Next-Generation Sequencing in the Diagnosis of Patients with Bardet–Biedl Syndrome—New Variants and Relationship with Hyperglycemia and Insulin Resistance

Jeziorny, Krzysztof; Antosik, Karolina; Jakiel, Paulina; Młynarski, Wojciech; Borowiec, Maciej; Zmysłowska, Agnieszka

doi:10.3390/genes11111283

Cited by 14 publications

(9 citation statements)

References 20 publications

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“…Many of the studies investigating glycaemia and diabetes mellitus in BBS have been in very small samples, which has led to inconsistent results between studies. In a study of 10 participants with BBS mainly with disease-causing variants in BBS9 and BBS10, strong associations were observed between hyperglycaemia and insulin resistance in participants with disease-causing variants in BBS9 [6]. This contrasts with earlier work including a small cohort study of 16 adults with BBS that found the majority were not glucose intolerant and had normal insulin resistance [7].…”

Section: Glycaemia and Diabetes Mellitus In Bardet Biedl Syndromementioning

confidence: 72%

Diabetes mellitus in Bardet Biedl syndrome

Pomeroy

Offenwanger²,

Timmler

2022

Current Opinion in Endocrinology, Diabetes &Amp; Obesity

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Purpose of reviewBardet Biedl syndrome (BBS) is a rare disease characterized by obesity and hyperphagia. Despite the very high prevalence of paediatric and adult obesity in this population, the prevalence of diabetes mellitus is not well described.Recent findingsStudies in small and moderately large cohorts suggest a high prevalence of traditional risk factors for diabetes mellitus in people with BBS. People with BBS appear to have a high prevalence of insulin resistance and metabolic syndrome. Small cohort studies have identified high rates of sleep disordered breathing, including sleep apnoea syndrome. Recent research has characterized traditional behavioural risk factors such as sleep hygiene and physical inactivity in people with BBS. High rates of insufficient sleep and prolonged sedentary time suggest behavioural targets of interventions to treat or prevent diabetes mellitus. Hyperphagia, likely caused by defects in the hypothalamic melanocortin-4 receptor (MC4R) neuronal pathway, pose additional challenges to behavioural interventions to prevent diabetes mellitus.SummaryUnderstanding the prevalence of diabetes mellitus and other metabolic disorders in people with BBS and the impact of traditional risk factors on glucose regulation are important to developing effective treatments in this population.

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Section: Glycaemia and Diabetes Mellitus In Bardet Biedl Syndromementioning

confidence: 72%

Diabetes mellitus in Bardet Biedl syndrome

Pomeroy

Offenwanger²,

Timmler

2022

Current Opinion in Endocrinology, Diabetes &Amp; Obesity

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“…Nowadays, NGS is the technology of choice for the study of BBS [23][24][25] . It allows the identification of new causative variants and further reanalysis to assess new BBS genes that may have been identified after a primary analysis or had not been covered by any of the classical methods initially used 26,27 .…”

Section: Discussionmentioning

confidence: 99%

Allelic overload and its clinical modifier effect in Bardet-Biedl syndrome

et al. 2022

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Bardet–Biedl syndrome (BBS) is an autosomal recessive ciliopathy characterized by extensive inter- and intra-familial variability, in which oligogenic interactions have been also reported. Our main goal is to elucidate the role of mutational load in the clinical variability of BBS. A cohort of 99 patients from 77 different families with biallelic pathogenic variants in a BBS-associated gene was retrospectively recruited. Human Phenotype Ontology terms were used in the annotation of clinical symptoms. The mutational load in 39 BBS-related genes was studied in index cases using different molecular and next-generation sequencing (NGS) approaches. Candidate allele combinations were analysed using the in silico tools ORVAL and DiGePred. After clinical annotation, 76 out of the 99 cases a priori fulfilled established criteria for diagnosis of BBS or BBS-like. BBS1 alleles, found in 42% of families, were the most represented in our cohort. An increased mutational load was excluded in 41% of the index cases (22/54). Oligogenic inheritance was suspected in 52% of the screened families (23/45), being 40 tested by means of NGS data and 5 only by traditional methods. Together, ORVAL and DiGePred platforms predicted an oligogenic effect in 44% of the triallelic families (10/23). Intrafamilial variable severity could be clinically confirmed in six of the families. Our findings show that the presence of more than two alleles in BBS-associated genes correlated in six families with a more severe phenotype and associated with specific findings, highlighting the role of the mutational load in the management of BBS cases.

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“…Patients provided written informed consent for participation in the study. The diagnosis of ALMS or BBS syndrome was confirmed in patients by sequencing the related genes, as previously described [ 25 , 26 ]. Urine samples were collected from three patients with genetically confirmed ALMS syndrome (with pathogenic variants: NM_001378454.1:c.8161C>T(;)11204C>A, NM_001378454.1:c.4108dup(;)7373_7376del and NM_001378454.1:c.1900C>T(;)11877_11878del in ALMS1 and MIM No.…”

Section: Methodsmentioning

confidence: 99%

Proteomic and Transcriptomic Landscapes of Alström and Bardet–Biedl Syndromes

Smyczyńska

Stańczak

Kuljanin

et al. 2022

Genes

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Alström syndrome (ALMS) and Bardet–Biedl syndrome (BBS) are rare genetic diseases with a number of common clinical features ranging from early-childhood obesity and retinal degeneration. ALMS and BBS belong to the ciliopathies, which are known to have the expression products of genes, encoding them as cilia-localized proteins in multiple target organs. The aim of this study was to perform transcriptomic and proteomic analysis on cellular models of ALMS and BBS syndromes to identify common and distinct pathological mechanisms present in both syndromes. For this purpose, epithelial cells were isolated from the urine of patients and healthy subjects, which were then cultured and reprogrammed into induced pluripotent stem (iPS) cells. The pathways of genes associated with the metabolism of lipids and glycosaminoglycan and the transport of small molecules were found to be concomitantly downregulated in both diseases, while transcripts related to signal transduction, the immune system, cell cycle control and DNA replication and repair were upregulated. Furthermore, protein pathways associated with autophagy, apoptosis, cilium assembly and Gli1 protein were upregulated in both ciliopathies. These results provide new insights into the common and divergent pathogenic pathways between two similar genetic syndromes, particularly in relation to primary cilium function and abnormalities in cell differentiation.

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Next-Generation Sequencing in the Diagnosis of Patients with Bardet–Biedl Syndrome—New Variants and Relationship with Hyperglycemia and Insulin Resistance

Cited by 14 publications

References 20 publications

Diabetes mellitus in Bardet Biedl syndrome

Diabetes mellitus in Bardet Biedl syndrome

Allelic overload and its clinical modifier effect in Bardet-Biedl syndrome

Proteomic and Transcriptomic Landscapes of Alström and Bardet–Biedl Syndromes

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