Allelic overload and its clinical modifier effect in Bardet-Biedl syndrome

Bardet–Biedl syndrome (BBS) is an autosomal recessive ciliopathy characterized by extensive inter- and intra-familial variability, in which oligogenic interactions have been also reported. Our main goal is to elucidate the role of mutational load in the clinical variability of BBS. A cohort of 99 pa...

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Autores: Perea Romero, Irene, Solarat, Carlos, Blanco Kelly, Fiona, Sánchez Navarro, Iker, Bea-Mascato, Brais, Martin Salazar, Eduardo, Lorda Sánchez, Isabel, Tahsin Swafir, Saoud, Ávila Fernández, Almudena, Martín-Mérida, Inmaculada, Trujillo Tiebas, María José, Carreño, Ester, Jimenez-Rolando, Belen, Garcia-Sandoval, Blanca, Mínguez, Pablo, Cortón, Marta, Valverde, Diana, Ayuso García, María del Carmen Tomasa
Formato: artículo
Fecha de publicación:2022
País:España
Recursos:Universidad Autónoma de Madrid
Repositorio:Biblos-e Archivo. Repositorio Institucional de la UAM
Idioma:inglés
OAI Identifier:oai:repositorio.uam.es:10486/708273
Acesso em linha:http://hdl.handle.net/10486/708273
https://dx.doi.org/10.1038/s41525-022-00311-2
Access Level:acceso abierto
Palavra-chave:Bardet-Biedl syndrome
oligogenic
Medicina
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spelling Allelic overload and its clinical modifier effect in Bardet-Biedl syndromePerea Romero, IreneSolarat, CarlosBlanco Kelly, FionaSánchez Navarro, IkerBea-Mascato, BraisMartin Salazar, EduardoLorda Sánchez, IsabelTahsin Swafir, SaoudÁvila Fernández, AlmudenaMartín-Mérida, InmaculadaTrujillo Tiebas, María JoséCarreño, EsterJimenez-Rolando, BelenGarcia-Sandoval, BlancaMínguez, PabloCortón, MartaValverde, DianaAyuso García, María del Carmen TomasaBardet-Biedl syndromeoligogenicMedicinaBardet–Biedl syndrome (BBS) is an autosomal recessive ciliopathy characterized by extensive inter- and intra-familial variability, in which oligogenic interactions have been also reported. Our main goal is to elucidate the role of mutational load in the clinical variability of BBS. A cohort of 99 patients from 77 different families with biallelic pathogenic variants in a BBS-associated gene was retrospectively recruited. Human Phenotype Ontology terms were used in the annotation of clinical symptoms. The mutational load in 39 BBS-related genes was studied in index cases using different molecular and next-generation sequencing (NGS) approaches. Candidate allele combinations were analysed using the in silico tools ORVAL and DiGePred. After clinical annotation, 76 out of the 99 cases a priori fulfilled established criteria for diagnosis of BBS or BBS-like. BBS1 alleles, found in 42% of families, were the most represented in our cohort. An increased mutational load was excluded in 41% of the index cases (22/54). Oligogenic inheritance was suspected in 52% of the screened families (23/45), being 40 tested by means of NGS data and 5 only by traditional methods. Together, ORVAL and DiGePred platforms predicted an oligogenic effect in 44% of the triallelic families (10/23). Intrafamilial variable severity could be clinically confirmed in six of the families. Our findings show that the presence of more than two alleles in BBSassociated genes correlated in six families with a more severe phenotype and associated with specific findings, highlighting the role of the mutational load in the management of BBS casesWe sincerely thank clinicians and patients for their work and unconditional support. This work was supported by the Instituto de Salud Carlos III (ISCIII) of the Spanish Ministry of Health (FIS; PI15/00049, PI16/00425, PI19/00321, and PI19/00332), Centro de Investigación Biomédica en Red Enfermedades Raras (CIBERER, 06/07/0036), IISFJD BioBank (PT13/0010/0012), Comunidad de Madrid (CAM, RAREGenomics Project, B2017/BMD-3721), Xunta de Galicia (Centro de Investigación de Galicia CINBIO 2019- 2022; Ref. ED431G-2019/06), and Consolidación e estructuración de unidades de investigación competitivas e outras accións de fomento (Xunta de Galicia, ED431C2018/54), European Regional Development Fund (FEDER), the Organización Nacional de Ciegos Españoles (ONCE), Fundación Ramón Areces, Fundación Conchita Rábago and the University Chair UAM-IIS-FJD of Genomic Medicine. Irene Perea-Romero is supported by a PhD fellowship from the predoctoral Program from ISCIII (FI17/00192). Carlos Solarat is supported by graduate studentship awards (FPU predoctoral fellowship; FPU 19/00175) from the Spanish Ministry of Education, Culture and Sports. Pablo Minguez is supported by Miguel Servet program from ISCIII (CP16/00116). The funders played no role in study design, data collection, data analysis, manuscript preparation, and/or publication decisionsNature Publishing GroupDepartamento de MedicinaFacultad de Medicina20222022-07-14research articlehttp://purl.org/coar/resource_type/c_2df8fbb1VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10486/708273https://dx.doi.org/10.1038/s41525-022-00311-2reponame:Biblos-e Archivo. Repositorio Institucional de la UAMinstname:Universidad Autónoma de MadridInglésengopen accesshttp://purl.org/coar/access_right/c_abf2info:eu-repo/semantics/openAccessoai:repositorio.uam.es:10486/7082732026-06-23T12:46:27Z
dc.title.none.fl_str_mv Allelic overload and its clinical modifier effect in Bardet-Biedl syndrome
title Allelic overload and its clinical modifier effect in Bardet-Biedl syndrome
spellingShingle Allelic overload and its clinical modifier effect in Bardet-Biedl syndrome
Perea Romero, Irene
Bardet-Biedl syndrome
oligogenic
Medicina
title_short Allelic overload and its clinical modifier effect in Bardet-Biedl syndrome
title_full Allelic overload and its clinical modifier effect in Bardet-Biedl syndrome
title_fullStr Allelic overload and its clinical modifier effect in Bardet-Biedl syndrome
title_full_unstemmed Allelic overload and its clinical modifier effect in Bardet-Biedl syndrome
title_sort Allelic overload and its clinical modifier effect in Bardet-Biedl syndrome
dc.creator.none.fl_str_mv Perea Romero, Irene
Solarat, Carlos
Blanco Kelly, Fiona
Sánchez Navarro, Iker
Bea-Mascato, Brais
Martin Salazar, Eduardo
Lorda Sánchez, Isabel
Tahsin Swafir, Saoud
Ávila Fernández, Almudena
Martín-Mérida, Inmaculada
Trujillo Tiebas, María José
Carreño, Ester
Jimenez-Rolando, Belen
Garcia-Sandoval, Blanca
Mínguez, Pablo
Cortón, Marta
Valverde, Diana
Ayuso García, María del Carmen Tomasa
author Perea Romero, Irene
author_facet Perea Romero, Irene
Solarat, Carlos
Blanco Kelly, Fiona
Sánchez Navarro, Iker
Bea-Mascato, Brais
Martin Salazar, Eduardo
Lorda Sánchez, Isabel
Tahsin Swafir, Saoud
Ávila Fernández, Almudena
Martín-Mérida, Inmaculada
Trujillo Tiebas, María José
Carreño, Ester
Jimenez-Rolando, Belen
Garcia-Sandoval, Blanca
Mínguez, Pablo
Cortón, Marta
Valverde, Diana
Ayuso García, María del Carmen Tomasa
author_role author
author2 Solarat, Carlos
Blanco Kelly, Fiona
Sánchez Navarro, Iker
Bea-Mascato, Brais
Martin Salazar, Eduardo
Lorda Sánchez, Isabel
Tahsin Swafir, Saoud
Ávila Fernández, Almudena
Martín-Mérida, Inmaculada
Trujillo Tiebas, María José
Carreño, Ester
Jimenez-Rolando, Belen
Garcia-Sandoval, Blanca
Mínguez, Pablo
Cortón, Marta
Valverde, Diana
Ayuso García, María del Carmen Tomasa
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Departamento de Medicina
Facultad de Medicina
dc.subject.none.fl_str_mv Bardet-Biedl syndrome
oligogenic
Medicina
topic Bardet-Biedl syndrome
oligogenic
Medicina
description Bardet–Biedl syndrome (BBS) is an autosomal recessive ciliopathy characterized by extensive inter- and intra-familial variability, in which oligogenic interactions have been also reported. Our main goal is to elucidate the role of mutational load in the clinical variability of BBS. A cohort of 99 patients from 77 different families with biallelic pathogenic variants in a BBS-associated gene was retrospectively recruited. Human Phenotype Ontology terms were used in the annotation of clinical symptoms. The mutational load in 39 BBS-related genes was studied in index cases using different molecular and next-generation sequencing (NGS) approaches. Candidate allele combinations were analysed using the in silico tools ORVAL and DiGePred. After clinical annotation, 76 out of the 99 cases a priori fulfilled established criteria for diagnosis of BBS or BBS-like. BBS1 alleles, found in 42% of families, were the most represented in our cohort. An increased mutational load was excluded in 41% of the index cases (22/54). Oligogenic inheritance was suspected in 52% of the screened families (23/45), being 40 tested by means of NGS data and 5 only by traditional methods. Together, ORVAL and DiGePred platforms predicted an oligogenic effect in 44% of the triallelic families (10/23). Intrafamilial variable severity could be clinically confirmed in six of the families. Our findings show that the presence of more than two alleles in BBSassociated genes correlated in six families with a more severe phenotype and associated with specific findings, highlighting the role of the mutational load in the management of BBS cases
publishDate 2022
dc.date.none.fl_str_mv 2022
2022-07-14
dc.type.none.fl_str_mv research article
http://purl.org/coar/resource_type/c_2df8fbb1
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/10486/708273
https://dx.doi.org/10.1038/s41525-022-00311-2
url http://hdl.handle.net/10486/708273
https://dx.doi.org/10.1038/s41525-022-00311-2
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Nature Publishing Group
publisher.none.fl_str_mv Nature Publishing Group
dc.source.none.fl_str_mv reponame:Biblos-e Archivo. Repositorio Institucional de la UAM
instname:Universidad Autónoma de Madrid
instname_str Universidad Autónoma de Madrid
reponame_str Biblos-e Archivo. Repositorio Institucional de la UAM
collection Biblos-e Archivo. Repositorio Institucional de la UAM
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repository.mail.fl_str_mv
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