Ignite Creation Date:
2024-07-17 @ 12:04 PM
Last Modification Date:
2024-10-26 @ 3:32 PM
Study NCT ID:
NCT06467175
Status:
NOT_YET_RECRUITING
Last Update Posted:
2024-06-20
First Post:
2024-06-11
Brief Title:
The Benefits of Long-read High-throughput Genomic Sequencing for the Causal Diagnosis of Cerebellar Ataxias
Sponsor:
Centre Hospitalier Universitaire Dijon
Organization:
Centre Hospitalier Universitaire Dijon
Study Overview
Official Title:
The Benefits of Long-read High-throughput Genomic Sequencing for the Causal Diagnosis of Cerebellar Ataxias
Status:
NOT_YET_RECRUITING
Status Verified Date:
2024-06
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
ALICA
Brief Summary:
Cerebellar ataxias are a group of rare neurological disorders that are clinically and genetically heterogeneous with several hundred genes and diseases known to date Over the last decade their diagnosis has been revolutionised by the development of high-throughput sequencing technologies such as exomegenome sequencing ESGS making it possible to obtain a molecular diagnosis in a growing number of patients However almost 40 of patients remain without a molecular diagnosis raising questions about the limitations of sequencing technologies based on a technique known as short-read One limitation of short-read is its poor ability to detect repeated motif expansions a frequent mechanism in neurology and associated with more than thirty neurogenetic diseases Although tools for analysing ESGS data have gradually been developed in response to this problem their effectiveness and reliability remain moderate To date the gold standard for detecting these expansions remains targeted approaches such as PCR and Southern blot which are long tedious and costly processes that require an independent search for each expansion forcing clinicians to select expansions and limiting diagnostic yield In addition there are diseases associated with expansions so rare that no French laboratory offers a diagnostic test
The recent development of long fragment genome sequencing long-read - lrGS could provide a solution to all these problems These technologies are based on a sequencing process during which DNA is preserved in the form of large molecules of several tens of thousands of bases Regions of the genome containing expansions can therefore be studied directly in their entirety avoiding the difficulties of reconstruction from small fragments which is the case in short-read sequencing In addition lrGS can characterize the size of repeated motifs and thus detect any causal expansion in an individual in a single analysis
A number of recently published studies particularly in neurology have demonstrated the ability of lrGS to detect pathologies with known expansions SCA36 C9ORF72 but also to discover new ones and thus explain the molecular basis of rare pathologies SCA27b NOTCH2NLC Although these sequencing technologies have been around for a number of years access is still restricted to research work and is limited by their higher cost
Their value as a second-line diagnostic tool has yet to be demonstrated The investigators propose to evaluate the feasibility and diagnostic yield of Oxford Nanopore lrGS in duo or trio patients 1 or 2 first-degree relatives in patients with cerebellar ataxia without molecular diagnosis after short-read GS This will be the first study to transfer this lrGS technique to the second line in real-life conditions for the causal genetic diagnosis of cerebellar ataxia
The recent development of long fragment genome sequencing long-read - lrGS could provide a solution to all these problems These technologies are based on a sequencing process during which DNA is preserved in the form of large molecules of several tens of thousands of bases Regions of the genome containing expansions can therefore be studied directly in their entirety avoiding the difficulties of reconstruction from small fragments which is the case in short-read sequencing In addition lrGS can characterize the size of repeated motifs and thus detect any causal expansion in an individual in a single analysis
A number of recently published studies particularly in neurology have demonstrated the ability of lrGS to detect pathologies with known expansions SCA36 C9ORF72 but also to discover new ones and thus explain the molecular basis of rare pathologies SCA27b NOTCH2NLC Although these sequencing technologies have been around for a number of years access is still restricted to research work and is limited by their higher cost
Their value as a second-line diagnostic tool has yet to be demonstrated The investigators propose to evaluate the feasibility and diagnostic yield of Oxford Nanopore lrGS in duo or trio patients 1 or 2 first-degree relatives in patients with cerebellar ataxia without molecular diagnosis after short-read GS This will be the first study to transfer this lrGS technique to the second line in real-life conditions for the causal genetic diagnosis of cerebellar ataxia
Detailed Description:
None
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None