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

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 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.

Mutation profile of Bardet‐Biedl syndrome patients from India: Implicative role of multiallelic rare variants and oligogenic inheritance pattern

“…The presence/absence of modifier alleles helps in genetic counseling and has potential disease management benefits when identified earlier. 61 Further in silico or in vitro assays are required to identify and confirm the epistatic effect, if any, among the BBS genes observed in families II and IV. Figure 3 shows the cosegregation analysis performed these pedigrees.…”

Exome sequencing in a Romanian Bardet‐Biedl syndrome cohort revealed an overabundance of causal BBS12 variants

“…Instead, BBS12 p.Arg355* was overabundant in our cohort and contributed to BBS12 emerging as the most common causal gene. Still, BBS12 is among the major contributors to BBS accounting for 8%–11% in most reported cohorts (Khan et al, 2016; Stoetzel et al, 2007), including a recent study of 99 affected individuals for which BBS12 was causal in 14% of cases (Perea‐Romero et al, 2022).…”

“…Although the rarity of BBS and underlying genetic heterogeneity limit conclusive statements about commonly observed gene pairings, some genes appear to be more frequently implicated in oligogenic phenomena. In a recent study, BBS1 , BBS4 , BBS2 , CFAP418/BBS21 , and BBS12 were reported as common driver genes involved in oligogenic phenomena (Perea‐Romero et al, 2022). Accordingly, we detected a third allele in two families with primary causal variants in BBS12 .…”

“…Copy number variants (CNV) also contribute to the mutational burden of BBS, and exon disruptive CNVs are detectable in up to 18% of clinically assessed cases (Lindstrand et al, 2014(Lindstrand et al, , 2016Redin et al, 2012). BBS is inherited predominantly in an autosomal recessive manner; however, this classical mode of inheritance has been challenged by extensive molecular and functional investigation reporting second-site variation in other BBS genes which could possibly explain phenotypic variability (Allison, 2021;Badano, Leitch, et al, 2006;Cardenas-Rodriguez et al, 2013;Davis et al, 2011;Katsanis, Ansley, et al, 2001;Kousi et al, 2020;Perea-Romero et al, 2022;Zaghloul & Katsanis, 2009).…”

Clinical and Functional Assessment of Digenicity in Renal Phosphate Wasting

“…However, the mechanistic downstream effect and functional consequences have never been assessed [15,16]. Examples of digenicity in hereditary kidney disease include Alport syndrome caused by pathogenic alterations in more than one of the three COL4A3-5 genes [17]; cystinuria with variants in both SLC3A1 and SLC7A9 [18]; and Bardet-Biedl syndrome, wherein oligogenicity has been postulated for a long time [19].…”