Supporting Remote Survey Data Analysis by Co-researchers with Learning Disabilities through Inclusive and Creative Practices and Data Science Approaches

Through a process of robust co-design, we created a bespoke accessible survey platform to explore the role of co-researchers with learning disabilities (LDs) in research design and analysis. A team of co-researchers used this system to create an online survey to challenge public understanding of LDs [3]. Here, we describe and evaluate the process of remotely co-analyzing the survey data across 30 meetings in a research team consisting of academics and nonacademics with diverse abilities amid new COVID-19 lockdown challenges. Based on survey data with >1,500 responses, we first coanalyzed demographics using graphs and art & design approaches. Next, co-researchers co-analyzed the output of machine learningbased structural topic modelling (STM) applied to open-ended text responses. We derived an efficient five-steps STM co-analysis process for creative, inclusive, and critical engagement of data by coresearchers. Co-researchers observed that by trying to understand and impact public opinion, their own perspectives also changed

‘Building bridges’: reflections and recommendations for co-producing health research

Abstract Background Co-produced research is when all stakeholders, including experts by experience and researchers, work together to conceptualise, design, deliver and disseminate research to enhance understanding and knowledge. This type of participatory inquiry is being increasingly used across health research; however, it continues to be a complex area to navigate given existing institutional structures. Main body We collaborated across three independent co-produced research studies to share insights, reflections, and knowledge of our work in the fields of HIV, mental health, and disability research. We co-designed and delivered a three-hour online workshop at a conference to share these reflections using the metaphor of ‘building bridges’ to describe our co-production journey. We generated key principles of co-production from our different experiences working in each individual research project as well as together across the three projects. Our principles are to: (1) be kind, have fun and learn from each other; (2) share power (as much as you can with people); (3) connect with people you know and don’t know; (4) remain connected; and (5) use clear and simple language. Conclusion We recommend that co-produced research needs additional funding, resource, and flexibility to remain impactful and ethical. Co-produced research teams need to be mindful of traditional power structures and ensure that the process is transparent, fair, and ethical. Addressing equality, diversity, and inclusion of traditionally underrepresented groups in research is essential as are the skills, expertise, and experiences of all members of the co-production team

Standardized practices for RNA diagnostics using clinically accessible specimens reclassifies 75% of putative splicing variants

Purpose: Genetic variants causing aberrant premessenger RNA splicing are increasingly being recognized as causal variants in genetic disorders. In this study, we devise standardized practices for polymerase chain reaction (PCR)-based RNA diagnostics using clinically accessible specimens (blood, fibroblasts, urothelia, biopsy). Methods: A total of 74 families with diverse monogenic conditions (31% prenatal-congenital onset, 47% early childhood, and 22% teenage-adult onset) were triaged into PCR-based RNA testing, with comparative RNA sequencing for 19 cases. Results: Informative RNA assay data were obtained for 96% of cases, enabling variant reclassification for 75% variants that can be used for genetic counseling (71%), to inform clinical care (32%) and prenatal counseling (41%). Variant-associated mis-splicing was highly reproducible for 28 cases with samples from ≥2 affected individuals or heterozygotes and 10 cases with ≥2 biospecimens. PCR amplicons encompassing another segregated heterozygous variant was vital for clinical interpretation of 22 of 79 variants to phase RNA splicing events and discern complete from partial mis-splicing. Conclusion: RNA diagnostics enabled provision of a genetic diagnosis for 64% of recruited cases. PCR-based RNA diagnostics has capacity to analyze 81.3% of clinically significant genes, with long amplicons providing an advantage over RNA sequencing to phase RNA splicing events. The Australasian Consortium for RNA Diagnostics (SpliceACORD) provide clinically-endorsed, standardized protocols and recommendations for interpreting RNA assay data

Missense variants in TAF1 and developmental phenotypes: Challenges of determining pathogenicity

We recently described a new neurodevelopmental syndrome (TAF1/MRXS33 intellectual disability syndrome) (MIM# 300966) caused by pathogenic variants involving the X-linked gene TAF1, which participates in RNA polymerase II transcription. The initial study reported eleven families, and the syndrome was defined as presenting early in life with hypotonia, facial dysmorphia, and developmental delay that evolved into intellectual disability (ID) and/or autism spectrum disorder (ASD). We have now identified an additional 27 families through a genotype-first approach. Familial segregation analysis, clinical phenotyping, and bioinformatics were capitalized on to assess potential variant pathogenicity, and molecular modelling was performed for those variants falling within structurally characterized domains of TAF1. A novel phenotypic clustering approach was also applied, in which the phenotypes of affected individuals were classified using 51 standardized Human Phenotype Ontology (HPO) terms. Phenotypes associated with TAF1 variants show considerable pleiotropy and clinical variability, but prominent among previously unreported effects were brain morphological abnormalities, seizures, hearing loss, and heart malformations. Our allelic series broadens the phenotypic spectrum of TAF1/MRXS33 intellectual disability syndrome and the range of TAF1 molecular defects in humans. It also illustrates the challenges for determining the pathogenicity of inherited missense variants, particularly for genes mapping to chromosome X. This article is protected by copyright. All rights reserved.status: publishe

Missense variants in TAF1 and developmental phenotypes: Challenges of determining pathogenicity (vol 41, pg 449, 2020)

status: publishe

Missense variants in TAF1 and developmental phenotypes: challenges of determining pathogenicity.

We recently described a new neurodevelopmental syndrome (TAF1/MRXS33 intellectual disability syndrome) (MIM# 300966) caused by pathogenic variants involving the X-linked gene TAF1, which participates in RNA polymerase II transcription. The initial study reported eleven families, and the syndrome was defined as presenting early in life with hypotonia, facial dysmorphia, and developmental delay that evolved into intellectual disability (ID) and/or autism spectrum disorder (ASD). We have now identified an additional 27 families through a genotype-first approach. Familial segregation analysis, clinical phenotyping, and bioinformatics were capitalized on to assess potential variant pathogenicity, and molecular modelling was performed for those variants falling within structurally characterized domains of TAF1. A novel phenotypic clustering approach was also applied, in which the phenotypes of affected individuals were classified using 51 standardized Human Phenotype Ontology (HPO) terms. Phenotypes associated with TAF1 variants show considerable pleiotropy and clinical variability, but prominent among previously unreported effects were brain morphological abnormalities, seizures, hearing loss, and heart malformations. Our allelic series broadens the phenotypic spectrum of TAF1/MRXS33 intellectual disability syndrome and the range of TAF1 molecular defects in humans. It also illustrates the challenges for determining the pathogenicity of inherited missense variants, particularly for genes mapping to chromosome X. This article is protected by copyright. All rights reserved

De novo variants in the non-coding spliceosomal snRNA gene RNU4-2 are a frequent cause of syndromic neurodevelopmental disorders.

Around 60% of individuals with neurodevelopmental disorders (NDD) remain undiagnosed after comprehensive genetic testing, primarily of protein-coding genes 1 . Increasingly, large genome-sequenced cohorts are improving our ability to discover new diagnoses in the non-coding genome. Here, we identify the non-coding RNA RNU4-2 as a novel syndromic NDD gene. RNU4-2 encodes the U4 small nuclear RNA (snRNA), which is a critical component of the U4/U6.U5 tri-snRNP complex of the major spliceosome 2 . We identify an 18 bp region of RNU4-2 mapping to two structural elements in the U4/U6 snRNA duplex (the T-loop and Stem III) that is severely depleted of variation in the general population, but in which we identify heterozygous variants in 119 individuals with NDD. The vast majority of individuals (77.3%) have the same highly recurrent single base-pair insertion (n.64_65insT). We estimate that variants in this region explain 0.41% of individuals with NDD. We demonstrate that RNU4-2 is highly expressed in the developing human brain, in contrast to its contiguous counterpart RNU4-1 and other U4 homologs, supporting RNU4-2 's role as the primary U4 transcript in the brain. Overall, this work underscores the importance of non-coding genes in rare disorders. It will provide a diagnosis to thousands of individuals with NDD worldwide and pave the way for the development of effective treatments for these individuals. </p