ArticleNature communications2023
Diagnostic implications of pitfalls in causal variant identification based on 4577 molecularly characterized families.
Article in Nature communications, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed.
- Automated reanalysis of genomic data for rare disease diagnostics at scale.Nature medicine · 2026Article
- Determinants of DNA-sequence-based Diagnostic Yield in the CSER Consortium.medRxiv : the preprint server for health sciences · 2026Article
- A perspective: PLA2G4A as drug target for vascular inflammation in Alzheimer's disease.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Review
- Expanded clinical and genetic characterization of autosomal recessive HMGCR-related muscular dystrophy.Journal of neuromuscular diseases · 2026Article
- Candidate Genes for Non-Syndromic Pediatric Cataracts.Clinical ophthalmology (Auckland, N.Z.) · 2026Review
- Novel biallelic COL25A1 variants broaden the clinical spectrum from congenital cranial dysinnervation disorders to fetal lethal phenotypes.European journal of human genetics : EJHG · 2025Article
- The Cleveland Family Speech and Reading Study: A Review of Long-Term Outcomes Linking Phenotypes and Genotypes for Speech Sound Disorders.Journal of speech, language, and hearing research : JSLHR · 2025Article
- GREGoR: accelerating genomics for rare diseases.Nature · 2025Article
- Treading the Path with Caution: Interpreting the Whole Exome Sequencing Data for Mendelian Disorders.Indian journal of pediatrics · 2025Article
- Adult genomic medicine: lessons from a multisite study of 2700 patients.Genome medicine · 2025Article
- ADAT3 variants disrupt the activity of the ADAT tRNA deaminase complex and impair neuronal migration.Brain : a journal of neurology · 2025Article
- The evolving genetic landscape of neuromuscular fetal akinesias.Journal of neuromuscular diseases · 2025Review
- Co-Occurrence of Variants in 3 Genes in a Patient with Congenital Skeletal Dysplasia and Cardiac Anomalies: Diagnostic Challenge Posed by a Blended Phenotype.Molecular syndromology · 2025Article
- Identification of technically challenging variants: Whole-genome sequencing improves diagnostic yield in patients with high clinical suspicion of rare diseases.HGG advances · 2025Article
- ADAT3-related neurodevelopmental disorder in 24 new patients with a high frequency of the p.Val144Met and a new founder variant.Scientific reports · 2025Article
- Near-complete Middle Eastern genomes refine autozygosity and enhance disease-causing and population-specific variant discovery.Nature genetics · 2025Article
- Genomics of rare diseases in the Greater Middle East.Nature genetics · 2025Review
- Human ABL1 deficiency syndrome (HADS) is a recognizable syndrome distinct from ABL1-related congenital heart defects and skeletal malformations syndrome.Human genetics · 2024Article
- Further delineation of the phenotypic and metabolomic profile of ALDH1L2-related neurodevelopmental disorder.Clinical genetics · 2024Article
- Beyond the exome: utility of long-read whole genome sequencing in exome-negative autosomal recessive diseases.Genome medicine · 2023Article
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Authors and funding
17 authors.
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Abstract
Despite large sequencing and data sharing efforts, previously characterized pathogenic variants only account for a fraction of Mendelian disease patients, which highlights the need for accurate identification and interpretation of novel variants. In a large Mendelian cohort of 4577 molecularly characterized families, numerous scenarios in which variant identification and interpretation can be challenging are encountered. We describe categories of challenges that cover the phenotype (e.g. novel allelic disorders), pedigree structure (e.g. imprinting disorders masquerading as autosomal recessive phenotypes), positional mapping (e.g. double recombination events abrogating candidate autozygous intervals), gene (e.g. novel gene-disease assertion) and variant (e.g. complex compound inheritance). Overall, we estimate a probability of 34.3% for encountering at least one of these challenges. Importantly, our data show that by only addressing non-sequencing-based challenges, around 71% increase in the diagnostic yield can be expected. Indeed, by applying these lessons to a cohort of 314 cases with negative clinical exome or genome reports, we could identify the likely causal variant in 54.5%. Our work highlights the need to have a thorough approach to undiagnosed diseases by considering a wide range of challenges rather than a narrow focus on sequencing technologies. It is hoped that by sharing this experience, the yield of undiagnosed disease programs globally can be improved.
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