ArticleGenetics in medicine : official journal of the American College of Medical Genetics2020
Targeted resequencing of FECH locus reveals that a novel deep intronic pathogenic variant and eQTLs may cause erythropoietic protoporphyria (EPP) through a methylation-dependent mechanism.
Article in Genetics in medicine : official journal of the American College of Medical Genetics, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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8 citing papers in PubMed, 16 citations in OpenAlex.
- Ferrochelatase Gene Variants Associated with Cholestasis in Adults: A Case Report.Journal of clinical and translational hepatology · 2025Article
- Case report: Xeroderma pigmentosum Group A with erythropoietic protoporphyria in a young Chinese patient.Frontiers in endocrinology · 2024Article
- Splicing defects in rare diseases: transcriptomics and machine learning strategies towards genetic diagnosis.Briefings in bioinformatics · 2023Review
- Genomic analyses of 10,376 individuals in the Westlake BioBank for Chinese (WBBC) pilot project.Nature communications · 2022Article
- Ultraviolet A phototest positivity is associated with higher free erythrocyte protoporphyrin IX concentration and lower transferrin saturation values in erythropoietic protoporphyria.Photodermatology, photoimmunology & photomedicine · 2022Article
- Recognized and Emerging Features of Erythropoietic and X-Linked Protoporphyria.Diagnostics (Basel, Switzerland) · 2022Review
- Microcytosis in Erythropoietic Protoporphyria.Frontiers in physiology · 2022Article
- Laboratory Diagnosis of Porphyria.Diagnostics (Basel, Switzerland) · 2021Review
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
purposeExisting data do not explain the reason why some individuals homozygous for the hypomorphic FECH allele develop erythropoietic protoporphyria (EPP) while the majority are completely asymptomatic. This study aims to identify novel possible genetic variants contributing to this variable phenotype.
methodsHigh-throughput resequencing of the FECH gene, qualitative analysis of RNA, and quantitative DNA methylation examination were performed on a cohort of 72 subjects.
resultsA novel deep intronic variant was found in four homozygous carriers developing a clinically overt disease. We demonstrate that this genetic variant leads to the insertion of a pseudo-exon containing a stop codon in the mature FECH transcript by the abolition of an exonic splicing silencer site and the concurrent institution of a new methylated CpG dinucleotide. Moreover, we show that the hypomorphic FECH allele is linked to a single haplotype of about 20 kb in size that encompasses three noncoding variants that were previously associated with expression quantitative trait loci (eQTLs).
conclusionThis study confirms that intronic variants could explain the variability in the clinical manifestations of EPP. Moreover, it supports the hypothesis that the control of the FECH gene expression can be mediated through a methylation-dependent modulation of the precursor messenger RNA (pre-mRNA) splicing pattern.
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