ORPHA: 110; DO: 0110126;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 15q24.1 | Bardet-Biedl syndrome 4 | 615982 | Autosomal recessive | 3 | BBS4 | 600374 |
A number sign (#) is used with this entry because Bardet-Biedl syndrome-4 (BBS4) is caused by homozygous mutation in the BBS4 gene (600374) on chromosome 15q24.
BBS4 is a rare multisystemic disorder characterized primarily by retinal dystrophy, obesity, polydactyly, and renal dysfunction that accounts for less than 3% of BBS (Katsanis et al., 2002). Anosmia has been described in patients with BBS4 (Iannaccone et al., 2005), as well as polydactyly confined to the hands (Carmi et al., 1995).
For a general phenotypic description and a discussion of genetic heterogeneity of Bardet-Biedl syndrome, see BBS1 (209900).
Iannaccone et al. (2005) described 3 patients with BBS4 from an Italian family (Mykytyn et al., 2001). The proband had a history of retinal degeneration with early-onset night blindness and reduced visual acuity (20/100 by age 12), obesity, syndactyly of the right hand, and dental abnormalities. He had cryptorchidism but not hypogenitalism, and borderline intelligence but not overt mental retardation. He had completed high school and was employed. He was anosmic. His sister had retinal degeneration with early-onset night blindness and poor visual acuity, polydactyly of the right foot, brachydactyly, clinodactyly of the fifth finger in both hands, mild obesity, delayed secondary sexual development, and dental abnormalities. Her degree of cognitive impairment made her ineligible for olfactory testing. The cousin of these sibs also had a history of retinal degeneration with early-onset night blindness; he also had syndactyly of the right hand, mild obesity, and cystic changes in the left kidney. Like the proband, he had cryptorchidism without hypogenitalism, and normal intelligence. He had markedly reduced olfactory function. Iannaccone et al. (2005) concluded that the BBS4 gene plays a role in olfaction, supporting the hypothesis that ciliary dysfunction is an important aspect of BBS pathogenesis. They suggested that the spectrum of clinical manifestations associated with BBS be broadened to include decreased olfaction.
Carmi et al. (1995) compared the clinical manifestations of BBS in 3 unrelated, extended Arab-Bedouin kindreds in which linkage had been demonstrated to chromosomes 3 (BBS3; 600151), 15 (BBS4), and 16 (BBS2; 615981). Observed differences included the limb distribution of the postaxial polydactyly and the extent and age-association of obesity. It appeared that the chromosome 3 locus is associated with polydactyly of all 4 limbs, while polydactyly of the chromosome 15 type is mostly confined to the hands. The chromosome 15 type is associated with early-onset morbid obesity, while the chromosome 16 type appears to present the 'leanest' end of BBS.
Carmi et al. (1995) used a DNA pooling approach with DNA samples from a highly inbred Bedouin kindred to identify a Bardet-Biedl syndrome locus on chromosome 15. Homozygosity mapping using pooled DNA samples assumes that all or most of the affected individuals share a common chromosomal region inherited from a common ancestral founder. The pooled DNA was used as a PCR template with primers for short tandem repeat polymorphisms (STRPs). Pools consisting of DNA from unaffected sibs and parents of affected individuals were used as controls. Markers not linked to the disease locus are expected to show similar allele frequencies in the affected and controlled pools as a result of independent assortment. On the other hand, STRPs in linkage disequilibrium with the disease phenotype show a shift in allele frequencies toward a single homozygous allele in the affected DNA pool. Following identification of linked loci by linkage disequilibrium (homozygosity mapping), individual members of the pedigree were genotyped using the STRP markers. All 8 STRPs resulted in a positive lod score. Carmi et al. (1995) commented that the locus on chromosome 15 in the q22.3-q23 region is not near any of the known human retinopathy loci and is not in the region of syntenic homology with any of the known mouse obesity loci. The phenotype of the patients in the chromosome 15 kindred was very similar to that described for the previously linked loci. Identification of the genes involved in these 4 genetic forms of BBS may aid in the understanding of common disorders such as obesity, hypertension, and diabetes.
Mykytyn et al. (2001) identified 3 homozygous mutations (e.g., 600374.0001, 600374.0002) in the BBS4 gene in 5 consanguineous families. They also identified a heterozygous BBS4 mutation in a small nonconsanguineous family.
Katsanis et al. (2002) detected mutation in the BBS4 gene (e.g., 600374.0003, 600374.0004) in 5 of 177 BBS families in a multiethnic patient cohort.
Carmi, R., Elbedour, K., Stone, E. M., Sheffield, V. C. Phenotypic differences among patients with Bardet-Biedl syndrome linked to three different chromosome loci. Am. J. Med. Genet. 59: 199-203, 1995. [PubMed: 8588586] [Full Text: https://doi.org/10.1002/ajmg.1320590216]
Carmi, R., Rokhlina, T., Kwitek-Black, A. E., Elbedour, K., Nishimura, D., Stone, E. M., Sheffield, V. C. Use of a DNA pooling strategy to identify a human obesity syndrome locus on chromosome 15. Hum. Molec. Genet. 4: 9-13, 1995. [PubMed: 7711739] [Full Text: https://doi.org/10.1093/hmg/4.1.9]
Iannaccone, A., Mykytyn, K., Persico, A. M., Searby, C. C., Baldi, A., Jablonski, M. M., Sheffield, V. C. Clinical evidence of decreased olfaction in Bardet-Biedl syndrome caused by a deletion in the BBS4 gene. Am. J. Med. Genet. 132A: 343-346, 2005. [PubMed: 15654695] [Full Text: https://doi.org/10.1002/ajmg.a.30512]
Katsanis, N., Eichers, E. R., Ansley, S. J., Lewis, R. A., Kayserili, H., Hoskins, B. E., Scambler, P. J., Beales, P. L., Lupski, J. R. BBS4 is a minor contributor to Bardet-Biedl syndrome and may also participate in triallelic inheritance. Am. J. Hum. Genet. 71: 22-29, 2002. [PubMed: 12016587] [Full Text: https://doi.org/10.1086/341031]
Mykytyn, K., Braun, T., Carmi, R., Haider, N. B., Searsby, C. C., Shastri, M., Beck, G., Wright, A. F., Iannaccone, A., Elbedour, K., Riise, R., Baldi, A., Raas-Rothschild, A., Gorman, S. W., Duhl, D. M., Jacobson, S. G., Casavant, T., Stone, E. M., Sheffield, V. C. Identification of the gene that, when mutated, causes the human obesity syndrome BBS4. Nature Genet. 28: 188-191, 2001. [PubMed: 11381270] [Full Text: https://doi.org/10.1038/88925]