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.

A survey of Canadian adult rheumatologists' knowledge, comfort level, and barriers in assessing psychosocial needs of young adults with rheumatic diseases.

To assess adult rheumatologists' comfort level, current practices, and barriers to provision of optimal care in supporting young adults with pediatric-onset rheumatic conditions in Canada. Survey questions were informed by literature review, a needs assessment, and using milestones listed by the Royal College of Physicians and Surgeons of Canada for the entrustable professional activities (EPAs) applicable to care for rheumatology patients transitioning to adult practice. The electronic survey was distributed to adult rheumatology members of the Canadian Rheumatology Association over 4 months. Four hundred and fifty-one rheumatologists received the survey, with a response rate of 15.2%. Most respondents were from Ontario and had been in practice ≥ 10 years. Three quarters reported a lack of training in transition care although the same proportion were interested in learning more about the same. Approximately 40% felt comfortable discussing psychosocial concerns such as gender identity, sexuality, contraception, drug and alcohol use, vaping, and mental health. Despite this, 45-50% reported not discussing vaping or gender identity at all. The most frequently reported barriers to providing transition care were lack of primary care providers, allied health support, and training in caring for this age group. Most adult rheumatologists lack formal training in transition care and view it as a barrier to providing care for this unique patient population. Future educational initiatives for adult rheumatology trainees should include issues pertaining to adolescents and young adults. More research is needed to assess the effectiveness of resources such as transition navigators in ensuring a successful transition process.

A Phenotypic Description of Congenital Myotonic Dystrophy using PhenoStacks.

BACKGROUND: Congenital Myotonic Dystrophy (CDM1) is a rare neuromuscular condition caused by a triplet repeat expansion in the DMPK gene. Despite there being a well-recognized clinical syndrome, there has not been an effort to use a standardized ontology system to describe the disease characteristics in existing literature. Thus, comparing or contrasting different cohorts from the literature can be challenging, and coding disease features for clinical research or for registry data items is not uniform. PhenoStacks is a visualization analytics tool which helps graphically illustrate phenotypes of patients with genetic disorders using Human Phenotype Ontology (HPO) terms and can sort phenotypes by different disease characteristics. OBJECTIVE: To demonstrate the efficacy of PhenoStacks and the HPO system as clinical research tools when describing CDM1 cohorts. METHODS: Health Endpoints and Longitudinal progression in congenital myotonic dystrophy (HELP-CDM) is an ongoing study which longitudinally follows patients with CDM1. Items from the HELP-CDM data sheet were matched to corresponding HPO terms and analyzed using PhenoStacks. RESULTS: In total 40 subjects' phenotypes were visualized through PhenoStacks and 73 HPO terms were used for the analysis. Frequent phenotypic features included "high narrow palate", "facial palsy", "ptosis", "hyporeflexia", and "weak voice". Contractures were associated with higher repeat sizes. Hypoplastic muscles and infantile axial hypotonia were more frequently observed in infants. CONCLUSIONS: PhenoStacks is a valuable clinical and scientific tool as it identifies variability within cohorts and highlights significant phenotypic features.

Developmental Milestones and Quality of Life Assessment in a Congenital Myotonic Dystrophy Cohort.

BACKGROUND: Congenital myotonic dystrophy (CDM) is a neuromuscular disorder caused by a CTG triplet repeat expansion in the DMPK gene. In addition to the expected motor delay, affected children often have significant developmental disability in language and cognitive realms, which ultimately impacts on quality of life. OBJECTIVE: In a prospective cohort of children with CDM to 1) present the profile of language and motor developmental milestones, and 2) describe their early childhood health related quality of life (HRQOL). METHODS: A five year cohort study of eligible incident cases of CDM was performed via the Canadian Pediatric Surveillance Program (CPSP). Consenting subjects were then followed from infancy in a prospective cohort study. Caregivers were contacted every 3 months for the first year of life, and then twice yearly in order to obtain data concerning language skills, motor development and parent proxy HRQOL from the PedsQL and Infant and Toddler Quality of life (ITQOL) questionnaires. RESULTS: Milestones were achieved at later ages in patients when compared to healthy children. Girls appeared to be more delayed than boys in both language and motor skills. HRQOL scores remained stable in this cohort, for both the PedsQL and ITQOL. CONCLUSIONS: Understanding developmental milestones and quality of life are important parameters when judging a child's overall health. For CDM patients delineating developmental milestones and QOL have important clinical care and research implications.