3q29 duplications: A cohort of 46 patients and a literature review.

Duplications of the 3q29 cytoband are rare chromosomal copy number variations (CNVs) (overlapping or recurrent ~1.6 Mb 3q29 duplications). They have been associated with highly variable neurodevelopmental disorders (NDDs) with various associated features or reported as a susceptibility factor to the development of learning disabilities and neuropsychiatric disorders. The smallest region of overlap and the phenotype of 3q29 duplications remain uncertain. We here report a French cohort of 31 families with a 3q29 duplication identified by chromosomal microarray analysis (CMA), including 14 recurrent 1.6 Mb duplications, eight overlapping duplications (>1 Mb), and nine small duplications (<1 Mb). Additional genetic findings that may be involved in the phenotype were identified in 11 patients. Focusing on apparently isolated 3q29 duplications, patients present mainly mild NDD as suggested by a high rate of learning disabilities in contrast to a low proportion of patients with intellectual disabilities. Although some are de novo, most of the 3q29 duplications are inherited from a parent with a similar mild phenotype. Besides, the study of small 3q29 duplications does not provide evidence for any critical region. Our data suggest that the overlapping and recurrent 3q29 duplications seem to lead to mild NDD and that a severe or syndromic clinical presentation should warrant further genetic analyses.

How neurologists are viewed by their colleagues: exploring stereotypes and social representations of neurologists.

INTRODUCTION: The choice of medical specialization is influenced by various factors, including personal, educational, and interpersonal aspects. However, stereotypes and social representations (SRs) can also play a significant role in biasing the choice of a particular medical specialty. The aim of this study is to describe and understand the social representation (SR) of French Neurologist among medical peers, and factors explaining stereotypes about neurology. METHODS: A nationwide web-based survey was sent to the French medical community (students, residents, and graduated physicians) to collect sociodemographic and professional data, status, experience, and acquaintance in Neurology as well as qualitative hierarchical evocation question to assess the SR of French Neurologists. RESULTS: Overall, 367 people participated in the survey, including 112 medical students, 170 residents, and 85 graduated physicians. Only 14.3% of students listed neurology among their top 5 specialty choices, and 63.8% disagreed with the statement "I could have chosen (or I will choose) neurology after the validation of my 6th year of medical studies." Qualitative analysis revealed that the most frequently occurring words used to describe neurologists were "stroke", "complicated", "no treatment," "clinical", and "brain" and five themes corresponded to SRs of neurologist: his/her personal and professional traits (36.4% of the corpus), his/her daily practice (18.1%), the negative aspects of the neurological practice (15.3%), and the neurological pathology and daily skills (30.2%). CONCLUSION: The perception of neurologists by other physicians is nuanced. Neurologists are described as rigorous specialists, maybe excessively so but the cliché of a contemplative specialty with no effective treatment remains. The specialty and neurological patients suffer also from a reputation of complexity. Further interventions among medical students and better information are required to increase the attractiveness of our specialty.

Clinico-biological refinement of BCL11B-related disorder and identification of an episignature: A series of 20 unreported individuals.

PURPOSE: BCL11B-related disorder (BCL11B-RD) arises from rare genetic variants within the BCL11B gene, resulting in a distinctive clinical spectrum encompassing syndromic neurodevelopmental disorder, with or without intellectual disability, associated with facial features and impaired immune function. This study presents an in-depth clinico-biological analysis of 20 newly reported individuals with BCL11B-RD, coupled with a characterization of genome-wide DNA methylation patterns of this genetic condition. METHODS: Through an international collaboration, clinical and molecular data from 20 individuals were systematically gathered, and a comparative analysis was conducted between this series and existing literature. We further scrutinized peripheral blood DNA methylation profile of individuals with BCL11B-RD, contrasting them with healthy controls and other neurodevelopmental disorders marked by established episignature. RESULTS: Our findings unveil rarely documented clinical manifestations, notably including Rubinstein-Taybi-like facial features, craniosynostosis, and autoimmune disorders, all manifesting within the realm of BCL11B-RD. We refine the intricacies of T cell compartment alterations of BCL11B-RD, revealing decreased levels naive CD4+ T cells and recent thymic emigrants while concurrently observing an elevated proportion of effector-memory expressing CD45RA CD8+ T cells (TEMRA). Finally, a distinct DNA methylation episignature exclusive to BCL11B-RD is unveiled. CONCLUSION: This study serves to enrich our comprehension of the clinico-biological landscape of BCL11B-RD, potentially furnishing a more precise framework for diagnosis and follow-up of individuals carrying pathogenic BCL11B variant. Moreover, the identification of a unique DNA methylation episignature offers a valuable diagnosis tool for BCL11B-RD, thereby facilitating routine clinical practice by empowering physicians to reevaluate variants of uncertain significance within the BCL11B gene.

Episignatures in practice: independent evaluation of published episignatures for the molecular diagnostics of ten neurodevelopmental disorders.

Variants of uncertain significance (VUS) are a significant issue for the molecular diagnosis of rare diseases. The publication of episignatures as effective biomarkers of certain Mendelian neurodevelopmental disorders has raised hopes to help classify VUS. However, prediction abilities of most published episignatures have not been independently investigated yet, which is a prerequisite for an informed and rigorous use in a diagnostic setting. We generated DNA methylation data from 101 carriers of (likely) pathogenic variants in ten different genes, 57 VUS carriers, and 25 healthy controls. Combining published episignature information and new validation data with a k-nearest-neighbour classifier within a leave-one-out scheme, we provide unbiased specificity and sensitivity estimates for each of the signatures. Our procedure reached 100% specificity, but the sensitivities unexpectedly spanned a very large spectrum. While ATRX, DNMT3A, KMT2D, and NSD1 signatures displayed a 100% sensitivity, CREBBP-RSTS and one of the CHD8 signatures reached <40% sensitivity on our dataset. Remaining Cornelia de Lange syndrome, KMT2A, KDM5C and CHD7 signatures reached 70-100% sensitivity at best with unstable performances, suffering from heterogeneous methylation profiles among cases and rare discordant samples. Our results call for cautiousness and demonstrate that episignatures do not perform equally well. Some signatures are ready for confident use in a diagnostic setting. Yet, it is imperative to characterise the actual validity perimeter and interpretation of each episignature with the help of larger validation sample sizes and in a broader set of episignatures.

Medical oncologist stereotypes among medical students, residents and physicians: a national cross-sectional study.

OBJECTIVES: The perception of oncologists could impact the attractiveness of the specialty and dialogue between oncologists and other physicians. The aim of the study was to describe and understand the stereotypes and social representation (SR) associated with oncologists among medical students, residents and physicians in France. METHODS: This nationwide web-based survey conducted in 2021 was based on hierarchical evocation methods. Qualitative analyses were based on the Reinert method with factorial analyses. Each respondent's SR was graded from 1 to 5 (from 1: very positive SR to 5: very negative SR). RESULTS: Oncologists suffer from a rather negative SR. The negative representation was mostly related to difficulties in practising and the proximity with death and end of life. Oncologists were also associated with more positive notions like interdisciplinarity or intellectual complexity. Attendance to an oncology course was associated with a better SR of oncology (p=0.036), whereas having someone in the family practising oncology had a negative impact (p=0.028). CONCLUSIONS: SR of oncologists is rather contrasted. It was positively influenced by attendance to an oncology course, which could be an option to correct stereotypes and update on this rapidly evolving specialty.

Molecular consequences of PQBP1 deficiency, involved in the X-linked Renpenning syndrome.

Mutations in the PQBP1 gene (polyglutamine-binding protein-1) are responsible for a syndromic X-linked form of neurodevelopmental disorder (XL-NDD) with intellectual disability (ID), named Renpenning syndrome. PQBP1 encodes a protein involved in transcriptional and post-transcriptional regulation of gene expression. To investigate the consequences of PQBP1 loss, we used RNA interference to knock-down (KD) PQBP1 in human neural stem cells (hNSC). We observed a decrease of cell proliferation, as well as the deregulation of the expression of 58 genes, comprising genes encoding proteins associated with neurodegenerative diseases, playing a role in mRNA regulation or involved in innate immunity. We also observed an enrichment of genes involved in other forms of NDD (CELF2, APC2, etc). In particular, we identified an increase of a non-canonical isoform of another XL-NDD gene, UPF3B, an actor of nonsense mRNA mediated decay (NMD). This isoform encodes a shorter protein (UPF3B_S) deprived from the domains binding NMD effectors, however no notable change in NMD was observed after PQBP1-KD in fibroblasts containing a premature termination codon. We showed that short non-canonical and long canonical UPF3B isoforms have different interactomes, suggesting they could play distinct roles. The link between PQBP1 loss and increase of UPF3B_S expression was confirmed in mRNA obtained from patients with pathogenic variants in PQBP1, particularly pronounced for truncating variants and missense variants located in the C-terminal domain. We therefore used it as a molecular marker of Renpenning syndrome, to test the pathogenicity of variants of uncertain clinical significance identified in PQPB1 in individuals with NDD, using patient blood mRNA and HeLa cells expressing wild-type or mutant PQBP1 cDNA. We showed that these different approaches were efficient to prove a functional effect of variants in the C-terminal domain of the protein. In conclusion, our study provided information on the pathological mechanisms involved in Renpenning syndrome, but also allowed the identification of a biomarker of PQBP1 deficiency useful to test variant effect.

How do medical students, residents and graduated physicians really perceive radiologists? A cross-national study.

BACKGROUND: Radiology has always been an attractive specialty for residents, but its attractiveness has recently decreased in France regarding the median choice rank after at the National Residency Board. AIM: To study Radiologists' perceptions and social representations (SRs) among a group of medical students, residents and graduated physicians in France, to better understand the view of Radiologists to debunk stereotypes. METHODS: The nationwide web-based survey was based on valid hierarchical evocation methods. We determined the corpus's central core and SRs' principal themes with prototypical and correspondence factor analysis (CFA), respectively. RESULTS: Overall, 419 answers were analyzed. Radiologists' SRs were divided into 3 classes: negative stereotypes of Radiologists, negative stereotypes of the Radiologists' daily practice and Radiologists' skills. After multivariate analysis, variables that seemed to have a positive influence on Radiologists' SRs were considering radiology as a potential choice of specialty (p < 0.001) and the existence of practical experience in Radiology (p = 0.008). Women seemed to have a more negative SR of Radiologists than men (p = 0.035). DISCUSSION: This was the largest qualitative study on the subject and the only one among medical students, residents and graduated physicians, allowing a global picture. SRs of Radiologists seemed to be negative, potentially caused by poor knowledge of the Radiologists' profession. CONCLUSION: SRs of Radiologists among medical students and graduated physicians appears to be negative. Promoting the specialty among medical students and encouraging their immersion in a Radiology department could help to debunk many stereotypes about the daily life and missions of Radiologists.

What do medical students and graduated physicians think about infectious disease specialists?

OBJECTIVES: This study evaluated the social representation and stereotypes on infectious disease (ID) specialists among medical students and physicians in France after the COVID-19 pandemic. METHODS: A survey applying the hierarchical evocation model assessed the social representations (SRs) of ID specialists. RESULTS: All in all, 372 answers were analyzed. The positive elements related to the personal and professional qualities of ID specialists ('intellectual prestige", "open-mindedness"), in contrast with negative stereotypes related to their perceived daily life and practice characteristics ("hospital-based", "intense", "overspecialized"). Variables such as "I would not have chosen (or I won't choose) ID after the national ranking exam" and "I know someone who is an ID specialist" were associated with worse SR scores (p < 0.001 and p = 0.022 respectively). CONCLUSIONS: These findings provide insights into the attractiveness of ID as a specialty. Rounds in ID departments may enhance the interest of the specialty as a possible residency choice.

Mental health and working conditions among French medical students: A nationwide study.

BACKGROUND: Medical students' mental health is a public health problem that has worsened with COVID 19's pandemic. There is a lack of French data. The principal aim was to assess French medical students' mental health. METHODS: An online cross-sectional survey was performed between May 27 and June 27, 2021. An anonymous questionnaire was sent via academic email addresses by medical faculties and secondly on social media. We assessed 7-day anxiety and depressive symptoms were evaluated with the Hospitalization Anxiety and Depression scale, 12-month major depressive episode (MDE) with the Composite International Diagnostic Interview- Short Form, burnout with the Maslach Burnout Inventory, 12-month suicidal ideation, humiliation, sexual harassment, and sexual aggression during their curriculum. Multivariable logistic regression was performed to identify main MDE associated factors. OUTCOMES: 11,754 participants (response rate: 15.3%) were included. Prevalence of 7-day anxiety symptoms, 7-day depressive symptoms, 12-month MDE, and 12-month suicidal thoughts were 52%, 18%, 25%, and 19% respectively. Burnout syndrome concerned 67% of clinical students and residents and 39% of preclinical students. Prevalence of humiliation, sexual harassment, and sexual abuse during their curriculum were 23%, 25%, and 4%, respectively. Having important (OR = 1.44, IC 95 [1.31-1.58], p < 0.001) or very important financial issues (OR = 2.47, IC 95 [2.15-2.85], p < 0.001), experienced humiliation (OR = 1.63, IC 95 [1.46-1.81], p < 0.001), sexual harassment (OR = 1.43, IC 95 [1.28-1.59], p < 0.001) and sexual abuse (OR = 1.52, IC 95 [1.24-1.85], p < 0.001) were associated with an increased risk of MDE. INTERPRETATION: This is the largest study on French medical students' mental health. These results point to very particular conditions in French students environment that need to be addressed to improve their mental health.

Genetics of Usher Syndrome: New Insights From a Meta-analysis.

OBJECTIVE: To describe the genetic and phenotypic spectrum of Usher syndrome after 6 years of studies by next-generation sequencing, and propose an up-to-date classification of Usher genes in patients with both visual and hearing impairments suggesting Usher syndrome, and in patients with seemingly isolated deafness. STUDY DESIGN: The systematic review and meta-analysis protocol was based on Cochrane and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We performed 1) a meta-analysis of data from 11 next-generation sequencing studies in 684 patients with Usher syndrome; 2) a meta-analysis of data from 21 next-generation studies in 2,476 patients with seemingly isolated deafness, to assess the involvement of Usher genes in seemingly nonsyndromic hearing loss, and thus the proportion of patients at high risk of subsequent retinitis pigmentosa (RP); 3) a statistical analysis of differences between parts 1) and 2). RESULTS: In patients with both visual and hearing impairments, the biallelic disease-causing mutation rate was assessed for each Usher gene to propose a classification by frequency: USH2A: 50% (341/684) of patients, MYO7A: 21% (144/684), CDH23: 6% (39/684), ADGRV1: 5% (35/684), PCDH15: 3% (21/684), USH1C: 2% (17/684), CLRN1: 2% (14/684), USH1G: 1% (9/684), WHRN: 0.4% (3/684), PDZD7 0.1% (1/684), CIB2 (0/684). In patients with seemingly isolated sensorineural deafness, 7.5% had disease-causing mutations in Usher genes, and are therefore at high risk of developing RP. These new findings provide evidence that usherome dysfunction is the second cause of genetic sensorineural hearing loss after connexin dysfunction. CONCLUSION: These results promote generalization of early molecular screening for Usher syndrome in deaf children.