Kidney failure in Bardet–Biedl syndrome

Abstract

The aim of this study was to explore kidney failure (KF) in Bardet–Biedl syndrome (BBS), focusing on high‐risk gene variants, demographics, and morbidity. We employed the Clinical Registry Investigating BBS (CRIBBS) to identify 44 (7.2%) individuals with KF out of 607 subjects. Molecularly confirmed BBS was identified in 37 KF subjects and 364 CRIBBS registrants. KF was concomitant with recessive causal variants in 12 genes, with BBS10 the most predominant causal gene (26.6%), while disease penetrance was highest in SDCCAG8 (100%). Two truncating variants were present in 67.6% of KF cases. KF incidence was increased in genes not belonging to the BBSome or chaperonin‐like genes (p < 0.001), including TTC21B, a new candidate BBS gene. Median age of KF was 12.5 years, with the vast majority of KF occurring by 30 years (86.3%). Females were disproportionately affected (77.3%). Diverse uropathies were identified, but were not more common in the KF group (p = 0.672). Kidney failure was evident in 11 of 15 (73.3%) deaths outside infancy. We conclude that KF poses a significant risk for premature morbidity in BBS. Risk factors for KF include female sex, truncating variants, and genes other than BBSome/chaperonin‐like genes highlighting the value of comprehensive genetic investigation.

Bardet-Biedl Syndrome: Current Perspectives and Clinical Outlook

“…49 Recently, using CRIBBS registry, Meyer et al identified Eagle Barrett syndrome in four children. 50 Reproduction is difficult but some patients gave birth to children.…”

“…[69][70][71][72] Currently, thanks to the progress in genetics, twenty-six genes have been associated with the syndrome, an increasing number over years (Table 2). 50 However, mutations in BBS1 to BBS18 account for about 70-80% of cases worldwide 73 and about 50% of diagnosis in the western countries are due to mutations in three genes: BBS1, BBS2 and BBS10. 19,74 In Caucasian populations, indeed, mutations in BBS1 and BBS10 are detected in 21-30% of patients, 75 a percentage rising to 40-50% in Northern European patients.…”

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

“…Several minor features have also been documented in individuals with BBS, including facial dysmorphism, developmental delay, speech deficit, neurological abnormalities, metabolic and endocrine disturbance, diabetes mellitus, cardiovascular defects and Hirschsprung disease (Branfield Day et al, 2016; Olson et al, 2019). Assembly and analysis of consistent and longitudinal clinical data from the Clinical Registry Investigating Bardet‐Biedl Syndrome (CRIBBS), have refined further the incidence and variability of clinical phenotypes (Meyer et al, 2022; Pomeroy, Krentz, et al, 2021; Pomeroy, VanWormer, et al, 2021).…”

“…Assembly and analysis of consistent and longitudinal clinical data from the Clinical Registry Investigating Bardet-Biedl Syndrome (CRIBBS), have refined further the incidence and variability of clinical phenotypes (Meyer et al, 2022;Pomeroy, Krentz, et al, 2021;.…”

Aberrant centrosome biogenesis disrupts nephron progenitor cell renewal and fate resulting in fibrocystic kidney disease

“…NPH is characterized by smaller, hyperechogenic kidneys with cortico-medullary cysts and poor cortico-medullary differentiation, tubular atrophy, disintegration, and irregular thickening of the tubular basement membrane, leading to fibrotic kidneys with shrunken appearance 18 . Similarly, JS and JATD patients commonly display abnormal congenital kidney developmental phenotypes such as dysplastic, fibrocystic kidneys and reach ESKD within childhood or adolescence 19,20 . So far, ciliopathies have been linked to mutations in ~ 200 genes 6,7 , a significant number of which encode centrosomal proteins, and many of these mutations result in congenital kidney developmental defects and early-onset fibrocystic disease phenotypes.…”