Screening for mutation hotspots in Bardet-Biedl syndrome patients from India.
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ABSTRACT: Bardet-Biedl syndrome (BBS) is a genetically heterogeneous autosomal recessive disorder characterized by multiple organ defects involving retina, kidney, liver and brain. Disease-causing mutations in BBS genes narrowed down by homozygosity mapping in small consanguineous and non-consanguineous pedigrees were reported in 80 per cent of the study population. This study was aimed to screen these genes (BBS3, BBS10) and specific exons of BBS genes (BBS1, BBS5, MKKS, BBS9, BBS11 and BBS12) for recurrent mutations in a selected sample of BBS patients.The recurrent mutations in BBS genes were screened in the BBS affected individuals by PCR based direct sequencing. The pathogenicity of the observed mutations were confirmed by co-segregation analysis, screening of healthy unrelated controls and in silico analysis.In the 64 BBS patients (44 males, 20 females) were studied, mutations were predominant in BBS10 and ARL6 genes; the c.272T>C; p.(I91T) mutation in ARL6 gene was a recurrent mutation. One novel non-sense mutation c.425T>G; p(L142FNx01) was obtained in BBS5 gene (family BSI-31).BBS10 gene mutations clustered in exon 2 of the gene suggesting the exon as a probable hotspot for mutations in Indian population. A cost- and time-effective strategy for the molecular diagnosis of BBS was designed based on these results.
<h4>Background & objectives</h4>Bardet-Biedl syndrome (BBS) is a genetically heterogeneous autosomal recessive disorder characterized by multiple organ defects involving retina, kidney, liver and brain. Disease-causing mutations in BBS genes narrowed down by homozygosity mapping in small consanguineous and non-consanguineous pedigrees were reported in 80 per cent of the study population. This study was aimed to screen these genes (BBS3, BBS10) and specific exons of BBS genes (BBS1, BBS5, MKKS, B ...[more]
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.
Project description:BACKGROUND:The importance of hyperphagia as a cause for energy imbalance in humans with Bardet-Biedl syndrome (BBS) has not been established. We therefore compared hyperphagic symptoms in patients with BBS vs. controls. METHODS:We studied 13 patients with BBS and 23 non-syndromic controls with similar age, sex and body mass index (BMI) z-score. A 13-item hyperphagia questionnaire was completed by patients' parents/guardians. RESULTS:Total hyperphagia questionnaire score was higher in BBS than controls (27.6?±?9.0 vs. 19.1?±?7.9, P?=?0.005). Behaviour and drive subscales were higher for BBS than controls (12.5?±?4.1 vs. 7.8?±?3.2, P?=?0.001, and 11.2?±?4.1 vs. 8.3?±?3.8, P?=?0.04, respectively); severity was not significantly different between groups (3.8?±?1.5 vs. 3.0?±?1.3, P?=?0.072). After adjustment for demographic variables and BMI z-score, total and behaviour subscale scores remained significantly different between groups, suggesting food-seeking activity, rather than preoccupation with food may be the main hyperphagic feature among patients with BBS. CONCLUSION:Appetite dysregulation may contribute to obesity in BBS.
Project description:BackgroundBardet-Biedl syndrome (BBS) is a rare inherited multisystemic disorder with autosomal recessive or complex digenic triallelic inheritance. There is currently no treatment for BBS, but some morbidities can be managed. Accurate molecular diagnosis is often crucial for the definition of appropriate patient management and for the development of a potential personalized therapy.MethodsWe developed a next-generation-sequencing (NGS) protocol for the screening of the 18 most frequently mutated genes to define the genotype and clarify the mutation spectrum of a cohort of 20 BBS Italian patients.ResultsWe defined the causative variants in 60% of patients; four of those are novel. 33% of patients also harboured variants in additional gene/s, suggesting possible oligogenic inheritance. To explore the function of different genes, we looked for correlations between genotype and phenotype in our cohort. Hypogonadism was more frequently detected in patients with variants in BBSome proteins, while renal abnormalities in patients with variations in BBSome chaperonin genes.ConclusionsNGS is a powerful tool that can help understanding BBS patients' phenotype through the identification of mutations that could explain differences in phenotype severity and could provide insights for the development of targeted therapy. Furthermore, our results support the existence of additional BBS loci yet to be identified.
Project description:PurposeBardet-Biedl syndrome (BBS) is a ciliopathy with a wide spectrum of symptoms due to primary cilia dysfunction, including genitourinary developmental anomalies as well as impaired reproduction, particularly in males. Primary cilia are known to be required at the following steps of reproduction function: (i) genitourinary organogenesis, (ii) in fetal firing of hypothalamo-pituitary axe, (iii) sperm flagellum structure, and (iv) first zygotic mitosis conducted by proximal sperm centriole. BBS phenotype is not fully understood.MethodsThis study explored all steps of reproduction in 11 French male patients with identified BBS mutations.ResultsBBS patients frequently presented with genitourinary malformations, such as cryptorchidism (5/11), short scrotum (5/8), and micropenis (5/8), but unexpectedly, with normal testis size (7/8). Ultrasonography highlighted epididymal cysts or agenesis of one seminal vesicle in some cases. Sexual hormones levels were normal in all patients except one. Sperm numeration was normal in 8 out of the 10 obtained samples. Five to 45% of sperm presented a progressive motility. Electron microscopy analysis of spermatozoa did not reveal any homogeneous abnormality. Moreover, a psychological approach pointed to a decreased self-confidence linked to blindness and obesity explaining why so few BBS patients express a child wish.ConclusionsPrimary cilia dysfunction in BBS impacts the embryology of the male genital tract, especially epididymis, penis, and scrotum through an insufficient fetal androgen production. However, in adults, sperm structure does not seem to be impacted. These results should be confirmed in a greater BBS patient cohort, focusing on fertility.
Project description:The Bardet-Biedl syndrome (BBS) is a significant genetic cause of chronic and end-stage renal failure in children. Despite being a relatively rare recessive condition, BBS has come to prominence during the past few years owing to revelations of primary cilia dysfunction underlying pathogenesis. The study of this multi-system disorder, which includes obesity, cognitive impairment, genito-urinary tract malformations and limb deformities, is beginning to reveal insights into several aspects of mammalian development and organogenesis. Involvement of BBS proteins in disparate pathways such as the non-canonical Wnt and Sonic Hedgehog pathways is highlighting their interplay in disease pathogenesis. Here we review the recent developments in this emerging field, with the emphasis on the renal component of the syndrome and potential future directions.
Project description:Bardet-Biedl syndrome (BBS; OMIM no. 209?900) and Alström syndrome (ALMS; OMIM no. 203?800) are rare, multisystem genetic disorders showing both a highly variable phenotype and considerable phenotypic overlap; they are included in the emerging group of diseases called ciliopathies. The genetic heterogeneity of BBS with 14 causal genes described to date, serves to further complicate mutational analysis. The development of the BBS-ALMS array which detects known mutations in these genes has allowed us to detect at least one mutation in 40.5% of BBS families and in 26.7% of ALMS families validating this as an efficient and cost-effective first pass screening modality. Furthermore, using this method, we found two BBS families segregating three BBS alleles further supporting oligogenicity or modifier roles for additional mutations. We did not observe more than two mutations in any ALMS family.
Project description:We report miRNA profiling in patients with Alström syndrome (ALMS) and Bardet-Biedl syndrome (BBS). The aim of this study was to determine if the expression of circulating miRNAs in patients with ALMS and BBS differs from that in healthy and obese individuals and determine if miRNA levels correlate with metabolic tests, BMI-SDS and patient age.
Project description:Bardet-Biedl syndrome (BBS, OMIM 209900) is a ciliopathy causing multivisceral abnormalities. This disease is mainly characterized by obesity, post-axial polydactyly, hypogenitalism, intellectual disabilities, pigmentary retinopathy, and renal deficiency. The prevalence of BBS has been estimated in different populations, ranging from 1 in 160,000 in European populations to 1 in 13,000 in Bedouins from Kuwait. In the present report, we present the first epidemiological study of Bardet-Biedl syndrome in Tunisia. From 1984 to 2009, 46 Tunisian families, including 67 affected members, were diagnosed as BBS. The patients' ages ranged between 6 months and 37 years, with median age of 10.4 years. High level of consanguinity was noted in our cohort (93.47%). The overall minimum prevalence in our population was estimated to be approximately 1 in 156,000 individuals. Our study reflects the actual frequency of BBS in North Africa and showed that this disease seems uncommon.
Project description:Forty-two patients with a clinical diagnosis of Bardet-Biedl syndrome ages 2-61 years were given a neuropsychological test battery to evaluate cognitive, sensory, and behavioral functioning. These tests included the Wechsler scales of intelligence, Rey Auditory Verbal Learning Test, Boston Naming Test, D-KEFS Verbal Fluency Test, D-KEFS Color-Word Interference Test, D-KEFS Sorting Test, Wide Range Achievement Test: Math and Reading Subtests, Purdue Pegboard, The University of Pennsylvania Smell Identification Test, Social Communication Questionnaire, Social Responsiveness Scale, and Behavior Assessment System for Children, Second Edition, Parent Rating Scale. On the age appropriate Wechsler scale, the mean Verbal Comprehension was 81 (n = 36), Working Memory was 81 (n = 36), Perceptual Reasoning was 78 (n = 24) and Full Scale IQ was 75 (n = 26). Memory for a word list (Rey Auditory Verbal Learning Test) was in the average range with a mean of 89 (n = 19). Fine motor speed was slow on the Purdue with mean scores 3-4 standard deviations below norms. All subjects were microsmic on the University of Pennsylvania Smell Identification Test. Of these 42 patients, only 6 were able to complete all auditory and visual tests; 52% were unable to complete the visual tests due to impaired vision. A wide range of behavioral issues were endorsed on questionnaires given to parents. Most had social skill deficits but no pattern of either externalizing or internalizing problems. We identify a characteristic neuro-behavioral profile in our cohort comprised of reduced IQ, impaired fine-motor function, and decreased olfaction.
Project description:Bardet-Biedl syndrome (BBS) is a genetically heterogeneous disorder of the primary cilium associated with obesity. In BBS mouse models, ciliary dysfunction leads to impaired leptin signaling and hyperleptinemia before obesity onset. To study the pathophysiology of obesity in BBS, we compared patients with BBS and body mass index Z-score (BMI-Z)-matched controls.Fifty patients with BBS were matched 2:1 by age, sex, race, and BMI-Z with 100 controls. Patients with BBS and controls were compared for differences in body composition (dual-energy x-ray absorptiometry, abdominal magnetic resonance imaging), blood pressure Z-score (BP-Z; standardized for age, sex, and height), and fasting concentrations of leptin, lipids, insulin, and glucose. Patients with BBS were also compared by genotype.Leptin, triglycerides, intraabdominal fat mass, and diastolic BP-Z were significantly greater in patients with BBS than in the controls. BBS1 (27%) and BBS10 (30%) mutations were the most prevalent. Patients with BBS10 mutations had significantly higher BMI-Z, greater visceral adiposity, and greater insulin resistance than those with BBS1 mutations.Patients with BBS had higher leptin than expected for their degree of adiposity, consistent with the notion that ciliopathy-induced leptin signaling dysfunction is associated with leptin resistance. The preferential deposition of fat intraabdominally in patients with BBS may indicate a predisposition for metabolic complications, including hypertension and hypertriglyceridemia. The observation of disparate results in the BBS10 vs. BBS1 mutation groups is the first demonstration of physiological differences among patients with BBS caused by mutations in distinct genes. These results suggest that the obesity of BBS is distinct from nonsyndromic obesity.