A 4.6 Mb Inversion Leading to PCDH15-LINC00844 and BICC1-PCDH15 Fusion Transcripts as a New Pathogenic Mechanism Implicated in Usher Syndrome Type 1
Usher type 1 syndrome is a rare autosomal recessive disorder involving congenital severe-to-profound hearing loss, development of vision impairment in the first decade, and severe balance difficulties. The PCDH15 gene, one of the five genes implicated in this disease, is involved in 8–20% of cases....
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doaj-7b788bb3d7c2403c815d579012188e3e2020-11-25T02:52:40ZengFrontiers Media S.A.Frontiers in Genetics1664-80212020-07-011110.3389/fgene.2020.00623552973A 4.6 Mb Inversion Leading to PCDH15-LINC00844 and BICC1-PCDH15 Fusion Transcripts as a New Pathogenic Mechanism Implicated in Usher Syndrome Type 1Christel Vaché0Jacques Puechberty1Valérie Faugère2Floriane Darmaisin3Alessandro Liquori4David Baux5Catherine Blanchet6Catherine Blanchet7Gema Garcia-Garcia8Isabelle Meunier9Franck Pellestor10Michel Koenig11Anne-Françoise Roux12Laboratoire de Génétique Moléculaire, CHU de Montpellier, Université de Montpellier, Montpellier, FranceService de Génétique Clinique, CHU de Montpellier, Montpellier, FranceLaboratoire de Génétique Moléculaire, CHU de Montpellier, Université de Montpellier, Montpellier, FranceLaboratoire de Génétique Moléculaire, CHU de Montpellier, Université de Montpellier, Montpellier, FranceLaboratoire de Génétique Moléculaire, CHU de Montpellier, Université de Montpellier, Montpellier, FranceLaboratoire de Génétique Moléculaire, CHU de Montpellier, Université de Montpellier, Montpellier, FranceService ORL, CHU de Montpellier, Montpellier, FranceCentre de Référence Maladies Sensorielles Génétiques, CHU de Montpellier, Université de Montpellier, Montpellier, FranceLaboratoire de Génétique Moléculaire, CHU de Montpellier, Université de Montpellier, Montpellier, FranceCentre de Référence Maladies Sensorielles Génétiques, CHU de Montpellier, Université de Montpellier, Montpellier, FranceLaboratoire de Génétique Chromosomique, Plateforme ChromoStem, CHU de Montpellier, Montpellier, FranceLaboratoire de Génétique Moléculaire, CHU de Montpellier, Université de Montpellier, Montpellier, FranceLaboratoire de Génétique Moléculaire, CHU de Montpellier, Université de Montpellier, Montpellier, FranceUsher type 1 syndrome is a rare autosomal recessive disorder involving congenital severe-to-profound hearing loss, development of vision impairment in the first decade, and severe balance difficulties. The PCDH15 gene, one of the five genes implicated in this disease, is involved in 8–20% of cases. In this study, we aimed to identify and characterize the two causal variants in a French patient with typical Usher syndrome clinical features. Massively parallel sequencing-based gene panel and screening for large rearrangements were used, which detected a single multi-exon deletion in the PCDH15 gene. As the second pathogenic event was likely localized in the unscreened regions of the gene, PCDH15 transcripts from cultured nasal cells were analyzed and revealed a loss of junction between exon 13 and exon 14. This aberration could be explained by the identification of two fusion transcripts, PCDH15-LINC00844 and BICC1-PCDH15, originating from a 4.6 Mb inversion. This complex chromosomal rearrangement could not be detected by our diagnostic approach but was instead characterized by long-read sequencing, which offers the possibility of detecting balanced structural variants (SVs). This finding extends our knowledge of the mutational spectrum of the PCDH15 gene with the first ever identification of a large causal paracentric inversion of chromosome 10 and illustrates the utility of screening balanced SVs in an exhaustive molecular diagnostic approach.https://www.frontiersin.org/article/10.3389/fgene.2020.00623/fullUsher syndromePCDH15paracentric inversionfusion transcriptslong-read sequencing |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Christel Vaché Jacques Puechberty Valérie Faugère Floriane Darmaisin Alessandro Liquori David Baux Catherine Blanchet Catherine Blanchet Gema Garcia-Garcia Isabelle Meunier Franck Pellestor Michel Koenig Anne-Françoise Roux |
spellingShingle |
Christel Vaché Jacques Puechberty Valérie Faugère Floriane Darmaisin Alessandro Liquori David Baux Catherine Blanchet Catherine Blanchet Gema Garcia-Garcia Isabelle Meunier Franck Pellestor Michel Koenig Anne-Françoise Roux A 4.6 Mb Inversion Leading to PCDH15-LINC00844 and BICC1-PCDH15 Fusion Transcripts as a New Pathogenic Mechanism Implicated in Usher Syndrome Type 1 Frontiers in Genetics Usher syndrome PCDH15 paracentric inversion fusion transcripts long-read sequencing |
author_facet |
Christel Vaché Jacques Puechberty Valérie Faugère Floriane Darmaisin Alessandro Liquori David Baux Catherine Blanchet Catherine Blanchet Gema Garcia-Garcia Isabelle Meunier Franck Pellestor Michel Koenig Anne-Françoise Roux |
author_sort |
Christel Vaché |
title |
A 4.6 Mb Inversion Leading to PCDH15-LINC00844 and BICC1-PCDH15 Fusion Transcripts as a New Pathogenic Mechanism Implicated in Usher Syndrome Type 1 |
title_short |
A 4.6 Mb Inversion Leading to PCDH15-LINC00844 and BICC1-PCDH15 Fusion Transcripts as a New Pathogenic Mechanism Implicated in Usher Syndrome Type 1 |
title_full |
A 4.6 Mb Inversion Leading to PCDH15-LINC00844 and BICC1-PCDH15 Fusion Transcripts as a New Pathogenic Mechanism Implicated in Usher Syndrome Type 1 |
title_fullStr |
A 4.6 Mb Inversion Leading to PCDH15-LINC00844 and BICC1-PCDH15 Fusion Transcripts as a New Pathogenic Mechanism Implicated in Usher Syndrome Type 1 |
title_full_unstemmed |
A 4.6 Mb Inversion Leading to PCDH15-LINC00844 and BICC1-PCDH15 Fusion Transcripts as a New Pathogenic Mechanism Implicated in Usher Syndrome Type 1 |
title_sort |
4.6 mb inversion leading to pcdh15-linc00844 and bicc1-pcdh15 fusion transcripts as a new pathogenic mechanism implicated in usher syndrome type 1 |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Genetics |
issn |
1664-8021 |
publishDate |
2020-07-01 |
description |
Usher type 1 syndrome is a rare autosomal recessive disorder involving congenital severe-to-profound hearing loss, development of vision impairment in the first decade, and severe balance difficulties. The PCDH15 gene, one of the five genes implicated in this disease, is involved in 8–20% of cases. In this study, we aimed to identify and characterize the two causal variants in a French patient with typical Usher syndrome clinical features. Massively parallel sequencing-based gene panel and screening for large rearrangements were used, which detected a single multi-exon deletion in the PCDH15 gene. As the second pathogenic event was likely localized in the unscreened regions of the gene, PCDH15 transcripts from cultured nasal cells were analyzed and revealed a loss of junction between exon 13 and exon 14. This aberration could be explained by the identification of two fusion transcripts, PCDH15-LINC00844 and BICC1-PCDH15, originating from a 4.6 Mb inversion. This complex chromosomal rearrangement could not be detected by our diagnostic approach but was instead characterized by long-read sequencing, which offers the possibility of detecting balanced structural variants (SVs). This finding extends our knowledge of the mutational spectrum of the PCDH15 gene with the first ever identification of a large causal paracentric inversion of chromosome 10 and illustrates the utility of screening balanced SVs in an exhaustive molecular diagnostic approach. |
topic |
Usher syndrome PCDH15 paracentric inversion fusion transcripts long-read sequencing |
url |
https://www.frontiersin.org/article/10.3389/fgene.2020.00623/full |
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