A pilot rating system to evaluate the quality of goal attainment scales used as outcome measures in rehabilitation.

Goal Attainment Scaling (GAS) is a method for writing person-centred approach evaluation scales that can be used as an outcome measure in clinical or research settings in rehabilitation. To be used in a research setting, it requires a high methodological quality approach. The aim of this study was to explore the feasibility and reliability of the GAS quality rating system, to ensure that GAS scales used as outcome measures are valid and reliable. Secondary objectives were: (1) to compare goal attainment scores' reliability according to how many GAS levels are described in the scale; and (2) to explore if GAS scorings are influenced by who scores goal attainment. The GAS scales analysed here were set collaboratively by 57 cognitively impaired adults clients and their occupational therapist. Goals had to be achieved within an inpatient one-month stay, during which clients participated in an intervention aimed at improving planning skills in daily life. The GAS quality rating system proved to be feasible and reliable. Regarding GAS scores, interrater reliability was higher when only three of the five GAS levels were described, i.e., "three milestone GAS" (0.74-0.92), than when all five levels were described (0.5-0.88), especially when scored by the clients (0.5 -0.88).

Interference effect of food and emotional stimuli in Stroop-like tasks for children and adults with Prader-Willi Syndrome.

Interference effect of food and emotional stimuli in Stroop-like tasks for children and adults with Prader-Willi Syndrome. The aim of this work was to study the way items related to food or emotion are processed by a population known to have difficulties with dietary restriction, namely individuals with Prader-Willi Syndrome (PWS). Given the presence of intellectual disability (ID) in PWS, our experiments were designed to examine whether these difficulties were specific to PWS or linked with their ID. Two modified Stroop tasks (i.e., a food version and an emotional version) were administered to seventy-four children (aged between 6 and 16 years old) divided into three groups (one with PWS, one with ID matched on age and Intellectual Quotient (IQ), and one healthy group matched on age) and to eighty-four adults (aged between 18 and 48 years old) distributed in the same three groups. For both tasks, a picture version was used for the children and a word version for the adults. For the food Stroop task, (Experiment 1), materials were composed of low or high-caloric food items and stimuli not related to food. The results show a food Stroop effect for children and adults with PWS that was absent in the group of healthy participants. Moreover, a food Stroop effect was also significant for adults with ID. For the emotional Stroop task (Experiment 2), materials were composed of negative, positive and neutral stimuli. The emotional Stroop effect was also obtained for children and adults with PWS as well as for the healthy group, but not for the age- and IQ-matched group. For the PWS groups, results show a preservation to process positive pictures for children and difficulties to process negative stimuli for both age-groups. These results suggest that people with PWS have difficulties in disengaging their attention when food stimuli are present in their environment and poorer abilities to process negative ones. These difficulties endure in adulthood.

Diabetes Mellitus in Prader-Willi Syndrome: Natural History during the Transition from Childhood to Adulthood in a Cohort of 39 Patients.

Type 2 diabetes mellitus (T2DM) affects 20% of patients with Prader-Willi syndrome (PWS), with many cases diagnosed during the transition period. Our aim was to describe the natural history of T2DM in patients with PWS before the age of 25 years and to develop screening and preventive strategies. Thirty-nine patients followed in the French PWS Reference Center were included (median age 25.6 years [23.7; 31.7]). Twenty-one had been treated with growth hormone (GH), fifteen had not, and three had an unknown status. The median age at T2DM diagnosis was 16.8 years (11-24) and the median BMI was 39 kg/m2 [34.6; 45], with 34/35 patients living with obesity. The patients displayed frequent psychiatric (48.3% hospitalization,) and metabolic (56.4% hypertriglyceridemia,) comorbidities and a parental history of T2DM (35.7%) or overweight (53.6%) compared to the PWS general population. There was no difference in BMI and metabolic complications between the GH-treated and non-GH-treated groups at T2DM diagnosis. Patients with PWS who develop early T2DM have severe obesity, a high frequency of psychiatric and metabolic disorders, and a family history of T2DM and overweight. These results underline the need for early identification of patients at risk, prevention of obesity, and repeated blood glucose monitoring during the transition period.

Study of the deficit in planning abilities of adults with Prader-Willi Syndrome.

BACKGROUND: Prader-Willi syndrome (PWS) is a complex developmental genetic disorder associated with intellectual disability and deficits in executive functions which result in disorganisation and poor personal autonomy. AIMS: This study aimed to determine impairments in planning skills of adults with PWS, in relation with their intellectual disabilities, as well as the influence of food compulsions on their performance. METHODS AND PROCEDURES: A modified version of the Zoo Map from the Behavioural Assessment of the Dysexecutive Syndrome was used in three groups: a group of adults with PWS in comparison with two groups both matched on chronological age, one with typical development (TD) and one with intellectual disability (ID). OUTCOMES AND RESULTS: Compared to TD adults, both adults with PWS and ID showed increased planning time and lower raw scores on the planning task. The execution time and the number of errors were higher in the PWS group compared to the comparison groups. All three groups performed worse in the non-food condition only for number of errors and raw score. CONCLUSIONS AND IMPLICATIONS: Planning abilities were impaired in PWS adults. Results also showed that intellectual level plays a role in participants' performance. These findings are essential to understand the difficulties of people with PWS daily life.

Patients with PWS and related syndromes display differentially methylated regions involved in neurodevelopmental and nutritional trajectory.

BACKGROUND: Prader-Willi syndrome is a rare genetic neurodevelopmental disorder caused by a paternal deficiency of maternally imprinted gene expression located in the chromosome 15q11-q13 region. Previous studies have demonstrated that several classes of neurodevelopmental disorders can be attributed to either over- or under-expression of specific genes that may lead to impairments in neuronal generation, differentiation, maturation and growth. Epigenetic changes that modify gene expression have been highlighted in these disorders. One recent study focused on epigenetic analysis and compared patients with PWS with patients with other imprinting disorders. No study, however, has yet focused on epigenetics in patients with PWS specifically by comparing the mutations associated with this syndrome. OBJECTIVE: This study investigated the epigenetic modifications in patients with PWS and patients with PWS-related disorders caused by inactivation of two genes of the PWS chromosomal region, SNORD116 and MAGEL2. Our approach also aimed to compare the epigenetic modifications in PWS and PWS-related disorders. METHODS: We compared genome-wide methylation analysis (GWAS) in seven blood samples from patients with PWS phenotype (five with deletions of the PWS locus, one with a microdeletion of SNORD116 and one with a frameshift mutation of MAGEL2 presenting with Schaaf-Yang syndrome), as well as two control patients. Controls were infants that had been studied for suspicion of genetic diseases that was not confirmed by the genetic analysis and the clinical follow-up. RESULTS: The analysis identified 29,234 differentially methylated cytosines, corresponding to 5,308 differentially methylated regions (DMRs), which matched with 2,280 genes. The DMRs in patients with PWS were associated with neurodevelopmental pathways, endocrine dysfunction and social and addictive processes consistent with the key features of the PWS phenotype. In addition, the separate analysis for the SNORD116 and MAGEL2 deletions revealed that the DMRs associated with the SNORD116 microdeletion were found in genes implicated in metabolic pathways and nervous system development, whereas MAGEL2 mutations mostly concerned genes involved in macromolecule biosynthesis. CONCLUSION: The PWS is associated with epigenetic modifications with differences in SNORD116 and MAGEL2 mutations, which seem to be relevant to the different associated phenotypes.

Paradoxical low severity of COVID-19 in Prader-Willi syndrome: data from a French survey on 647 patients.

BACKGROUND: Patients with Prader-Willi syndrome (PWS) often have comorbidities, especially obesity, that may constitute a risk factor for severe forms of COVID-19. We aimed to assess prevalence and medical course of SARS-CoV-2 infection in children and adults with PWS. From November 2020 to January 2021, we performed a detailed medical survey on 342 adults and 305 children with PWS followed in the French reference center. RESULTS: We obtained responses from 288 adults (84%) and 239 children (78%). From March 2020 to January 2021, 38 adults (13.2%) and 13 children (5.4%) with PWS had SARS-CoV-2 infection. Mean age of adults was 34.1 ± 11.9 years and mean body mass index was 40.6 ± 12.7 kg/m2; 82% had obesity and 37% had diabetes. Only 3 children (23%) had obesity and none had diabetes. Similar to the general population, the most frequent symptoms of COVID-19 were asthenia, fever, cough, headache and shortness of breath. All patients had a favorable outcome. CONCLUSION: PWS itself is not a risk factor for severe COVID-19 in children and adults. On the contrary, evolution of SARS-CoV-2 infection in adults with PWS seems more favorable than expected, given their comorbidities.

Improvement of Planning Abilities in Adults with Prader-Willi Syndrome: A Randomized Controlled Trial.

Prader-Willi Syndrome (PWS) is a neurodevelopmental genetic disorder with executive deficits. Planning is one of the impaired executive functions implied in the regulation of behavior and everyday actions. We aimed to explore the feasibility and the effectiveness of a metacognitive strategy training designed to improve planning in adults with PWS using a double-blind between-group (training versus usual care) randomized controlled trial, with computerized tests and paper-pencil ecological outcome measures targeting planning, other executive functions, and achievement of personalized goal. Results showed better performances in several executive tasks and in achievement of personalized goals after both interventions, but better improvement for the experimental group (n = 27) compared to control (n = 26) only on the task assessing planning abilities. Interviews with occupational therapists demonstrated the feasibility of this training with this population. Despite a small number of sessions, the metacognitive strategy training showed encouraging results on planning abilities of patients.

A study of voice and non-voice processing in Prader-Willi syndrome.

BACKGROUND: Prader-Willi syndrome (PWS) is a rare and complex neurodevelopmental disorder of genetic origin. It manifests itself in endocrine and cognitive problems, including highly pronounced hyperphagia and severe obesity. In many cases, impaired acquisition of social and communication skills leads to autism spectrum features, and individuals with this syndrome are occasionally diagnosed with autism spectrum disorder (ASD) using specific scales. Given that communicational skills are largely based on vocal communication, it is important to study human voice processing in PWS. We were able to examine a large number of participants with PWS (N = 61) recruited from France's national reference center for PWS and other hospitals. We tested their voice and nonvoice recognition abilities, as well as their ability to distinguish between voices and nonvoices in a free choice task. We applied the hierarchical drift diffusion model (HDDM) with Bayesian estimation to compare decision-making in participants with PWS and controls. RESULTS: We found that PWS participants were impaired on both voice and nonvoice processing, but displayed a compensatory ability to perceive voices. Participants with uniparental disomy had poorer voice and nonvoice perception than participants with a deletion on chromosome 15. The HDDM allowed us to demonstrate that participants with PWS need to accumulate more information in order to make a decision, are slower at decision-making, and are predisposed to voice perception, albeit to a lesser extent than controls. CONCLUSIONS: The categorization of voices and nonvoices is generally preserved in participants with PWS, though this may not be the case for the lowest IQ.

Face processing and exploration of social signals in Prader-Willi syndrome: a genetic signature.

BACKGROUND: Faces are critical social cues that must be perfectly processed in order to engage appropriately in everyday social interactions. In Prader-Willi Syndrome (PWS), a rare genetic disorder characterized by cognitive and behavioural difficulties including autism spectrum disorder, the literature referring to face processing is sparse. Given reports of poor social interactions in individuals with PWS, we sought to assess their face and emotion recognition skills during eyetracking recordings. RESULTS: Compared with controls, patients with PWS performed more poorly on face/emotion recognition. We observed atypical facial exploration by patients with maternal disomy. These patients looked preferentially at the mouth region, whereas patients with a deletion and controls were more attracted to the eye region. During social scenes, the exploration became more atypical as the social content increased. CONCLUSIONS: Our comprehensive study brings new insights into the face processing of patients with PWS. Atypical facial exploration was only displayed by patients with the maternal disomy subtype, corresponding to their higher rate of autism spectrum disorder. This finding strongly argues in favor of early identification of this genetic subgroup in order to optimize care by implementing tailored interventions for each patient as soon as possible.

Cognitive Training Targeting Planning Dysfunction in Adults with Prader-Willi Syndrome: Brief Report of a Study Protocol.

Background: Prader-Willi syndrome (PWS) is a neurodevelopmental genetic disorder involving executive deficits notably with planning. The main objective of the study is to assess the effectiveness of cognitive training on daily life planning difficulties in PWS patients. Methods/design: The study is a double-blind randomized controlled trial which will compare the effectiveness of a metacognitive strategy intervention designed to improve planning difficulties for PWS patients to usual occupational therapy. Sixty adults will be included over 20 months. The main outcome measure will be the performance on the Modified Six Elements Test from the BADS; secondary outcome measures will be computerized executive tasks and questionnaires. Daily life planning difficulties will be identified and transformed into measurable goals using Goal Attainment Scaling. Discussion: The project will provide knowledge on the difficulties experienced by PWS patients, in relation to their executive functioning in order to implement effective intervention for planning in daily life.

A model to characterize psychopathological features in adults with Prader-Willi syndrome.

High prevalence of behavioral and psychiatric disorders in adults with Prader-Willi Syndrome (PWS) has been reported in last few years. However, data are confusing and often contradictory. In this article, we propose a model to achieve a better understanding of the psychopathological features in adults with PWS. The study is based on clinical observations of 150 adult inpatients, males and females. Non-parametric statistics were performed to analyse the association of psychopathological profiles with genotype, gender and age. We propose a model of psychiatric disorders in adults with PWS based on cognitive, emotional and behavioural issues. This model defines four psychopathological profiles: Basic, Impulsive, Compulsive, and Psychotic. The Basic profile is defined by traits and symptoms that are present in varying degrees in all persons with PWS. In our cohort, this Basic profile corresponds to 55% of the patients. The rest show, in addition to these characteristics, salient features of impulsivity (Impulsive profile, 19%), compulsivity (Compulsive profile, 7%), or psychosis (Psychotic profile, 19%). The analysis of factors associated with different profiles reveals an effect of genotype on Basic and Psychotic profiles (Deletion: 70% Basic, 9% Psychotic; Non-deletion: 23% Basic, 43% Psychotic) and a positive correlation between male sex and impulsivity, unmediated by sex hormone treatment. This is a clinical study, based on observation proposing an original model to understand the psychiatric and behavioural disorders in adults with PWS. Further studies are needed in order to test the validity of this model.

Effect of Genotype and Previous GH Treatment on Adiposity in Adults With Prader-Willi Syndrome.

CONTEXT: Adults with Prader-Willi syndrome (PWS) have an increased proportion of sc fat mass compared with body mass index (BMI)-matched controls, but whether the genotype influences body composition and metabolic profile remains controversial. OBJECTIVE: To assess body composition and metabolic features in adults with PWS, according to genetic subtype. In addition, the effect of previous GH treatment was assessed. Main Outcomes and Measures: Body composition (Dual Energy X-ray Absorptiometry) and metabolic parameters were compared in PWS adults (mean age, 25.5 ± 8.9 y) with deletion (n = 47) or uniparental disomy (UPD) (n = 26), taking into account GH treatment in childhood and/or adolescence. In subgroups, adipocyte size, fasting total ghrelin levels, and resting energy expenditure were measured, and hyperphagia was assessed by the Dykens Hyperphagia Questionnaire. MAIN OUTCOMES AND MEASURES: Body composition (Dual Energy X-ray Absorptiometry) and metabolic parameters were compared in PWS adults (mean age, 25.5 ± 8.9 y) with deletion (n = 47) or uniparental disomy (UPD) (n = 26), taking into account GH treatment in childhood and/or adolescence. In subgroups, adipocyte size, fasting total ghrelin levels, and resting energy expenditure were measured, and hyperphagia was assessed by the Dykens Hyperphagia Questionnaire. RESULTS: In the whole sample, the deletion group had a higher BMI compared with UPD (40.9 ± 11.5 vs 34.6 ± 9.6 kg/m2, P = .02), but there was no difference between groups in percent body fat, metabolic profile, adipocyte size, resting energy expenditure, hyperphagia score, or ghrelin levels. In subjects previously treated with GH, BMI was not different between UPD and deletion groups (33.0 ± 9.7 vs 33.5 ± 11.1 kg/m2). In addition, previous GH treatment was associated with decreased percent body fat and adipocyte volume only in the deletion group. CONCLUSION: A deletion genotype in adults with PWS is associated with increased BMI. GH treatment in childhood and/or adolescence limits this deleterious phenotypic effect with improved adiposity markers. This study suggests relationships between the molecular phenotype of PWS and adipose tissue development as well as sensitivity to GH.

Deficits in voice and multisensory processing in patients with Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is a rare neurodevelopmental and genetic disorder that is characterized by various expression of endocrine, cognitive and behavioral problems, among which a true obsession for food and a deficit of satiety that leads to hyperphagia and severe obesity. Neuropsychological studies have reported that PWS display altered social interactions with a specific weakness in interpreting social information and in responding to them, a symptom closed to that observed in autism spectrum disorders (ASD). Based on the hypothesis that atypical multisensory integration such as face and voice interactions would contribute in PWS to social impairment we investigate the abilities of PWS to process communication signals including the human voice. Patients with PWS recruited from the national reference center for PWS performed a simple detection task of stimuli presented in an uni-o or bimodal condition, as well as a voice discrimination task. Compared to control typically developing (TD) individuals, PWS present a specific deficit in discriminating human voices from environmental sounds. Further, PWS present a much lower multisensory benefits with an absence of violation of the race model indicating that multisensory information do not converge and interact prior to the initiation of the behavioral response. All the deficits observed in PWS were stronger for the subgroup of patients suffering from Uniparental Disomy, a population known to be more sensitive to ASD. Altogether, our study suggests that the deficits in social behavior observed in PWS derive at least partly from an impairment in deciphering the social information carried by voice signals, face signals, and the combination of both. In addition, our work is in agreement with the brain imaging studies revealing an alteration in PWS of the "social brain network" including the STS region involved in processing human voices.

Executive functions and Prader-Willi syndrome: global deficit linked with intellectual level and syndrome-specific associations.

The aim of this study was to support the growing evidence suggesting that Prader-Willi Syndrome (PWS) might present with an impairment of executive functions (EFs) and to investigate whether this impairment is specific to patients with PWS or due to their intellectual disability (ID). Six tasks were administered to assess EFs (inhibition, switching, updating, cognitive estimation, and planning) to 17 patients with PWS and 17 age-matched healthy individuals. Performance was significantly impaired in the PWS group on all EFs and after controlling for IQ level, intergroup differences remained only for switching and cognitive estimation. In conclusion, PWS seems to be associated with a global impairment of EFs that appears to be closely linked with intellectual impairment but also with the PWS itself.

Behavioral profile of adults with Prader-Willi syndrome: correlations with individual and environmental variables.

BACKGROUND: Maladaptive behavior has been reported as a phenotypical feature in Prader-Willi syndrome (PWS). It severely limits social adaptation and the quality of life of children and adults with the syndrome. Different factors have been linked with the intensity and form of these behavioral disturbances but there is no consensus about the cause. Consequently, there is still controversy regarding management strategies and there is a need for new data. METHODS: The behavior of 100 adults with PWS attending a dedicated center was assessed using the Developmental Behavior Checklist for Adults (DBC-A) and the PWS-specific Hyperphagia Questionnaire. The DBC-A was completed separately by trained caregivers at the center and relatives or caregivers in a natural setting. Genotype, gender, age, degree of obesity and cognitive impairment were analyzed as variables with a hypothetical influence on behavioral features. RESULTS: Patients showed a relatively high rate of behavioral disturbances other than hyperphagia. Disruptive and social relating were the highest scoring DBC-A subscales whereas anxiety/antisocial and self-absorbed were the lowest. When hospital caregiver and natural caregiver scores were compared, scores for the latter were higher for all subscales except for disruptive and anxiety/antisocial. These effects of institutional management were underlined. In the DBC-A, 22 items have descriptive indications of PWS behavior and were used for further comparisons and correlation analysis. In contrast to previous reports, rates of disturbed behavior were lower in patients with a deletion genotype. However, the behavioral profile was similar for both genotypes. No differences were found in any measurement when comparing type I and type II deletions. The other analyzed variables showed little relevance. CONCLUSIONS: Significant rates of behavioral disorders were highlighted and their typology described in a large cohort of adults with PWS. The deletion genotype was related to a lower severity of symptoms. Some major behavioral problems, such as hyperphagia, may be well controlled if living circumstances are adapted to the specific requirements of individuals with PWS.

Growth hormone therapy for children and adolescents with Prader-Willi syndrome is associated with improved body composition and metabolic status in adulthood.

CONTEXT: Children with Prader-Willi syndrome (PWS) who receive GH treatment have improved growth and body composition; however, data are lacking for adults when treatment is discontinued after completion of growth. OBJECTIVES: Our aim was to compare body composition and metabolic status in adults with PWS according to GH treatment in childhood and adolescence. DESIGN: 64 adults (mean age: 25.4 years) with a genetic diagnosis of PWS were evaluated: 20 received GH in childhood (T), which had been discontinued at the time of this study, and 44 did not receive GH (C). Mean duration of treatment in the T group was 4.4 ± 2.7 years, age at baseline was 11.8 ± 2.7 years, mean time between the end of treatment and the current evaluation was 7.0 ± 4.4 years. MAIN OUTCOMES MEASURES: Dual-energy X-ray absorptiometry was used to assess body composition and fasting biological analyses evaluated metabolic status. RESULTS (MEAN ± SD): Body mass index and percentage of fat mass were significantly lower in the T group (32.4 ± 10.3 vs 41.2 ± 11.1 kg/m(2), P = 0.05 and 44.0 ± 9.6 vs 50.1 ± 7.2%, P = 0.02, respectively). Insulinemia and HOMA-IR in non-diabetic subjects were significantly lower in the T group (5.8 ± 5.9 vs 13.9 ± 11.6 µUI/ml, P = 0.03, and 1.6 ± 1.3 vs 2.7 ± 2.1, P = 0.04, respectively). Non-diabetic and diabetic subjects from the T group had a significantly lower HbA1c. Lipid profiles were similar between groups. CONCLUSIONS: GH treatment in childhood and adolescence is associated with significantly decreased body mass index and improved body composition and metabolic status in adults with PWS at several years after discontinuing treatment.

Oxytocin may be useful to increase trust in others and decrease disruptive behaviours in patients with Prader-Willi syndrome: a randomised placebo-controlled trial in 24 patients.

BACKGROUND: Prader-Willi syndrome (PWS) is a complex neurodevelopmental genetic disorder with hypothalamic dysfunction, early morbid obesity with hyperphagia, and specific psychiatric phenotypes including cognitive and behavioural problems, particularly disruptive behaviours and frequent temper outbursts that preclude socialization. A deficit in oxytocin (OT)-producing neurons of the hypothalamic paraventricular nucleus has been reported in these patients. METHODS: In a double-blind, randomised, placebo-controlled study, 24 adult patients with PWS received a single intranasal administration of 24 IU of OT or placebo and were tested 45 min later on social skills. Behaviours were carefully monitored and scored using an in-house grid as follows: over the two days before drug administration, on the half-day following administration, and over the subsequent two days. All patients were in a dedicated PWS centre with more than ten years of experience. Patients are regularly admitted to this controlled environment. RESULTS: Patients with PWS who received a single intranasal administration of OT displayed significantly increased trust in others (P = 0.02) and decreased sadness tendencies (P = 0.02) with less disruptive behaviour (P = 0.03) in the two days following administration than did patients who received placebo. In the half-day following administration, we observed a trend towards less conflict with others (p = 0.07) in the OT group compared with the placebo group. Scores in tests assessing social skills were not significantly different between the two groups. CONCLUSIONS: This study needs to be reproduced and adapted. It nevertheless opens new perspectives for patients with PWS and perhaps other syndromes with behavioural disturbances and obesity. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov: NCT01038570.

Identification of a novel BBS gene (BBS12) highlights the major role of a vertebrate-specific branch of chaperonin-related proteins in Bardet-Biedl syndrome.

Bardet-Biedl syndrome (BBS) is primarily an autosomal recessive ciliopathy characterized by progressive retinal degeneration, obesity, cognitive impairment, polydactyly, and kidney anomalies. The disorder is genetically heterogeneous, with 11 BBS genes identified to date, which account for ~70% of affected families. We have combined single-nucleotide-polymorphism array homozygosity mapping with in silico analysis to identify a new BBS gene, BBS12. Patients from two Gypsy families were homozygous and haploidentical in a 6-Mb region of chromosome 4q27. FLJ35630 was selected as a candidate gene, because it was predicted to encode a protein with similarity to members of the type II chaperonin superfamily, which includes BBS6 and BBS10. We found pathogenic mutations in both Gypsy families, as well as in 14 other families of various ethnic backgrounds, indicating that BBS12 accounts for approximately 5% of all BBS cases. BBS12 is vertebrate specific and, together with BBS6 and BBS10, defines a novel branch of the type II chaperonin superfamily. These three genes are characterized by unusually rapid evolution and are likely to perform ciliary functions specific to vertebrates that are important in the pathophysiology of the syndrome, and together they account for about one-third of the total BBS mutational load. Consistent with this notion, suppression of each family member in zebrafish yielded gastrulation-movement defects characteristic of other BBS morphants, whereas simultaneous suppression of all three members resulted in severely affected embryos, possibly hinting at partial functional redundancy within this protein family.

Pitfalls of homozygosity mapping: an extended consanguineous Bardet-Biedl syndrome family with two mutant genes (BBS2, BBS10), three mutations, but no triallelism.

The extensive genetic heterogeneity of Bardet-Biedl syndrome (BBS) is documented by the identification, by classical linkage analysis complemented recently by comparative genomic approaches, of nine genes (BBS1-9) that account cumulatively for about 50% of patients. The BBS genes appear implicated in cilia and basal body assembly or function. In order to find new BBS genes, we performed SNP homozygosity mapping analysis in an extended consanguineous family living in a small Lebanese village. This uncovered an unexpectedly complex pattern of mutations, and led us to identify a novel BBS gene (BBS10). In one sibship of the pedigree, a BBS2 homozygous mutation was identified, while in three other sibships, a homozygous missense mutation was identified in a gene encoding a vertebrate-specific chaperonine-like protein (BBS10). The single patient in the last sibship was a compound heterozygote for the above BBS10 mutation and another one in the same gene. Although triallelism (three deleterious alleles in the same patient) has been described in some BBS families, we have to date no evidence that this is the case in the present family. The analysis of this family challenged linkage analysis based on the expectation of a single locus and mutation. The very high informativeness of SNP arrays was instrumental in elucidating this case, which illustrates possible pitfalls of homozygosity mapping in extended families, and that can be explained by the rather high prevalence of heterozygous carriers of BBS mutations (estimated at one in 50 in Europeans).