Allelic overload and its clinical modifier effect in Bardet-Biedl syndrome
Perea Romero, Irene; López Solarat, Carlos; Blanco Kelly, Fiona; Sanchez Navarro, Iker; Bea Mascato, Brais; Martin Salazar, Jesús Eduardo; Lorda Sanchez, Isabel; Swafiri, Saoud Tahsin; Avila Fernández, Almudena; Martin Merida, Inmaculada; Trujillo Tiebas, Maria Jose; Carreño, Ester; Jiménez Rolando, Belen; García Sandoval, Blanca; Minguez, Pablo; Corton, Marta; Valverde Pérez, Diana; Ayuso, Carmen
DATE:
2022-07-14
UNIVERSAL IDENTIFIER: http://hdl.handle.net/11093/4424
EDITED VERSION: https://www.nature.com/articles/s41525-022-00311-2
DOCUMENT TYPE: article
ABSTRACT
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