Periodic Reporting for period 1 - STRIPE (Structural variants impacting peripheral neurodegeneration)
Periodo di rendicontazione: 2023-10-01 al 2025-09-30
Inherited peripheral neuropathies are rare neurological conditions that cause progressive nerve dysfunction, muscle wasting, walking problems, and lifelong disability. Despite advances in genetic testing, many patients still remain without a genetic diagnosis, often for years. This "diagnostic odyssey" delays access to specialist care and prevents families from receiving accurate genetic counselling. One major reason for the low diagnostic rate is that standard short-read DNA sequencing technologies are unable to detect certain types of genetic variation.
This project sets out to address this challenge by applying long-read genome sequencing, an emerging technology capable of reading continuous stretches of DNA much longer than conventional methods. This technology provides a more complete view of the genome and has the potential to uncover disease-causing genetic defects that were previously unrecognized.
The overall objectives are to apply nanopore genome sequencing to individuals with unsolved inherited neuropathies to identify candidate disease-causing genetic variants, determine how these variants affect gene function, and to establish novel gene-disease relationships.
This project sets out to address this challenge by applying long-read genome sequencing, an emerging technology capable of reading continuous stretches of DNA much longer than conventional methods. This technology provides a more complete view of the genome and has the potential to uncover disease-causing genetic defects that were previously unrecognized.
The overall objectives are to apply nanopore genome sequencing to individuals with unsolved inherited neuropathies to identify candidate disease-causing genetic variants, determine how these variants affect gene function, and to establish novel gene-disease relationships.
The project implemented nanopore sequencing in an unsolved rare disease cohort and generated high-quality genetic data from 54 individuals in 20 families. Downstream analyses included quality control, genome alignment, variant calling, phasing, variant filtering, and annotation and data interpretation. Identified candidate variants were validated in family-based segregation studies. This effort resulted in achieving a genetic diagnosis in five families in the cohort, representing a 25% increase in the diagnostic rate for this previously unsolved cohort.
The project also identified a novel disease-causing gene linked to a dominant peripheral neuropathy subtype. Functional analyses in patient-derived primary cells and additional cellular models made it possible to understand how the identified genetic changes disrupt normal cellular processes.
A detailed manuscript describing cohort findings and practical guidelines for interpreting long-read genomic data was prepared to assist other researchers, clinicians, and early adopters of this technology. Moreover, a scientific preprint describing the newly discovered neuropathy-causing gene was made publicly available.
The project also identified a novel disease-causing gene linked to a dominant peripheral neuropathy subtype. Functional analyses in patient-derived primary cells and additional cellular models made it possible to understand how the identified genetic changes disrupt normal cellular processes.
A detailed manuscript describing cohort findings and practical guidelines for interpreting long-read genomic data was prepared to assist other researchers, clinicians, and early adopters of this technology. Moreover, a scientific preprint describing the newly discovered neuropathy-causing gene was made publicly available.
The project generated several results that have beyond state-of-the-art impact:
- New disease gene discovery: The identification of a previously unrecognized neuropathy gene significantly advances the scientific understanding of inherited nerve disorders and opens new avenues for research.
- Improved diagnostic strategies: The project showed that long-read sequencing can resolve cases that short-read methods frequently miss. This builds strong evidence for adopting long-read technologies as a first-tier test in clinical settings.
- Collaborative efforts: The global taskforce established during the project for the identification of the novel neuropathy-causing gene illustrates how open data-sharing networks can rapidly validate rare disease findings and connect patients across continents.
- Practical guidelines: The methodological insights compiled during the project timeline provides accessible, step-by-step guidance for analyzing long-read genomes and data interpretation. These resources will help address global disparities by enabling laboratories with fewer resources to benefit from best-practice approaches.
- Foundations for future research: The newly identified neuropathy-causing gene points to promising directions for deeper functional studies, biomarker development, and potential therapeutic investigations.
- New disease gene discovery: The identification of a previously unrecognized neuropathy gene significantly advances the scientific understanding of inherited nerve disorders and opens new avenues for research.
- Improved diagnostic strategies: The project showed that long-read sequencing can resolve cases that short-read methods frequently miss. This builds strong evidence for adopting long-read technologies as a first-tier test in clinical settings.
- Collaborative efforts: The global taskforce established during the project for the identification of the novel neuropathy-causing gene illustrates how open data-sharing networks can rapidly validate rare disease findings and connect patients across continents.
- Practical guidelines: The methodological insights compiled during the project timeline provides accessible, step-by-step guidance for analyzing long-read genomes and data interpretation. These resources will help address global disparities by enabling laboratories with fewer resources to benefit from best-practice approaches.
- Foundations for future research: The newly identified neuropathy-causing gene points to promising directions for deeper functional studies, biomarker development, and potential therapeutic investigations.