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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.
Genet Med 2019GM

Abstract

PURPOSE

Existing 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.

METHODS

High-throughput resequencing of the FECH gene, qualitative analysis of RNA, and quantitative DNA methylation examination were performed on a cohort of 72 subjects.

RESULTS

A 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).

CONCLUSION

This 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.

Authors+Show Affiliations

Dipartimento di Bioscienze, Università degli Studi di Milano, Milan, Italy.Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, UOC Medicina Generale, Milan, Italy.EPIGET-Epidemiology, Epigenetics and Toxicology Lab Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy.Department of Oncology and Hemato-oncology, University of Milan; and Hematology 1, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, UOC Medicina Generale, Milan, Italy.Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, UOC Medicina Generale, Milan, Italy.EPIGET-Epidemiology, Epigenetics and Toxicology Lab Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy.Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, UOC Medicina Generale, Milan, Italy. elena.dipierro@policlinico.mi.it.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31273344

Citation

Chiara, Matteo, et al. "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." Genetics in Medicine : Official Journal of the American College of Medical Genetics, 2019.
Chiara M, Primon I, Tarantini L, et al. 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. Genet Med. 2019.
Chiara, M., Primon, I., Tarantini, L., Agnelli, L., Brancaleoni, V., Granata, F., ... Di Pierro, E. (2019). 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. Genetics in Medicine : Official Journal of the American College of Medical Genetics, doi:10.1038/s41436-019-0584-0.
Chiara M, et al. 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. Genet Med. 2019 Jul 5; PubMed PMID: 31273344.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Chiara,Matteo, AU - Primon,Ilaria, AU - Tarantini,Letizia, AU - Agnelli,Luca, AU - Brancaleoni,Valentina, AU - Granata,Francesca, AU - Bollati,Valentina, AU - Di Pierro,Elena, Y1 - 2019/07/05/ PY - 2019/01/14/received PY - 2019/06/05/accepted PY - 2019/7/6/entrez KW - CpG sites KW - deep intronic pathogenic variant KW - eQTLs KW - erythropoietic protoporphyria KW - pre-mRNA splicing pattern JF - Genetics in medicine : official journal of the American College of Medical Genetics JO - Genet. Med. N2 - PURPOSE: Existing 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. METHODS: High-throughput resequencing of the FECH gene, qualitative analysis of RNA, and quantitative DNA methylation examination were performed on a cohort of 72 subjects. RESULTS: A 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). CONCLUSION: This 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. SN - 1530-0366 UR - https://www.unboundmedicine.com/medline/citation/31273344/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 L2 - http://dx.doi.org/10.1038/s41436-019-0584-0 DB - PRIME DP - Unbound Medicine ER -