Bardet-Biedl Syndrome 6

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Retrieved

2019-09-22

Source

Omim

Trials

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Genes

MKS1, BBS10, SDCCAG8, LZTFL1, BBIP1, CEP290, ARL6, IFT27, BBS2, MKKS, BBS4, BBS1, TTC8, ALMS1, IFT172, C8orf37, NPHP1, TMEM67, TBC1D32, BBS7, TRIM32, BBS9, BBS5, BBS12, TRAPPC3, ASTN2, PIGX, CEP19, ZDHHC24, CCDC28B, LEP, GLIS2, RTEL1, PLLP, PYY3, SULT1A4, PEG13, AZIN1, STOML3, RIN2, MAGEL2, CBLL2, MARVELD2, MYO3B, INPP5E, USP35, MUL1, WDPCP, IFT74, CEP131, SCAPER, INVS, NPY2R, NPY, NMB, NDN, MYO9A, MYO7A, RAB8A, KIFC3, KIF2A, INSR, IL18, GPT, GFAP, ERG, CCT, TNFRSF11B, PRKN, PCM1, ADIPOQ, CEP164, STUB1, FEM1B, RAPGEF5, IQCB1, FEZ1, TRPV1, PDE6B, VEGFA, SULT1A3, RHO, RFX1, RCVRN, PECAM1, SLX1A-SULT1A3

Drugs

Adeno-associated virus serotype 8 containing the human RdCVF sequence and the human RdCVFL sequence, Combination of three adeno-associated viral vectors of serotype 8 containing the 5'-, the body- and the 3'- coding sequences of human CEP290 fused to inteins, Leuprolide acetate ( LUPRON INJECTION )

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A number sign (#) is used with this entry because Bardet-Biedl syndrome-6 (BBS6) is caused by homozygous or compound heterozygous mutation in the MKKS gene (604896) on chromosome 20p12.

Mutations in the MKKS gene can also cause McKusick-Kaufman syndrome (236700).

Description

BBS6 is an autosomal recessive disorder with cardinal features of postaxial polydactyly, retinitis pigmentosa, kidney defects, obesity, and mental retardation (Slavotinek et al., 2000). Zaghloul and Katsanis (2009) estimated that mutations in the MKKS gene account for 5.8% of the total BBS mutational load.

For a general phenotypic description and a discussion of genetic heterogeneity of Bardet-Biedl syndrome, see BBS1 (209900).

Clinical Features

Slavotinek et al. (2000) described patients from 4 families with BBS6. The first was a 13-year-old Hispanic girl with severe retinitis pigmentosa, postaxial polydactyly, mental retardation, and obesity (BMI greater than 40). A second proband and her affected brother had retinitis pigmentosa, postaxial polydactyly, mild mental retardation, morbid obesity (BMI greater than 50 and 37, respectively), lobulated kidneys with prominent calyces, and diabetes mellitus. A deceased sister had similar phenotypic features and also had vaginal atresia and syndactyly of both feet. A third family included a 4-year-old male proband with reduced visual acuity, postaxial polydactyly, obesity, and cystic kidneys, and a sib with hypospadias, postaxial polydactyly, obesity, and lobular cystic kidneys who died at age 18 months. A fourth family consisted of a female proband diagnosed at age 5 years because of severe retinitis pigmentosa, postaxial polydactyly, morbid obesity, and diabetes mellitus, and a male sib with retinitis pigmentosa, postaxial polydactyly, obesity, lobulated cystic kidneys, and diabetes mellitus.

Scheidecker et al. (2015) reported a 36-year-old patient with BBS6 who had moderately severe cone dystrophy with mildly decreased visual acuity and photophobia.

Molecular Genetics

Slavotinek et al. (2000) and Katsanis et al. (2000) identified mutations in the MKKS gene in patients with BBS. Slavotinek et al. (2000) ascertained 34 unrelated probands with classic features of BBS including retinitis pigmentosa, obesity, and polydactyly. They found MKKS mutations in 4 typical BBS probands. Three of the probands were from Newfoundland and were also included in the study of Katsanis et al. (2000).

Slavotinek et al. (2000) sought mutations in the MKKS gene because of phenotypic similarities between McKusick-Kaufman syndrome and Bardet-Biedl syndrome. McKusick-Kaufman syndrome (236700) includes hydrometrocolpos, postaxial polydactyly, and congenital heart disease, with autosomal recessive inheritance. Bardet-Biedl syndrome is likewise an autosomal recessive disorder and is characterized by obesity, retinal dystrophy, polydactyly, learning difficulties, hypogenitalism, and renal malformations, with secondary features that include diabetes mellitus.

Katsanis et al. (2000) performed a genome screen in BBS families from Newfoundland in which linkage to known BBS loci had been excluded. Fine mapping reduced the critical interval to a region including the MKKS gene. Given the mapping position and the clinical similarity between McKusick-Kaufman syndrome and Bardet-Biedl syndrome, they screened the MKKS gene and identified mutations in 5 Newfoundland and 2 European-American BBS pedigrees. Most were frameshift mutations, predicted to result in a nonfunctional protein.

Beales et al. (2001) collected a cohort of 163 BBS pedigrees from diverse ethnic backgrounds and evaluated them for mutations in the MKKS gene and for potential assignment of the disorder to any of the other known BBS loci. Using a combination of mutation and haplotype analysis, they described a spectrum of BBS6 alterations that are likely to be pathogenic; proposed substantially reduced critical intervals for BBS2 (209900) on 16q21, BBS3 (608845) on 3p, and BBS5 (603650) on 2q; and presented evidence for the existence of at least one more BBS locus, bringing the total to 7. The data suggested that BBS6 is a minor contributor to the syndrome and that some BBS6 alleles may act in conjunction with mutations at other BBS loci to cause or modify the BBS phenotype.

In a population-based study including 93 BBS patients from 74 families of various ethnicities, Billingsley et al. (2010) determined that the chaperonin-like BBS6, BBS10 (610148), and BBS12 (610683) genes are a major contributor to the disorder. Biallelic mutations in these 3 genes were found in 36.5% of the families: 4 patients had mutations in BBS6, 19 had mutations in BBS10, and 10 had mutations in BBS12. Overall, 26 (68%) of 38 mutations were novel. Six patients had mutations present in more than 1 chaperonin-like BBS gene, and 1 patient with a very severe phenotype had 4 mutations in BBS10. The phenotypes observed were beyond the classic BBS phenotype and overlapped with characteristics of MKKS (236700), including congenital heart defect, vaginal atresia, hydrometrocolpos, and cryptorchidism, and with Alstrom syndrome (203800), including diabetes, hearing loss, liver abnormalities, endocrine anomalies, and cardiomyopathy.