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Identification of a Novel Homozygous Mutation in BBS10 Gene in an Iranian Family with Bardet-Biedl Syndrome.

ABSTRACT: Background:Bardet-Biedl Syndrome (BBS) is a rare pleiotropic autosomal recessive disease related to ciliopathies with approximately 25 causative genes. BBS is a multisystemic disorder with wide spectrum of manifestations including truncal obesity, retinal dystrophy, male hypogenitalism, postaxial polydactyly, learning difficulties, and renal abnormalities. Methods:A consanguineous Iranian family with a 28-year-old daughter affected with BBS, resulting from a first cousin marriage, was examined. After clinical examination, Whole Exome Sequencing (WES) was applied. Following the analysis of exome data, Sanger sequencing was used to confirm as well as to co-segregate the candidate variant with the phenotype. Results:A novel homozygous variant [c. 2035G>A (p.E679K)] in exon 2 of the BBS10 gene was found which was categorized as likely pathogenic based on American College of Medical Genetics and Genomics (ACMG) guidelines and criteria. In this study, the variant was fully co-segregated with the phenotype in the family. Conclusion:Despite overlapping with other ciliopathies in terms of the phenotype, the BBS has high genetic heterogeneity and clinical variability even among affected members of a family. The symptoms observed in patients are largely related to the genes involved and the type of mutations in the BBS. In this study, in addition to phenotype description of the proband harboring a novel disease-causing variant in BBS10 gene, the spectrum of BBS symptoms was expanded. The findings of this study can be useful in genetic counseling, especially for risk estimation and prenatal diagnosis.

SUBMITTER: Dehani M

PROVIDER: S-EPMC8606112 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Novel homozygous protein-truncating mutation of BBS9 identified in a Chinese consanguineous family with Bardet-Biedl syndrome.

Project description:BackgroundBardet-Biedl syndrome (BBS) is a rare and genetically heterogeneous disease with a broad spectrum of clinical features, including but not limited to rod-cone dystrophy, postaxial polydactyly, central obesity, intellectual disability, hypogonadism, and renal dysfunction. Twenty-one BBS (Bardet-Biedl syndrome) genes have been identified to date. There is minimal mutation information on BBS in Chinese populations and the exact pathogenic mechanism of the null mutation of BBS9 remains unknown.MethodsA patient from a Chinese consanguineous family presented with polydactyly, truncal obesity, intellectual disability, genital anomaly, and retinitis pigmentosa was analyzed in this study. Blood DNA and RNA were extracted from the blood of the proband and the parents. The proband was screened for mutations by whole-exome sequencing. The likely pathogenic mutation detected in the proband was further confirmed by the Sanger sequence in the family. Real-time RT-PCR was used to measure the expression of BBS9 in the proband and the control.ResultsTargeted exome sequencing identified a novel homozygous null mutation (NM_198428.3: c.445C>T) in the 6th exon of the BBS9 gene in the proband and Sanger sequencing was used to validate the heterozygosity in the parents. The mutation was validated to induce the nonsense-mediated decay of BBS9 messenger RNAs by real-time RT-PCR.ConclusionsThe molecular findings helped to explain the clinical manifestations. The novel homozygous pathogenic variation expanded the mutational spectrum of the BBS9 gene in the Chinese population and will help to understand the pathogenic mechanism of BBS9 null mutation.

| S-EPMC8404240 | biostudies-literature

A novel BBS10 mutation identified in a patient with Bardet-Biedl syndrome with a violent emotional outbreak.

Project description:We report a 10-year-old girl with Bardet-Biedl syndrome caused by a novel mutation in the Bardet-Biedl syndrome 10 (BBS10) gene. She had multiple malformations, including a dysmorphic face, postaxial polydactyly, polycystic kidney and amblyopia. She presented with typical BBS features, including intellectual disability with emotional outbursts and mild obesity. Whole-exome sequencing identified compound heterozygous mutations with NM_024685.3:c.1677C>A [p.(Tyr559*)] and c.1974T>G [p.(Tyr658*)]. To our knowledge, the latter mutation has never been reported previously.

| S-EPMC5550758 | biostudies-literature

Identification of A Novel Compound Heterozygous Mutation in BBS12 in An Iranian Family with Bardet-Biedl Syndrome Using Targeted Next Generation Sequencing.

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.

| S-EPMC5893301 | biostudies-literature

Identification of a Novel Homozygous Missense (c.443A>T:p.N148I) Mutation in <i>BBS2</i> in a Kashmiri Family with Bardet-Biedl Syndrome.

Project description:BackgroundBardet-Biedl syndrome (BBS) is a rare autosomal recessive inherited disorder with distinctive clinical feature such as obesity, degeneration of retina, polydactyly, and renal abnormalities. The study was aimed at finding out the disease-causing variant/s in patients exhibiting clinical features of BBS.MethodsThe identification of disease-causing variant was done by using whole exome sequencing on Illumina HiSeq 4000 platform involving the SeqCap EZ Exome v3 kit (Roche NimbleGen). The identified variant was further validated by Sanger sequencing.ResultsWES revealed a novel homozygous missense mutation (NM_031885: c.443A>T:p.N148I) in exon 3 of the BBS2 gene. Sanger sequencing confirmed this variant as homozygous in both affected subjects and heterozygous in obligate parents, demonstrating autosomal recessive inheritance pattern. To the best of our knowledge, this variant was not present in literature and all publically available databases. The candidate variant is predicted to be pathogenic by a set of in-silico softwares.ConclusionClinical and genetic spectrum of BBS and BBS-like disorders is not completely defined in the Pakistani as well as in Kashmiri population. Therefore, more comprehensive genetic studies are required to gain insights into genotype-phenotype associations to facilitate carrier screening and genetic counseling of families with such disorders.

| S-EPMC7925018 | biostudies-literature

Novel homozygous nonsense mutation associated with Bardet-Biedl syndrome in fetuses with congenital renal malformation.

Project description:BackgroundThe Bardet-Biedl syndrome (BBS) is a rare autosomal recessive disorder, characterized by clinical and genetic heterogeneity. BBS is more commonly reported in adults and children than in fetuses. Here, a retrospective study on 210 fetuses with congenital renal malformation was conducted.MethodsThe fetuses were diagnosed using invasive prenatal tests, including chromosome karyotype analysis, whole exome sequencing (WES), and single-nucleotide polymorphism array. We found the intrauterine phenotype of a fetus presenting enlarged kidneys, enhanced echo, and oligohydramnios; therefore, the fetus was characterized to have BBS.ResultsChromosome karyotype analysis presented normal results. Analysis using an Affymetrix CytoScan 750K array revealed 2 homozygous regions. However, WES revealed a homozygous mutation of c.1177C>T (p.Arg393*) on exon 12 of BBS1 and a heterozygous variation of c.2704G>A (p.Asp902Asn) on exon 22 of CC2D2A. The American College of Medical Genetics and Genomics guidelines identified c.1177C>T and c.2704G>A as a pathogenic mutation and of uncertain significance, respectively. Sanger sequencing identified heterozygous mutation, that is, c.1177C>T and heterozygous variation, that is, c.2704G>A in the parents of the fetus.ConclusionsWES identified a novel homozygous nonsense mutation c.1177C>T in BBS1 of a Chinese fetus with congenital renal malformation. This finding provides insight into the BBS1 mutations in Asian populations in general and shows the necessity of genetic counseling.

| S-EPMC9371496 | biostudies-literature

Computational and Structural Analysis to Assess the Pathogenicity of Bardet-Biedl Syndrome Related Missense Variants Identified in Bardet-Biedl Syndrome 10 Gene (BBS10).

Project description:Bardet-Biedl Syndrome (BBS) is a rare inherited disorder resulting in multiple organ dysfunctions, whose cardinal clinical features include cognitive impairment, obesity, and renal dysfunction. Although it is highly heterogeneous at genetic levels, BBS10 is one of the major causative genes worldwide. The BBS10 protein is part of a multiprotein complex localized at the basal body of the primary cilium. With the advancement of sequencing technologies, novel missense mutations are regularly reported in BBS10. However, prioritizing missense variants and conducting further in-depth analysis are key challenges in addressing their pathogenic effect. This study aims to characterize the known missense mutations of BBS10 by combining nine different in silico tools (SIFT, SNAP2, PROVEAN, Align-GVGD, ConSurf, I Mutant, MuPro, PremPS, and Dynamut) and molecular dynamics (MD) simulations. A total of 101 BBS10 missense variants have been analyzed. Our results showed that six BBS10 missense variants (Ser191Leu, Cys19Gly, Ile342Thr, Cys371Ser, Ala417Glu, and Tyr613Cys) were potentially deleterious. Overall, this study provides a comprehensive workflow for screening BBS10 missense mutations to identify pathogenic variants effectively.

| S-EPMC9608418 | biostudies-literature

A novel mutation in BBS7 gene causes Bardet-Biedl syndrome in a Chinese family.

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.

| S-EPMC2603185 | biostudies-literature

Bardet-Biedl syndrome.

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

A novel test for recessive contributions to complex diseases implicates Bardet-Biedl syndrome gene BBS10 in idiopathic type 2 diabetes and obesity.

Project description:Rare-variant association studies in common, complex diseases are customarily conducted under an additive risk model in both single-variant and burden testing. Here, we describe a method to improve detection of rare recessive variants in complex diseases termed RAFT (recessive-allele-frequency-based test). We found that RAFT outperforms existing approaches when the variant influences disease risk in a recessive manner on simulated data. We then applied our method to 1,791 Finnish individuals with type 2 diabetes (T2D) and 2,657 matched control subjects. In BBS10, we discovered a rare variant (c.1189A>G [p.Ile397Val]; rs202042386) that confers risk of T2D in a recessive state (p = 1.38 × 10(-6)) and would be missed by conventional methods. Testing of this variant in an established in vivo zebrafish model confirmed the variant to be pathogenic. Taken together, these data suggest that RAFT can effectively reveal rare recessive contributions to complex diseases overlooked by conventional association tests.

| S-EPMC4225638 | biostudies-literature

Bardet-Biedl Syndrome as a Chaperonopathy: Dissecting the Major Role of Chaperonin-Like BBS Proteins (BBS6-BBS10-BBS12).

Project description:Bardet-Biedl syndrome (BBS) is a rare genetic disorder that belongs to the group of ciliopathies, defined as diseases caused by defects in cilia structure and/or function. The six diagnostic features considered for this syndrome include retinal dystrophy, obesity, polydactyly, cognitive impairment and renal and urogenital anomalies. Furthermore, three of the 21 genes currently known to be involved in BBS encode chaperonin-like proteins (MKKS/BBS6, BBS10, and BBS12), so BBS can be also considered a member of the growing group of chaperonopathies. Remarkably, up to 50% of clinically-diagnosed BBS families can harbor disease-causing variants in these three genes, which highlights the importance of chaperone defects as pathogenic factors even for genetically heterogeneous syndromes such as BBS. In addition, it is interesting to note that BBS families with deleterious variants in MKKS/BBS6, BBS10 or BBS12 genes generally display more severe phenotypes than families with changes in other BBS genes. The chaperonin-like BBS proteins have structural homology to the CCT family of group II chaperonins, although they are believed to conserve neither the ATP-dependent folding activity of canonical CCT chaperonins nor the ability to form CCT-like oligomeric complexes. Thus, they play an important role in the initial steps of assembly of the BBSome, which is a multiprotein complex essential for mediating the ciliary trafficking activity. In this review, we present a comprehensive review of those genetic, functional and evolutionary aspects concerning chaperonin-like BBS proteins, trying to provide a new perspective that expands the classical conception of BBS only from a ciliary point of view.

| S-EPMC5534436 | biostudies-literature

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