Submission Details

The BBS4 gene was first reported in relation to autosomal recessive Bardet-Biedl syndrome (BBS) in five consanguineous families in 2001 (PMID: 11381270) after the authors mapped the locus to a region of chromosome 15 (PMIDs: 7711739, 8588586). Initial reports and subsequent publications describe Bardet-Biedl syndrome 4 (MIM# 615982) as characterized by retinal degeneration (typically described as rod-cone dystrophy) plus a range of extraocular features, most commonly obesity, intellectual disability, developmental delay, polydactyly, and/or male hypogonadism. Other reported features of BBS4-related cases include additional ocular findings (myopia, strabismus), hearing anomalies, additional skeletal differences (syndactyly, brachydactyly, clinodactyly, club foot), dental anomalies, atypical behavior, poor coordination, kidney disease, abnormal renal morphology, liver abnormalities, cardiac anomalies, cryptorchidism, gastrointestinal concerns, hypertension, metabolic dysfunction, anosmia, and sleep apnea. Most affected individuals are reported to meet clinical criteria for BBS as described by Beales et al., 1999 (PMID: 10874630). Both intra- and inter-familial variability is observed. To our knowledge, there have not been any reports of non-syndromic retinal degeneration due to BBS4 as has been described with other BBS genes, most notably BBS1 (PMID: 23143442). However, there is one report of a consanguineous family with three affected siblings reported to have Leber congenital amaurosis (with classic signs of extinguished electroretinogram, infantile nystagmus, and pigmentary retinopathy) with only mild extraocular features reported (delayed walking, delayed speech, mild facial dysmorphism, and enophthalmos) (PMID: 22219648). Per the Retina GCEP, to remain consistent with the disease entities of other BBS genes and to reflect the phenotypic variability observed, cases caused by inherited biallelic BBS4 variants have been referred to as BBS4-related ciliopathy.

Thirteen variants (missense, splice site, nonsense, deletion, insertion) that have been reported in fourteen probands in eight publications (PMIDs: 11381270, 12016587, 20177705, 22219648, 24849935, 26518167, 27894351, 31196119) are included in this curation. Most reported individuals have a homozygous BBS4 variant as the likely disease-causing variant, and consanguinity is commonly reported in these affected individuals. Of note, while oligogenic inheritance has been suggested for BBS, including BBS4-related BBS (PMID: 12016587), probands with other disease-causing BBS variants or biallelic variants (regardless of classification) in other BBS genes were excluded from the curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached.

The mechanism of pathogenicity is known to be loss of function. This gene-disease relationship is also supported by animal and cell culture models, expression studies, and in vitro functional assays (PMIDs: 11381270, 15107855, 15173597, 15322545, 16794820, 17574030, 22219648, 23716571, 24500759, 30665891, 32759308). BBS4 is ubiquitously expressed, and studies show expression in disease-associated tissues including retina, kidney, and adipose tissue, with the highest expression in kidney (PMID: 11381270). This gene-disease association is also supported by biochemical evidence that BBS4 encodes a component of the BBSome, a protein complex that functions in ciliogenesis (PMID: 32759308). BBS4 localizes to the primary cilia, and BBS4 immunoprecipitation results in co-purification of BBS1 and 6 other proteins encoded by genes implicated in Bardet-Biedl syndrome (BBS1, BBS2, BBS5, BBS7, BBS8, and BBS9) (PMIDs: 17574030, 32759308). Bbs4-deficient renal cells and retinal pigment epithelial cells show abnormal ciliogenesis (PMID: 23716571, 32759308). In addition, BBS4 silenced preadipocytes have increased fat accumulation and increased triglycerides (PMID: 24500759). Bbs4 knockdown in zebrafish results in shortened body axis, broadened somites, kinked notochord, and mislocalization of rhodopsin in the retina. The abnormal phenotypes in morphant zebrafish are rescued by wild-type BBS4 mRNA (PMID: 22219648). Phenotypes observed in Bbs4 null mice reflect both retinal and syndromic features from the human disease. Retinal degeneration, obesity, metabolic disturbances, liver dysfunction, decreased olfactory responses, and atypical behaviors have been observed in Bbs4 null mice in addition to ciliary defects (PMIDs: 15173597, 15322545, 16794820).

In summary, BBS4 is definitively associated with BBS4-related ciliopathy. This has been repeatedly demonstrated in both research and diagnostic settings, and has been upheld over time without the emergence of contradictory evidence. This classification was approved by the ClinGen Retina Gene Curation Expert Panel on December 7th, 2023 (SOP Version 10).