Identification of compound heterozygous mutations in the BBS7 gene in a Korean family with Bardet-Biedl syndrome.
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ABSTRACT:
SUBMITTER: Shin SJ
PROVIDER: S-EPMC4272959 | biostudies-literature | 2015 Jan
REPOSITORIES: biostudies-literature
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Identification of compound heterozygous mutations in the BBS7 gene in a Korean family with Bardet-Biedl syndrome.
Shin Seok Joon SJ Kim Myungshin M Chae Hyojin H Kwon Ahlm A Kim Yonggoo Y Kim Sung Jun SJ Yoon Hye Eun HE Jekarl Dong Wook DW Lee Seungok S
Annals of laboratory medicine 20141208 1
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Project description:Bardet-Biedl syndrome (BBS) is a rare autosomal recessive ciliopathy characterized by retinitis pigmentosa (RP), truncal obesity, cognitive impairment, hypogonadism in men, polydactyly, and renal abnormalities with severe renal dysfunction. Twenty-two causative genes have already been reported for this disorder. In this study, we identified two unrelated Japanese patients with clinical diagnoses of BBS associated with compound heterozygous SCLT1 mutation. Patient 1 was a 10-year-old girl, and patient 2 was a 22-year-old man. Both the patients showed severe renal dysfunction in childhood, RP, mild intellectual disability, short stature, and truncal obesity, without oral aberrations and polydactyly. Patient 2 also had hypogonadism. We identified two missense variants in SCLT1, c.[1218G > A] and [1631A > G], in both the patients by next-generation sequencing. Subsequent cDNA analysis revealed that c.1218G > A affected exon 14 skipping in SCLT1. To date, SCLT1 has been reported as the causative gene of oral-facial-digital syndrome type IX, and Senior-Løken syndrome. The phenotypes of both the present patients were compatible with BBS. These results highlight SCLT1 as an additional candidate for BBS phenotype in an autosomal recessive manner.
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Project description:PurposeTo describe the clinical features of and identify a novel mutation in Bardet-Biedl syndrome 7 gene (BBS7) in a Chinese family.MethodsNineteen individuals at risk for inheriting Bardet-Biedl syndrome (BBS) in a Chinese family participated in the study. Physical examination was performed and blood was drawn for DNA extraction. Linkage analysis was conducted for all known BBS loci, and mutation screening of BBS7 gene and BBS12 gene was performed.ResultsA Chinese family with inherited BBS was identified. After performing linkage analysis on all 13 known loci, we found the disease phenotype of a Chinese family with BBS linked to a locus where BBS7 and BBS12 genes locate.ConclusionsThis study describes a novel mutation in BBS7 causing BBS in a Chinese family. This is the first report that a mutation in a BBS gene causes BBS in a Chinese population. These results expand the spectrum of human disease associated with mutations of BBS7 since the initial three mutations in BBS7 were first identified in 2003.
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Project description:Bardet-Biedl syndrome (BBS) is a pleiotropic and multisystemic disorder characterized by rod-cone dystrophy, polydactyly, learning difficulties, renal abnormalities, obesity and hypogonadism. This disorder is genetically heterogeneous. Until now, a total of nineteen genes have been identified for BBS whose mutations explain more than 80% of diagnosed cases. Recently, the development of next generation sequencing (NGS) technology has accelerated mutation screening of target genes, resulting in lower cost and less time consumption. Here, we screened the most common BBS genes (BBS1-BBS13) using NGS in an Iranian family of a proposita displaying symptoms of BBS. Among the 18 mutations identified in the proposita, one (BBS12 c.56T>G and BBS12 c.1156C>T) was novel. This compound heterozygosity was confirmed by Sanger sequencing in the proposita and her parents. Although our data were presented as a case report, however, we suggest a new probable genetic mechanism other than the conventional autosomal recessive inheritance of BBS. Additionally, given that in some Iranian provinces, like Khuzestan, consanguineous marriages are common, designing mutational panels for genetic diseases is strongly recommended, especially for those with an autosomal recessive inheritance pattern.
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Project description:Bardet-Biedl syndrome (BBS) is a genetically heterogeneous disorder, the primary features of which include obesity, retinal dystrophy, polydactyly, hypogenitalism, learning difficulties, and renal malformations. Conventional linkage and positional cloning have led to the mapping of six BBS loci in the human genome, four of which (BBS1, BBS2, BBS4, and BBS6) have been cloned. Despite these advances, the protein sequences of the known BBS genes have provided little or no insight into their function. To delineate functionally important regions in BBS2, we performed phylogenetic and genomic studies in which we used the human and zebrafish BBS2 peptide sequences to search dbEST and the translation of the draft human genome. We identified two novel genes that we initially named "BBS2L1" and "BBS2L2" and that exhibit modest similarity with two discrete, overlapping regions of BBS2. In the present study, we demonstrate that BBS2L1 mutations cause BBS, thereby defining a novel locus for this syndrome, BBS7, whereas BBS2L2 has been shown independently to be BBS1. The motif-based identification of a novel BBS locus has enabled us to define a potential functional domain that is present in three of the five known BBS proteins and, therefore, is likely to be important in the pathogenesis of this complex syndrome.
| S-EPMC1180240 | biostudies-literature
Project description:Bardet-Biedl syndrome (BBS) is a rare autosomal recessive ciliopathy characterized by obesity, postaxial polydactyly, retinitis pigmentosa, mental retardation, and kidney abnormalities. At least 19 genes have been shown to be associated with BBS, and therefore, genetic testing is highly complicated. We used an Illumina MiSeq platform for whole exome sequencing analysis of a family with strong clinical features of BBS. A homozygous c.1967_1968delTAinsC (p.Leu656fsX673; RefSeq NM_176824.2) mutation in BBS7 was identified in both affected children, while their healthy sibling and the non-consanguineous parents were heterozygous for this allele. Genotyping of 2,832 DNA samples obtained from Russian blood donors revealed 2 additional heterozygous subjects (0.07%) with the c.1967_1968delTAinsC mutation. These findings may facilitate the genetic diagnosis for Slavic BBS patients.
| S-EPMC4574611 | biostudies-literature
Project description:Bardet-Biedl syndrome (BBS) is a rare autosomal recessive ciliopathy characterised by retinal dystrophy, obesity, post-axial polydactyly, renal dysfunction, learning difficulties and hypogonadism. Many associated minor features can be helpful in making a diagnosis and are important in the clinical management of BBS. The diagnosis is based on clinical findings and can be confirmed by sequencing of known disease-causing genes in 80% of patients. BBS genes encode proteins that localise to the cilia and basal body and are involved in cilia biogenesis and function. Mutations lead to defective cilia accounting in part for the pleiotropic effects observed in BBS. We provide an overview of BBS including the clinical findings, current understanding of cilia biology, and a practical approach to diagnosis, genetic counselling and up-to-date management.
| S-EPMC3522196 | biostudies-other
Project description:Introduction: Bardet-Biedl syndrome (BBS) is a rare autosomal recessive disorder with clinical features of retinal dystrophy, obesity, postaxial polydactyly, renal anomalies, learning disabilities, hypogonadism, and genitourinary abnormalities. Nevertheless, previous studies on the phenotypic traits of BBS heterozygous carriers have generated inconclusive results. The aim of our study was to investigate the impact of BBS heterozygosity on carriers when compared to non-carriers within the Taiwanese population. Materials and Methods: This study follows a hospital-based case-control design. We employed the Taiwan Biobank version 2 (TWBv2) array to identify three specific loci associated with BBS (rs773862084, rs567573386, and rs199910690). In total, 716 patients were included in the case group, and they were compared to a control group of 2,864 patients who lacked BBS alleles. The control group was selected through gender and age matching at a ratio of 1:4. The association between BBS-related loci and comorbidity was assessed using logistic regression models. Results: We found that BBS heterozygous carriers exhibited a significant association with elevated BMI levels, especially the variant rs199910690 in MKS1 (p=0.0037). The prevalence of comorbidities in the carriers' group was not higher than that in the non-carriers' group. Besides, the average values of the biochemistry data showed no significant differences, except for creatinine level. Furthermore, we conducted a BMI-based analysis to identify specific risk factors for chronic kidney disease (CKD). Our findings revealed that individuals carrying the CA/AA genotype of the BBS2 rs773862084 variant or the CT/TT genotype of the MKS1 rs199910690 variant showed a reduced risk of developing CKD, irrespective of their BMI levels. When stratified by BMI level, obese males with the MKS1 rs199910690 variant and obese females with the BBS2 rs773862084 variant exhibited a negative association with CKD development. Conclusion: We found that aside from the association with overweight and obesity, heterozygous BBS mutations did not appear to increase the predisposition of individuals to comorbidities and metabolic diseases. To gain a more comprehensive understanding of the genetic susceptibility associated with Bardet-Biedl Syndrome (BBS), further research is warranted.
| S-EPMC11008491 | biostudies-literature
Project description:Bardet Biedl syndrome (BBS) is a multisystem genetically heterogeneous ciliopathy that most commonly leads to obesity, photoreceptor degeneration, digit anomalies, genito-urinary abnormalities, as well as cognitive impairment with autism, among other features. Sequencing of a DNA sample from a 17-year-old female affected with BBS did not identify any mutation in the known BBS genes. Whole-genome sequencing identified a novel loss-of-function disease-causing homozygous mutation (K102*) in C8ORF37, a gene coding for a cilia protein. The proband was overweight (body mass index 29.1) with a slowly progressive rod-cone dystrophy, a mild learning difficulty, high myopia, three limb post-axial polydactyly, horseshoe kidney, abnormally positioned uterus and elevated liver enzymes. Mutations in C8ORF37 were previously associated with severe autosomal recessive retinal dystrophies (retinitis pigmentosa RP64 and cone-rod dystrophy CORD16) but not BBS. To elucidate the functional role of C8ORF37 in a vertebrate system, we performed gene knockdown in Danio rerio and assessed the cardinal features of BBS and visual function. Knockdown of c8orf37 resulted in impaired visual behavior and BBS-related phenotypes, specifically, defects in the formation of Kupffer's vesicle and delays in retrograde transport. Specificity of these phenotypes to BBS knockdown was shown with rescue experiments. Over-expression of human missense mutations in zebrafish also resulted in impaired visual behavior and BBS-related phenotypes. This is the first functional validation and association of C8ORF37 mutations with the BBS phenotype, which identifies BBS21. The zebrafish studies hereby show that C8ORF37 variants underlie clinically diagnosed BBS-related phenotypes as well as isolated retinal degeneration.
| S-EPMC5081059 | biostudies-literature
Project description:Bardet-Biedl syndrome is a rare condition characterized by obesity, retinitis pigmentosa, polydactyly, development delay, and structural kidney anomalies. This syndrome has an autosomal recessive type of inheritance. For the first time, molecular genetic testing has been provided for a large cohort of Russian patients with Bardet-Biedl syndrome. Genetic testing was provided to 61 unrelated patients using an MPS panel that includes coding regions and intronic areas of all genes (n = 21) currently associated with Bardet-Biedl syndrome. The diagnosis was confirmed for 41% of the patients (n = 25). Disease-causing variants were observed in BBS1, BBS4, BBS7, TTC8, BBS9, BBS10, BBS12, and MKKS genes. In most cases, pathogenic and likely pathogenic variants were localized in BBS1, BBS10, and BBS7 genes; recurrent variants were also observed in these genes. The frequency of pathogenic and likely pathogenic variants in the BBS1 and BBS10 genes among Russian patients matches the research data in other countries. The frequency of pathogenic variants in the BBS7 gene is about 1.5%-2% of patients with Bardet-Biedl syndrome, while in the cohort of Russian patients, the fraction is 24%. In addition, the recurrent pathogenic variant c.1967_1968delinsC was detected in the BBS7 gene. The higher frequency of this variant in the Russian population, as well as the lack of association of this pathogenic variant with Bardet-Biedl syndrome in other populations, suggests that the variant c.1967_1968delinsC in the BBS7 gene is major and has a founder effect in the Russian population. Results provided in this article show the significant role of pathogenic variants in the BBS7 gene for patients with Bardet-Biedl syndrome in the Russian population.
| S-EPMC11291329 | biostudies-literature
Project description:BackgroundBardet-Biedl syndrome (BBS) is a rare multisystem developmental disorder. In this study, we report the genetic causes and clinical manifestations in two Chinese families with BBS.Materials and methodsTwo families were recruited in this study. Family A was a four-generation family with four affected and 15 unaffected members participating in the study, and family B was a consanguineous family with one affected and three unaffected members participating. Whole exome sequencing was performed in the two families, followed by a multistep bioinformatics analysis. Sanger sequencing was used to verify the variants and to perform a segregation analysis. Comprehensive ocular and systemic examinations were also conducted.ResultsNovel compound heterozygous variants c.235T?>?G (p.T79P) and c.534?+?1G?>?T were detected in the BBS2 gene in family A, and known homozygous variant c.748G?>?A (p.G250R) was detected in the MKKS gene in family B. Both families presented with retinitis pigmentosa; however, except for polydactyly, all other systemic manifestations were different. All of the affected family members in family A were overweight with a high body mass index (range from 26.5 to 41.9) and high blood pressure. Family A also presented with a delay in the onset of secondary sex characteristics and genital anomalies, while other systemic abnormalities were absent in family B.ConclusionsThis study presents one family with two novel BBS2 variants, expanding the variant spectrum of BBS, and one family with a known homozygous MKKS variant. The different phenotypes seen between the families with BBS2 and MKKS variants will contribute to the literature and our overall understanding of BBS.
| S-EPMC7817241 | biostudies-literature