ArticleBMC medical genomics2021
Unraveling synonymous and deep intronic variants causing aberrant splicing in two genetically undiagnosed epilepsy families.
Article in BMC medical genomics, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers, 1 of them a synthesis that pooled it.
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Who cites it
9 citing papers in PubMed, 1 synthesis or guideline pooled it, 14 citations in OpenAlex.
- Well-differentiated G1 and G2 pancreatic neuroendocrine tumors: a meta-analysis of published expanded DNA sequencing data.Frontiers in endocrinology · 2024Pooled it
- Pathogenic cryptic variants detectable through exome data reanalysis significantly increase the diagnostic yield in Joubert syndrome.European journal of human genetics : EJHG · 2025Article
- Genetic analysis of 37 cases with primary periodic paralysis in Chinese patients.Orphanet journal of rare diseases · 2024Article
- "Fifth-day fits" revisited: A literature review of benign idiopathic neonatal seizures and comparison with KCNQ2- and KCNQ3-associated benign familial epilepsy syndromes.Annals of the Child Neurology Society · 2023Review
- Functional investigation of SCN1A deep-intronic variants activating poison exons inclusion.Human genetics · 2023Article
- Intronic position +9 and -9 are potentially splicing sites boundary from intronic variants analysis of whole exome sequencing data.BMC medical genomics · 2023Article
- SpliceAI-visual: a free online tool to improve SpliceAI splicing variant interpretation.Human genomics · 2023Review
- The Power of Clinical Diagnosis for Deciphering Complex Genetic Mechanisms in Rare Diseases.Genes · 2023Review
- IRIDA Phenotype inGenes · 2022Article
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundVariants identified through parent-child trio-WES yield up to 28-55% positive diagnostic rate across a variety of Mendelian disorders, there remain numerous patients who do not receive a genetic diagnosis. Studies showed that some aberrant splicing variants, which are either not readily detectable by WES or could be miss-interpreted by regular detecting pipelines, are highly relevant to human diseases.
methodsWe retrospectively investigated the negative molecular diagnostics through trio-WES for 15 genetically undiagnosed patients whose clinical manifestations were highly suspected to be genetic disorders with well-established genotype-phenotype relationships. We scrutinized the synonymous variants from WES data and Sanger sequenced the suspected intronic region for deep intronic variants. The functional consequences of variants were analyzed by in vitro minigene experiments.
resultsHere, we report two abnormal splicing events, one of which caused exon truncating due to the activation of cryptic splicing site by a synonymous variant; the other caused partial intron retention due to the generation of splicing sites by a deep intronic variant.
conclusionsWe suggest that, despite initial negative genetic test results in clinically highly suspected genetic diseases, the combination of predictive bioinformatics and functional analysis should be considered to unveil the genetic etiology of undiagnosed rare diseases.
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