Journal Article

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

Perea-Romero, Irene, Martin-Merida, Inmaculada, Blanco-Kelly, Fiona, Avila-Fernandez, Almudena, Swafiri, Saoud Tahsin, Garcia-Sandoval, Blanca, Minguez, Pablo, Carreño, Ester, Ayuso, Carmen, Solarat, Carlos, Trujillo-Tiebas, Maria Jose, Sanchez-Navarro, Iker, Bea-Mascato, Brais, Martin-Salazar, Eduardo, Lorda-Sanchez, Isabel, Jimenez-Rolando, Belen, Valverde, Diana, Corton, Marta

2022

Overview

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 BBS-associated 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.

• Publisher: Nature Publishing Group
• Subject: Alleles / Bardet-Biedl syndrome / Disease / Genes / Genetic counseling / Genotype & phenotype / Hospitals / Mutation / Next-generation sequencing / Phenotypes / Polygenic inheritance