Whole Genome Sequencing Solves an Atypical Form of Bardet-Biedl Syndrome: Identification of Novel Pathogenic Variants of BBS9.

Bardet-Biedl syndrome (BBS) is a rare recessive multisystem disorder characterized by retinitis pigmentosa, obesity, postaxial polydactyly, cognitive deficits, and genitourinary defects. BBS is clinically variable and genetically heterogeneous, with 26 genes identified to contribute to the disorder when mutated, the majority encoding proteins playing role in primary cilium biogenesis, intraflagellar transport, and ciliary trafficking. Here, we report on an 18-year-old boy with features including severe photophobia and central vision loss since childhood, hexadactyly of the right foot and a supernumerary nipple, which were suggestive of BBS. Genetic analyses using targeted resequencing and exome sequencing failed to provide a conclusive genetic diagnosis. Whole-genome sequencing (WGS) allowed us to identify compound heterozygosity for a missense variant and a large intragenic deletion encompassing exon 12 in BBS9 as underlying the condition. We assessed the functional impact of the identified variants and demonstrated that they impair BBS9 function, with significant consequences for primary cilium formation and morphology. Overall, this study further highlights the usefulness of WGS in the diagnostic workflow of rare diseases to reach a definitive diagnosis. This report also remarks on a requirement for functional validation analyses to more effectively classify variants that are identified in the frame of the diagnostic workflow.

Obesity-Related Ciliopathies: Focus on Advances of Biomarkers.

Obesity-related ciliopathies, as a group of ciliopathies including Alström Syndrome and Bardet-Biedl Syndrome, exhibit distinct genetic and phenotypic variability. The understanding of these diseases is highly significant for understanding the functions of primary cilia in the human body, particularly regarding the relationship between obesity and primary cilia. The diagnosis of these diseases primarily relies on clinical presentation and genetic testing. However, there is a significant lack of research on biomarkers to elucidate the variability in clinical manifestations, disease progression, prognosis, and treatment responses. Through an extensive literature review, the paper focuses on obesity-related ciliopathies, reviewing the advancements in the field and highlighting the potential roles of biomarkers in the clinical presentation, diagnosis, and prognosis of these diseases.

Collaborative effort: managing Bardet-Biedl syndrome in pediatric patients. Case series and a literature review.

Bardet-Biedl Syndrome (BBS) is an autosomal recessive non-motile ciliopathy, caused by mutations in more than twenty genes. Their expression leads to the production of BBSome-building proteins or chaperon-like proteins supporting its structure. The prevalence of the disease is estimated at 1: 140,000 - 160,000 of life births. Its main clinical features are retinal dystrophy, polydactyly, obesity, cognitive impairment, hypogonadism, genitourinary malformations, and kidney disease. BBS is characterized by heterogeneous clinical manifestation and the variable onset of signs and symptoms. We present a case series of eight pediatric patients with BBS (6 boys and 2 girls) observed in one clinical center including two pairs of siblings. The patients' age varies between 2 to 13 years (average age of diagnosis: 22 months). At presentation kidney disorders were observed in seven patients, polydactyly in six patients' obesity, and psychomotor development delay in two patients. In two patients with kidney disorders, the genetic tests were ordered at the age of 1 and 6 months due to the presence of symptoms suggesting BBS and having an older sibling with the diagnosis of the syndrome. The mutations in the following genes were confirmed: BBS10, MKKS, BBS7/BBS10, BBS7, BBS9. All described patients developed symptoms related to the urinary system and kidney-function impairment. Other most common symptoms are polydactyly and obesity. In one patient the obesity class 3 was diagnosed with multiple metabolic disorders. In six patients the developmental delay was diagnosed. The retinopathy was observed only in one, the oldest patient. Despite having the same mutations (siblings) or having mutations in the same gene, the phenotypes of the patients are different. We aimed to addresses gaps in understanding BBS by comparing our data and existing literature through a narrative review. This research includes longitudinal data and explores genotype-phenotype correlations of children with BBS. BBS exhibits diverse clinical features and genetic mutations, making diagnosis challenging despite defined criteria. Same mutations can result in different phenotypes. Children with constellations of polydactyly and/or kidney disorders and/or early-onset obesity should be managed towards BBS. Early diagnosis is crucial for effective monitoring and intervention to manage the multisystemic dysfunctions associated with BBS.

Clinical features of a novel compound heterozygous genotype of the BBS2 gene: a case report.

Bardet-Biedl syndrome is a rare autosomal recessive genetic disorder with heterogenous clinical manifestations. The present study reports the clinical features of a novel compound heterozygous genotype of the BBS2 gene in a 14-year-old girl and her 6-year-old sister who had complaints of early-onset low vision. Fundus images revealed retinitis pigmentosa-like changes, and full-field electroretinograms showed no amplitude for the rod or cone response in both patients. Interestingly, nystagmus was observed in the older sister. On physical examination, the sisters had moderate obesity without polydactyly, hypogonadism, or intellectual disability. Exome sequencing revealed a novel compound heterozygous genotype of BBS2 in the sisters, namely the paternally inherited NM_031885.5:c.534 + 1G > T variant and the maternally inherited NM_031885.5:c.700C > T (p.Arg234Ter) variant. Both variants were classified as pathogenic according to the American College of Medical Genetics and Genomics guidelines. This study provides useful information on the genotype-phenotype relationships of the BBS2 gene for genetic counseling and diagnosis.

Rod-sparing in a bardet-biedl syndrome patient with mutations in the ARL6 gene.

PURPOSE: Bardet-Biedl Syndrome (BBS) is an autosomal recessive disorder characterized by pleiotropism that affects multiple organ systems. The primary features of BBS include rod-cone dystrophy, renal anomalies, post axial polydactyly, and neurologic deficits. The clinical picture of BBS is extensively heterogenous, with inter and intra familial patients varying in levels of syndromic manifestations and severity of symptoms. METHODS: In this study we examined a monocular BBS patient who was compound heterozygous for mutations in the ARL6 (BBS3) gene. RESULTS: The patient reported visual complaints consistent with a clinical picture of cone or cone-rod dystrophy. Fundus imaging showed retinal mottling on color photos and a parafoveal hyperfluorescent ring on short wave autofluorescence (SW-AF). Full field electroretinogram (ffERG) revealed normal scotopic step tracings and diminished amplitudes in the photopic steps. CONCLUSION: This rod-sparing result was consistent with cone-dystrophy and is the first known case of a rod-sparing ffERG phenotype in a BBS patient with mutations in the ARL6 gene. This contributes to the existing phenotype and may potentially contribute to furthering our understanding of BBS pathophysiology.

Refractive errors in patients with Bardet Biedl syndrome.

PURPOSE: Bardet-Biedl Syndrome (BBS) is a rare autosomal recessive ciliopathy. Within corneal development, primary cilia serve a critical role. We sought to investigate the association of BBS with corneal astigmatism among a cohort of patients with BBS. METHODS: This was a cross-sectional, retrospective study performed at a pediatric ophthalmology department of a tertiary hospital. The study enrolled 45 patients with genetically confirmed Bardet-Biedl syndrome, encompassing a total of 90 eyes observed from February 2011 to August 2021. Spherical and cylindrical refractive errors and keratometry outcome measures, including diopter (D) values at the flattest and steepest axes, were recorded. Corneal astigmatism of greater than 3D is considered extreme corneal astigmatism based on previously published data. RESULTS: Among 45 patients (M:26; F:19), the mean age was 16.4 ± 8.2 years, and the mean best-corrected visual acuity was 20/60. The most common molecular diagnosis was BBS1, seen in 24 of 45 (53.3%). Among all the patients, the mean spherical refractive error was -2.9 ± 3.8D. The mean cylindrical refractive error was 2.6 ± 1.5D. The mean keratometry values at the flattest axis was 43.5 ± 5.3D (39.4-75.0) and at the steepest axis was 47.2 ± 7.3D(41.5-84.0). Among all the patients with BBS, the mean corneal astigmatism was 3.7 ± 1.0D(0.5-7.1), which is considered extreme. CONCLUSION: A cohort of individuals with BBS demonstrated high corneal astigmatism. These results suggest an association between corneal astigmatism and primary ciliary dysfunction and may assist in clinical management and future therapeutic targets among BBS and other corneal disorders.

Phenotypic and genotypic analysis of 11 fetal cases with Bardet-Biedl syndrome.

OBJECTIVE: To present the prenatal sonographic features and genomic spectrum of pregnancies with fetal Bardet-Biedl syndrome (BBS). METHODS: This was a retrospective study of 11 cases with BBS diagnosed by prenatal ultrasound and confirmed by genetic testing. Clinical and laboratory data were collected and reviewed for these cases, including maternal demographics, prenatal sonographic findings, molecular testing sequencing results, and pregnancy outcomes. RESULTS: All cases had unremarkable first-trimester ultrasound scans without reporting limb malformations. All had second-trimester abnormal ultrasounds: postaxial polydactyly in nine cases (9/11), renal abnormalities in seven (7/11), reduced amniotic fluid volume in two (2/11), central nervous system anomalies in two (2/11), and ascites in three (3/11). Ten fetuses presented with at least two-system anomalies, and one (Case 11) presented with only postaxial polydactyly. Variants were detected in five genes, including BBS2, ARL6/BBS3, BBS7, CEP290/BBS14 and IFT74/BBS22. Ten pregnancies were terminated in the second trimester, while one continued to term. CONCLUSION: Enlarged hyperechogenic kidneys and postaxial polydactyly are the two most common sonographic features of fetal BBS. Prenatal diagnosis of BBS can be done with ultrasound and genetic testing although the diagnosis may be made in the second trimester.

The Clinical and Mutational Spectrum of Bardet-Biedl Syndrome in Saudi Arabia.

The retinal features of Bardet-Biedl syndrome (BBS) are insufficiently characterized in Arab populations. This retrospective study investigated the retinal features and genotypes of BBS in Saudi patients managed at a single tertiary eye care center. Data analysis of the identified 46 individuals from 31 families included visual acuity (VA), systemic manifestations, multimodal retinal imaging, electroretinography (ERG), family pedigrees, and genotypes. Patients were classified to have cone-rod, rod-cone, or generalized photoreceptor dystrophy based on the pattern of macular involvement on the retinal imaging. Results showed that nyctalopia and subnormal VA were the most common symptoms with 76% having VA ≤ 20/200 at the last visit (age: 5-35). Systemic features included obesity 91%, polydactyly 56.5%, and severe cognitive impairment 33%. The predominant retinal phenotype was cone-rod dystrophy 75%, 10% had rod-cone dystrophy and 15% had generalized photoreceptor dystrophy. ERGs were undetectable in 95% of patients. Among the 31 probands, 61% had biallelic variants in BBSome complex genes, 32% in chaperonin complex genes, and 6% had biallelic variants in ARL6; including six previously unreported variants. Interfamilial and intrafamilial variabilities were noted, without a clear genotype-phenotype correlation. Most BBS patients had advanced retinopathy and were legally blind by early adulthood, indicating a narrow therapeutic window for rescue strategies.

Afectación ocular como primera y única manifestación del síndrome de Bardet-Biedl: presentación de un caso / Ocular impairment as the first and only manifestation of Bardet–Biedl syndrome: A case report

El síndrome de Bardet-Biedl (SBB) es una ciliopatía que se asocia principalmente a distrofia retiniana, disfunción renal, polidactilia posaxial, obesidad, déficit cognitivo e hipogonadismo. Los síntomas vinculados a la distrofia retiniana no suelen aparecer hasta la primera década de vida, por lo que la detección tiende a retrasarse. La afectación ocular puede ser la forma inicial de manifestación de este síndrome, incluso puede ser la única, por lo que se debería tener en cuenta en el diagnóstico diferencial de una ambliopía en un niño que no mejora a pesar del correcto cumplimiento del tratamiento. Se presenta un caso de baja agudeza visual (AV) en una paciente pediátrica como manifestación inicial que lleva al diagnóstico del SBB y que es, además, el único síntoma que exhibe hasta la fecha, a pesar de tratarse de una enfermedad multisistémica.(AU)

Bardet–Biedl syndrome is a ciliopathy mainly associated with retinal dystrophy, renal dysfunction, post-axial polydactyly, obesity, cognitive deficit and hypogonadism. The symptoms associated with retinal dystrophy do not usually appear until the first decade of life, so the diagnosis is usually delayed. Ocular involvement may be the initial form of manifestation of this syndrome, it may even be the only one, so it should be taken into account in the differential diagnosis of amblyopia in a child who does not improve despite correct compliance with treatment. A case of low visual acuity in a pediatric patient is presented as an initial manifestation that leads to the diagnosis of Bardet–Biedl syndrome, and which is also the only symptom that the patient presents to date, despite being a multisystem disease.(AU)

Adipocyte-specific disruption of the BBSome causes metabolic and autonomic dysfunction.

Obesity is a major public health issue due to its association with type 2 diabetes, hypertension, and other cardiovascular risks. The BBSome, a complex of eight conserved Bardet-Biedl syndrome (BBS) proteins, has emerged as a key regulator of energy and glucose homeostasis as well as cardiovascular function. However, the importance of adipocyte BBSome in controlling these physiological processes is not clear. Here, we show that adipocyte-specific constitutive disruption of the BBSome through selective deletion of the Bbs1 gene adiponectin (AdipoCre/Bbs1fl/fl mice) does not affect body weight under normal chow or high-fat and high-sucrose diet (HFHSD). However, constitutive BBSome deficiency caused impairment in glucose tolerance and insulin sensitivity. Similar phenotypes were observed after inducible adipocyte-specific disruption of the BBSome (AdipoCreERT2/Bbs1fl/fl mice). Interestingly, a significant increase in renal sympathetic nerve activity, measured using multifiber recording in the conscious state, was observed in AdipoCre/Bbs1fl/fl mice on both chow and HFHSD. A significant increase in tail-cuff arterial pressure was also observed in chow-fed AdipoCre/Bbs1fl/fl mice, but this was not reproduced when arterial pressure was measured by radiotelemetry. Moreover, AdipoCre/Bbs1fl/fl mice had no significant alterations in vascular reactivity. On the other hand, AdipoCre/Bbs1fl/fl mice displayed impaired baroreceptor reflex sensitivity when fed HFHSD, but not on normal chow. Taken together, these data highlight the relevance of the adipocyte BBSome for the regulation of glucose homeostasis and sympathetic traffic. The BBSome also contributes to baroreflex sensitivity under HFHSD, but not normal chow.NEW & NOTEWORTHY The current study show how genetic manipulation of fat cells impacts various functions of the body including sensitivity to the hormone insulin.

Syndromic ciliopathy: a taiwanese single-center study.

BACKGROUND: Syndromic ciliopathies are a group of congenital disorders characterized by broad clinical and genetic overlap, including obesity, visual problems, skeletal anomalies, mental retardation, and renal diseases. The hallmark of the pathophysiology among these disorders is defective ciliary functions or formation. Many different genes have been implicated in the pathogenesis of these diseases, but some patients still remain unclear about their genotypes. METHODS: The aim of this study was to identify the genetic causes in patients with syndromic ciliopathy. Patients suspected of or meeting clinical diagnostic criteria for any type of syndromic ciliopathy were recruited at a single diagnostic medical center in Southern Taiwan. Whole exome sequencing (WES) was employed to identify their genotypes and elucidate the mutation spectrum in Taiwanese patients with syndromic ciliopathy. Clinical information was collected at the time of patient enrollment. RESULTS: A total of 14 cases were molecularly diagnosed with syndromic ciliopathy. Among these cases, 10 had Bardet-Biedl syndrome (BBS), comprising eight BBS2 patients and two BBS7 patients. Additionally, two cases were diagnosed with Alström syndrome, one with Oral-facial-digital syndrome type 14, and another with Joubert syndrome type 10. A total of 4 novel variants were identified. A recurrent splice site mutation, BBS2: c.534 + 1G > T, was present in all eight BBS2 patients, suggesting a founder effect. One BBS2 patient with homozygous c.534 + 1G > T mutations carried a third ciliopathic allele, TTC21B: c.264_267dupTAGA, a nonsense mutation resulting in a premature stop codon and protein truncation. CONCLUSIONS: Whole exome sequencing (WES) assists in identifying molecular pathogenic variants in ciliopathic patients, as well as the genetic hotspot mutations in specific populations. It should be considered as the first-line genetic testing for heterogeneous disorders characterized by the involvement of multiple genes and diverse clinical manifestations.

The characterization and comorbidities of heterozygous Bardet-Biedl syndrome carriers.

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.

Syndromic Retinitis Pigmentosa: A 15-Patient Study.

Retinitis pigmentosa is a group of genetically determined retinal dystrophies characterized by primary photoreceptor apoptosis and can occur in isolated or syndromic conditions. This study reviewed the clinical data of 15 patients with syndromic retinitis pigmentosa from a Rare Disease Reference Center in Brazil and the results of their next-generation sequencing tests. Five males and ten females participated, with the mean ages for ocular disease onset, fundoscopic diagnosis, and molecular evaluation being 9, 19, and 29 years, respectively. Bardet-Biedl syndrome (n = 5) and Usher syndrome (n = 3) were the most frequent diagnoses, followed by other rare conditions. Among the patients, fourteen completed molecular studies, with three negative results and eleven revealing findings in known genes, including novel variants in MKKS (c.432_435del, p.Phe144Leufs*14), USH2A (c.(7301+1_7302-1)_(9369+1_9370-1)del), and CEP250 (c.5383dup, p.Glu1795Glyfs*13, and c.5050del, p.Asp1684Thrfs*9). Except for Kearn-Sayre, all presented an autosomal recessive inheritance pattern with 64% homozygosity results. The long gap between symptom onset and diagnosis highlights the diagnostic challenges faced by the patients. This study reaffirms the clinical heterogeneity of syndromic retinitis pigmentosa and underscores the pivotal role of molecular analysis in advancing our understanding of these diseases.

Molecular and phenotypic characteristics of Bardet-Biedl syndrome in Chinese patients.

BACKGROUND: Bardet-Biedl syndrome (BBS) is a type of non-motile ciliopathy. To date, 26 genes have been reported to be associated with BBS. However, BBS is genetically heterogeneous, with significant clinical overlap with other ciliopathies, which complicates diagnosis. Disability and mortality rates are high in BBS patients; therefore, it is urgent to improve our understanding of BBS. Thus, our study aimed to describe the genotypic and phenotypic spectra of BBS in China and to elucidate genotype-phenotype correlations. METHODS: Twenty Chinese patients diagnosed with BBS were enrolled in this study. We compared the phenotypes of Chinese BBS patients in this study with those from other countries to analyze the phenotypic differences across patients worldwide. In addition, genotype-phenotype correlations were described for our cohort. We also summarized all previously reported cases of BBS in Chinese patients (71 patients) and identified common and specific genetic variants in the Chinese population. RESULTS: Twenty-eight variants, of which 10 are novel, in 5 different BBS-associated genes were identified in 20 Chinese BBS patients. By comparing the phenotypes of BBSome-coding genes (BBS2,7,9) with those of chaperonin-coding genes (BBS10,12), we found that patients with mutations in BBS10 and 12 had an earlier age of onset (1.10 Vs. 2.20, p < 0.01) and diagnosis (4.64 Vs. 13.17, p < 0.01), whereas patients with mutations in BBS2, 7, and 9 had a higher body mass index (28.35 Vs. 24.21, p < 0.05) and more vision problems (p < 0.05). Furthermore, in 91 Chinese BBS patients, mutations were predominant in BBS2 (28.89%) and BBS7 (15.56%), and the most frequent variants were in BBS2: c.534 + 1G > T (10/182 alleles) and BBS7: c.1002delT (7/182 alleles), marking a difference from the genotypic spectra of BBS reported abroad. CONCLUSIONS: We recruited 20 Chinese patients with BBS for genetic and phenotypic analyses, and identified common clinical manifestations, pathogenic genes, and variants. We also described the phenotypic differences across patients worldwide and among different BBS-associated genes. This study involved the largest cohort of Chinese patients with BBS, and provides new insights into the distinctive clinical features of specific pathogenic variants.

[Improved Care and Treatment Options for Patients with Hyperphagia-Associated Obesity in Bardet-Biedl Syndrome]. / Verbesserte Versorgungs-und Behandlungsoptionen für Patienten mit Hyperphagie-assoziierter Adipositas bei Bardet-Biedl-Syndrom.

Bardet-Biedl syndrome (BBS) is a rare, autosomal recessive multisystem disease. The pathophysiological origin is a dysfunction of the primary cilium. Clinical symptoms are heterogeneous and variable: retinal dystrophy, obesity, polydactyly, kidney abnormalities, hypogenitalism and developmental delays are the most common features. By the approval of the melanocortin 4 receptor agonist setmelanotide, a drug therapy for BBS-associated hyperphagia and obesity can be offered for the first time. Hyperphagia and severe obesity represent a considerable burden and are associated with comorbidity and increased mortality risk. Due to the limited experience with setmelanotide in BBS, a viable comprehensive therapy concept is to be presented. Therapy decision and management should be conducted in expert centers. For best therapeutic effects with setmelanotide adequate information of the patient about the modalities of the therapy (daily subcutaneous injection) and possible adverse drug events are necessary. Furthermore, the involvement of psychologists, nutritionists and nursing services (support for the application) should be considered together with the patient. The assessment of therapy response should be carried out with suitable outcome measurements and centrally reported to an adequate register.

Ocular impairment as the first and only manifestation of Bardet-Biedl syndrome: A case report.

Bardet-Biedl syndrome is a ciliopathy mainly associated with retinal dystrophy, renal dysfunction, post-axial polydactyly, obesity, cognitive deficit and hypogonadism. The symptoms associated with retinal dystrophy do not usually appear until the first decade of life, so the diagnosis is usually delayed. Ocular involvement may be the initial form of manifestation of this syndrome, it may even be the only one, so it should be taken into account in the differential diagnosis of amblyopia in a child who does not improve despite correct compliance with treatment. A case of low visual acuity in a pediatric patient is presented as an initial manifestation that leads to the diagnosis of Bardet-Biedl Syndrome, and which is also the only symptom that the patient presents to date, despite being a multisystem disease.

Bardet-Biedl syndrome: A clinical overview focusing on diagnosis, outcomes and best-practice management.

Bardet-Biedl syndrome (BBS) is a genetic disorder characterized by early-onset obesity, polydactyly, genital and kidney anomalies, developmental delay and vision loss due to rod-cone dystrophy. BBS is an autosomal recessive disorder with >20 implicated genes. The genotype-phenotype relationship in BBS is not clear, and there may be additional modifying factors. The underlying mechanism is dysfunction of primary cilia. In BBS, receptor trafficking in and out of the cilia is compromised, affecting multiple organ systems. Along with early-onset obesity, hyperphagia is a prominent symptom and contributes significantly to clinical morbidity and caregiver burden. While there is no cure for BBS, setmelanotide is a new pharmacotherapy approved for treatment of obesity in BBS. The differential diagnosis for BBS includes other ciliopathies, such as Alstrom syndrome, and other genetic obesity syndromes, such as Prader-Willi syndrome. Careful clinical history and genetic testing can help determine the diagnosis and a multidisciplinary team is necessary to guide clinical management.

Bardet-Biedl syndrome: A focus on genetics, mechanisms and metabolic dysfunction.

Bardet-Biedl syndrome (BBS) is a rare, monogenic, multisystem disorder characterized by retinal dystrophy, renal abnormalities, polydactyly, learning disabilities, as well as metabolic dysfunction, including obesity and an increased risk of type 2 diabetes. It is a primary ciliopathy, and causative mutations in more than 25 different genes have been described. Multiple cellular mechanisms contribute to the development of the metabolic phenotype associated with BBS, including hyperphagia as a consequence of altered hypothalamic appetite signalling as well as alterations in adipocyte biology promoting adipocyte proliferation and adipogenesis. Within this review, we describe in detail the metabolic phenotype associated with BBS and discuss the mechanisms that drive its evolution. In addition, we review current approaches to the metabolic management of patients with BBS, including the use of weight loss medications and bariatric surgery. Finally, we evaluate the potential of targeting hypothalamic appetite signalling to limit hyperphagia and induce clinically significant weight loss.

A Comprehensive Review of Syndromic Forms of Obesity: Genetic Etiology, Clinical Features and Molecular Diagnosis.

Syndromic obesity refers to obesity occurring with additional clinical findings, such as intellectual disability/developmental delay, dysmorphic features, and congenital malformations. PURPOSE OF REVIEW: To present a narrative review regarding the genetic etiology, clinical description, and molecular diagnosis of syndromic obesity, which is a rare condition with high phenotypic variability and genetic heterogeneity. The following syndromes are presented in this review: Prader-Willi, Bardet-Biedl, Pseudohypoparathyroidism, Alström, Smith-Magenis, Cohen, Temple, 1p36 deletion, 16p11.2 microdeletion, Kleefstra, SIM1-related, Börjeson-Forssman-Lehmann, WAGRO, Carpenter, MORM, and MYT1L-related syndromes. RECENT FINDINGS: There are three main groups of mechanisms for syndromic obesity: imprinting, transcriptional activity regulation, and cellular cilia function. For molecular diagnostic, methods of genome-wide investigation should be prioritized over sequencing of panels of syndromic obesity genes. In addition, we present novel syndromic conditions that need further delineation, but evidences suggest they have a higher frequency of obesity. The etiology of syndromic obesity tends to be linked to disrupted neurodevelopment (central) and is associated with a diversity of genes and biological pathways. In the genetic investigation of individuals with syndromic obesity, the possibility that the etiology of the syndromic condition is independent of obesity should be considered. The accurate genetic diagnosis impacts medical management, treatment, and prognosis, and allows proper genetic counseling.