Annals of clinical and translational neurology · 2021Article
- Commonalities across computational workflows for uncovering explanatory variants in undiagnosed cases.Genetics in medicine : official journal of the American College of Medical Genetics · 2021Article
- Genetic testing for unexplained perinatal disorders.Current opinion in pediatrics · 2021Review
- The History of Gene Hunting in Hereditary Spinocerebellar Degeneration: Lessons From the Past and Future Perspectives.Frontiers in genetics · 2021Review
- International consensus recommendations on the diagnostic work-up for malformations of cortical development.Nature reviews. Neurology · 2020Review
- Missed diagnoses: Clinically relevant lessons learned through medical mysteries solved by the Undiagnosed Diseases Network.Molecular genetics & genomic medicine · 2020Article
- Genetic testing for kidney disease of unknown etiology.Kidney international · 2020Review
- Regulatory genome variants in human susceptibility to infection.Human genetics · 2020Review
- Genotype-phenotype analysis of 523 patients by genetics evaluation and clinical exome sequencing.Pediatric research · 2020Article
- Fundoscopy-directed genetic testing to re-evaluate negative whole exome sequencing results.Orphanet journal of rare diseases · 2020Article
- Genetic testing offer for inherited neuromuscular diseases within the EURO-NMD reference network: A European survey study.PloS one · 2020Article
- Ranking of non-coding pathogenic variants and putative essential regions of the human genome.Nature communications · 2019Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
28 authors at 5 institutions in 1 country.
Funding
Abstract
PurposeTo describe examples of missed pathogenic variants on whole-exome sequencing (WES) and the importance of deep phenotyping for further diagnostic testing.MethodsGuided by phenotypic information, three children with negative WES underwent targeted single-gene testing.ResultsIndividual 1 had a clinical diagnosis consistent with infantile systemic hyalinosis, although WES and a next-generation sequencing (NGS)-based ANTXR2 test were negative. Sanger sequencing of ANTXR2 revealed a homozygous single base pair insertion, previously missed by the WES variant caller software. Individual 2 had neurodevelopmental regression and cerebellar atrophy, with no diagnosis on WES. New clinical findings prompted Sanger sequencing and copy number testing of PLA2G6. A novel homozygous deletion of the noncoding exon 1 (not included in the WES capture kit) was detected, with extension into the promoter, confirming the clinical suspicion of infantile neuroaxonal dystrophy. Individual 3 had progressive ataxia, spasticity, and magnetic resonance image changes of vanishing white matter leukoencephalopathy. An NGS leukodystrophy gene panel and WES showed a heterozygous pathogenic variant in EIF2B5; no deletions/duplications were detected. Sanger sequencing of EIF2B5 showed a frameshift indel, probably missed owing to failure of alignment.ConclusionThese cases illustrate potential pitfalls of WES/NGS testing and the importance of phenotype-guided molecular testing in yielding diagnoses.
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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.