Genetic characterization of Italian patients with Bardet-Biedl syndrome and correlation to ocular, renal and audio-vestibular phenotype: identification of eleven novel pathogenic sequence variants

Abstract

BackgroundBardet-Biedl syndrome (BBS) is a rare genetic disorder that features retinal degeneration, obesity, polydactyly, learning disabilities and renal abnormalities. The diagnosis is often missed at birth, the median age at diagnosis being 9 years. In the attempt to shed light on BBS and improve its diagnosis and treatment, we evaluated the genotype-phenotype relationship in patients with a molecular diagnosis of BBS.MethodsWe analyzed three common BBS genes, BBS1, BBS10 and BBS2, in 25 Italian patients fulfilling the clinical criteria of BBS. In 12 patients, we identified gene-specific biallelic variants and thus correlated genotype to the ophthalmic, renal and audio-vestibular phenotypes.ResultsAt least one sequence variant was found in 60% of patients. The most common mutated gene was BBS1 followed by BBS10. Of the 17 sequence variants we found, 11 have not previously been associated with BBS. In 12 patients, we identified biallelic pathogenic variants; they had retinitis pigmentosa with early onset of visual impairment. However, retinal dystrophy was less severe in patients with BBS1 than in those with BBS10 variants. Overall, we found a high prevalence of renal dysmorphism and dysfunction. Notably, patients with BBS10 variants had the most severe renal impairment, which resulted in a critical decline in renal function. All the patients who underwent audio-vestibular evaluation had dysfunction of the cochlear outer hair cells, thus confirming the presence of hearing defects.Conclusion BBS1, BBS2 and BBS10 are major causative genes in Italian BBS patients. BBS10 was associated with the worse outcome in terms of the renal, ocular and audiovestibular phenotypes. Cochlear dysfunction should be included among the hallmarks of BBS.Electronic supplementary materialThe online version of this article (doi:10.1186/s12881-017-0372-0) contains supplementary material, which is available to authorized users.

Meta‐analysis of genotype‐phenotype associations in Bardet‐Biedl syndrome uncovers differences among causative genes

“…Another caveat is that the data allowed us to assess the presence/absence of the BBS symptom, but not grading the severity of individual symptoms. This might explain, why we did not observe differences in retinal dystrophy between patients with causative mutations in BBS1 and other patients as was previously reported in small cohorts of patients using a quantitative test of the visual acuity (Daniels et al, ; Esposito et al, ). It is possible that the penetrance of renal anomalies showed the clearest link to the genotype only because the overall penetrance of renal anomalies was the lowest of all major BBS symptoms, allowing us to observe the stratification.…”

“…The literature search was performed according to the protocol preregistered in Prospero (CRD42018096099) and it followed the PRISMA guidelines whenever applicable (Table S1 and Figure S1). In total, we identified 85 relevant studies (Abu Safieh et al, ; Agha et al, ; Ajmal et al, ; Al‐Hamed et al, ; Alazami et al, ; Aldahmesh et al, ; Azari et al, ; Badano, ; Baker et al, ; Bee, Chawla, & Zhao, ; Bennouna‐Greene et al, ; Billingsley et al, ; Billingsley, Vincent, Deveault, & Heon, ; Branfield Day et al, ; Braun et al, ; Bujakowska et al, ; Castro‐Sanchez et al, ; Chaki et al, ; Chul Yoon et al, ; Cox et al, ; Davies, ; Deveault et al, ; Ece Solmaz et al, ; Esposito et al, ; Estrada‐Cuzcano, Koenekoop, et al, ; Estrada‐Cuzcano, Neveling, et al, ; Fan et al, ; Fattahi et al, ; Fedick et al, ; Frank et al, ; Gerth, Zawadzki, Werner, & Heon, ; Ghadami et al, ; González‐del Pozo et al, ; Harville et al, ; Heon et al, ; Hjortshoj, Gronskov, Brondum‐Nielsen, & Rosenberg, ; Hjortshoj et al, ; Hulleman et al, ; Iannaccone et al, ; Innes et al, ; Iurian, Arts, Brunner, & Fintina, ; Janssen et al, ; Kamme, Mayer, Strom, Andréasson, & Weisschuh, ; Katsanis et al, ; Katsanis et al, ; Kerr, Bhan, & Héon, ; A. O. Khan, Decker, Bachmann, Bolz, & Bergmann, ; S. Khan et al, , S. A. Khan et al, ; Laurier et al, ; Leitch et al, ; Lim et al, ; Lindstrand et al, ; Lindstrand et al, ; M'Hamdi et al, ; Maria et al,…”

“…The revealed patterns for polydactyly and renal anomalies were recapitulated also by the Bayesian pairwise comparisons analysis ( Figure 4a) Overall, we identified variable relationship between the penetrance of particular symptoms and the BBSome gene mutated. As some specific, sometimes contradictory, statements about the presence or absence of the genotype-phenotype relationships were previously proposed in smaller cohorts of BBS patients (Abu Safieh et al, 2010;Billingsley et al, 2010;Brinckman et al, 2013;Castro-Sanchez et al, 2015;Deveault et al, 2011;Esposito et al, 2017;Estrada-Cuzcano, Koenekoop, et al, 2012;Forsythe et al, 2017;Forsythe et al, 2015;Hjortshoj et al, 2010;Kerr et al, 2015;Moore et al, 2005;Pawlik et al, 2010;Schaefer et al, 2010), we addressed these statements using the frequentist statistics applied on the data from our complete patient database (Table S7).…”

The Kidney in Bardet-Biedl Syndrome: Possible Pathogenesis of Urine Concentrating Defect

“…Some reports showed that BBS1 mutations are associated with a less severe phenotype compared with other BBS genes [19] , especially BBS10 [20,21] . However, in a recent study, it was demonstrated that biallelic truncating mutations in any gene correlated with more severe renal disease compared with missense mutations, suggesting that any BBS gene, when strongly affected, may result in severe kidney dysfunction [21] .…”

Impact of Local and Systemic Factors on Kidney Dysfunction in Bardet-Biedl Syndrome

“…The majority of reports show that more than half of the BBS patients exhibit normal eGFR [11, 12]. A recent retrospective study on a total of 350 BBS patients from the United Kingdom showed that the prevalence of CKD stage II-V were 42% and 31% in adult and children respectively and no difference between genders have been reported [4].…”