Genetics in Medicine最新文献

Purpose: Transcriptomics by way of RNA sequencing (RNAseq) has emerged as a means to increase the diagnostic yield in genetic conditions. In this systematic review, we focus on the contribution of transcriptomics to improve the diagnostic yield in neurodevelopmental disorders.

Methods: We performed a systematic literature search in PubMed until January 2024, including articles describing diagnostic RNAseq on at least one individual with a primary neurodevelopmental phenotype. We extracted data on cohort size, phenotype, sample tissue, previously used diagnostic methods, added diagnostic yield of RNAseq, the use of control samples, and technical aspects of the RNA sequencing methodology.

Results: 17 articles were eligible for inclusion in the systematic review. We found an average added diagnostic yield of 15·5% through RNA sequencing for individuals with neurodevelopmental disorders. There is heterogeneity in the tissue type, reported quality measures, and the computational pipeline.

Conclusion: The significantly increased diagnostic yield demonstrates the value of this novel tool in the diagnostic setting of neurodevelopmental disorders. Our results offer an overview of common methodologies for RNAseq and allow us to formulate recommendations for genetic labs and clinicians when implementing RNAseq as a diagnostic tool. Lastly, we provide recommendations for future publications in order to increase transparency and reproducibility.

Purpose: Achondroplasia is the most common skeletal dysplasia, caused by gain-of-function variants in FGFR3, resulting in constitutive receptor activation and downstream inhibition of endochondral ossification. In 2021, the first targeted therapy, vosoritide, was approved in some countries following a landmark randomized trial. While findings are promising, evidence is limited to modest-sized cohorts. To address this, we conducted a systematic review and meta-analysis of available vosoritide data METHODS: A systematic search of PubMed, Cochrane, and Embase was conducted. Data was extracted according to Cochrane guidelines. Outcomes consistently reported were synthesized using R (v4.5) to generate forest plots.

Results: 10 studies were analyzed, encompassing 696 pediatric patients. Meta-analysis of single means showed that height z-score variation after 12 months of treatment was 0.32 (95%CI 0.25 - 0.40), annualized growth rate was 1.82 cm/year higher after treatment (95% CI 1.46 - 2.18), and the ratio between sitting height and height showed -0.0089 decrease (95% CI -0.0157 - -0.0020). Studies reported uniform profiles of adverse events, mostly limited to mild injection-site related issues and no serious complications.

Conclusion: This meta-analysis shows that real-world observational data on vosoritide in children with achondroplasia replicate clinical trial findings, with greater gains in linear growth and a similarly favorable safety profile.

Purpose: Rare disease genomic research suffers from a lack of diverse participation. We therefore implemented and evaluated a multi-faceted intervention to support recruitment of populations previously-underrepresented by race, ethnicity, primary language, household income, education level, or rural residence to the Rare Genomes Project (RGP).

Methods: For a prospective cohort, we tracked completion of our enrollment processes supported by interventions including clinician engagement, language support, proactive and flexible participant contact, and use of mobile phlebotomy. Participants were offered a survey upon enrollment to assess values and priorities.

Results: 161/195 (83%) participants completed enrollment. High-yield interventions included clinician referral forms and increased staff assistance. Genome sequencing data has been generated for 133 participants, with a diagnosis found for 17 (13%) and candidate for 23 (17%) thus far. Most diagnosed participants (13/17, 76%) benefited from clinician rather than self-referral. Perceived importance of a genetic diagnosis was ranked very/extremely high for 81/96 (84%) of participants. Spanish primary language was associated with higher perceived importance and high income with lower perceived importance, although only income remained significant in a multivariable model.

Conclusion: Overall, our equity-focused initiative enabled enrollment of participants from populations previously underrepresented in rare disease genomic research and offers insight into potential motivators.

Purpose: The global demand for clinical genome-wide sequencing (GWS) continues to grow. This study describes the global landscape of genetic service delivery and the barriers and facilitators to implementing clinical GWS.

Methods: A scoping review was conducted using MEDLINE and Embase (January 2009 - July 2025) to identify studies related to genetic service delivery, exome and genome sequencing, and implementation.

Results: Ninety-six articles representing 35 countries were analyzed using the updated Consolidated Framework for Implementation Research. The most frequently reported barriers were within the outer setting: insufficient Local Conditions (i.e., genetics workforce shortage; 54/96, 56%), limited Financing (29/96, 30%), and lack of national Policies and Laws (regulations) for genomic testing (20/96, 21%). Negative Local Attitudes about genomics were reported as a barrier in 11 South American, Middle Eastern, Asian, and African countries. Identified outer setting facilitators included Partnerships and Connections between interested parties (e.g., government, academic institutions; 14/96, 15%) and dedicated Funding for national genomics initiatives (6/96, 6%).

Conclusion: This scoping review identified common barriers to implementing GWS across countries with varying capacities for delivering these services. Findings may help countries to anticipate barriers, leverage facilitators, and develop strategies for implementing genomic testing and services.

Purpose: Developmental regression, characterized by the loss of acquired milestones, occurs in some individuals with neurdevelopmental disorders (NDDs), yet its molecular basis remains unclear. Studies suggest that DNA damage repair (DDR) genes, such as FAN1, may protect against neurological dysfunction by modulating the somatic stability of short tandem repeats (STRs). This study explores the contribution of DDR gene variants in NDD cases presenting with regression.

Methods: We analyzed 1,087 NDD patients, focusing on those carrying variants in DDR genes and presenting regression. We assessed the sensitivity to DNA damage using mitomycin C on lymphoblastoid cells. Somatic variants and STR expansions were evaluated through high-depth short-read genome sequencing. To further investigate the pathogenetic role of STR expansions, we performed long-read genome sequencing on the most severely affected proband.

Results: Probands with regression carried multiple DDR gene variants, several within the Fanconi anemia pathway. Their lymphoblastoid cells showed increased sensitivity to mitomycin C-induced cytotoxicity compared to parental and control samples. Probands with severe phenotypes and regression exhibited an accumulation of somatic variants and STR instability, enriched in neurodevelopmental genes.

Conclusions: Our findings suggest that polygenic DDR gene variants may contribute to developmental regression in NDDs by promoting the accumulation of somatic variants and STR expansions.