Allelic overload and its clinical modifier effect in Bardet-Biedl syndrome
Author
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; Martin-Merida, Inmaculada; Trujillo Tiebas, María José; Carreño, Ester; Jimenez-Rolando, Belen; Garcia-Sandoval, Blanca; Mínguez, Pablo; Cortón, Marta; Valverde, Diana; Ayuso García, María del Carmen TomasaEntity
UAM. Departamento de MedicinaPublisher
Nature Publishing GroupDate
2022-07-14Citation
10.1038/s41525-022-00311-2
npj Genomic Medicine 7 (2022): 41
ISSN
2056-7944 (online)DOI
10.1038/s41525-022-00311-2Funded by
We 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 decisionsProject
Gobierno de España. PI15/00049; Gobierno de España. PI16/00425; Gobierno de España. PI19/00321; Gobierno de España. PI19/00332; Comunidad de Madrid. B2017/BMD-3721/RAREGENOMICS-CMEditor's Version
https://doi.org/10.1038/s41525-022-00311-2Subjects
Bardet-Biedl syndrome; oligogenic; MedicinaRights
© The Author(s) 2022Abstract
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
Files in this item
Google Scholar:Perea Romero, Irene
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Solarat, Carlos
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Blanco-Kelly, Fiona
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Sánchez Navarro, Iker
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Bea-Mascato, Brais
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Martin Salazar, Eduardo
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Lorda Sánchez, Isabel
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Tahsin Swafir, Saoud
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Ávila Fernández, Almudena
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Martin-Merida, Inmaculada
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Trujillo Tiebas, María José
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Carreño, Ester
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Jimenez-Rolando, Belen
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Garcia-Sandoval, Blanca
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Mínguez, Pablo
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Cortón, Marta
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Valverde, Diana
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Ayuso García, María del Carmen Tomasa
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