CARTOGEN-N_Contribution of Optical Genome Mapping (OGM) in the Diagnosis of Multiple Congenital Malformations With or Without Intellectual Disability Without Genetic Abnormality Detected by Whole Genome Sequencing
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 发起方
- 入组人数
- 55
- 试验地点
- 1
- 主要终点
- diagnostic yield of optical genome mapping (OGM) in multiple congenital anomalies with or without intellectual disability when whole-genome sequencing (WGS) is non-contributive
研究概览
简要总结
Congenital malformations result from an embryonic or foetal developmental disorder (DD) affecting one or more systems (cardiac, skeletal, nervous, etc.). These are referred to as multiple congenital anomalies (MCAs). They may be associated with an intellectual disability (ID)1.
Chromosomal analysis on Chromosomal Microarray Analysis (CMA) and gene panels or exome sequencing are the respective gold standard methods for chromosomal and molecular diagnosis of DD respectively2. In cases where no diagnosis is established after these first-line tests, short-read whole genome sequencing (WGS), via the Plan France Medicine Genomic 2020-2025 (AURAGEN), may be considered. This approach allows for diagnosis in nearly 40% of patients with DD3,4. However, many patients remain in diagnostic deadlock, likely due to the technical limitations of these methods, which potentially be overcome by emerging methodologies such as optical genome mapping (OGM)5,6,7,8,9. The investigators propose to systematically perform OGM in 30 patients presenting with MCA+/-ID who have inconclusive WGS result10.
The main objective is to assess the contribution of OGM in identifying structural variants not detected or poorly characterised by WGS in this clinical context. This work will also contribute to the ongoing of OGM in routine diagnostics and determine its role in the overall genetic diagnosis of MCA+/-ID. Additionally it may lead to the identification of new candidate genes and/or mechanisms of pathogenicity. If the results are promising, further clinical could expand this preliminary work into a larger-scale project. Improving the genetic diagnosis of DD should enhance the medical management of patients, currently in diagnostic deadlock, and their families.
详细描述
Study Workflow
Pre-analytical Phase
Participation in the study will be offered to all patients meeting the inclusion and non-inclusion criteria by an investigator from the Department of Genetics, during a medical consultation in which the non-contributive whole-genome sequencing (WGS) result will have been communicated (Figure 1). Information regarding the study procedures and objectives will be provided at that time. The information sheet and consent form will be given to the patient (if an adult) or to the holders of parental authority (if the patient is a minor). After obtaining consent for both the genetic investigations and participation in the research project, the patient may be enrolled in the study. Blood samples required for the study will be collected, transferred to the laboratory, and secured for analysis according to the following protocol:
Patient > 20 kg:
2 × 5 mL EDTA blood tubes
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Diagnostic
- 盲法
- None
盲法说明
Each sample will be pseudonymized as follows:
CARTOGEN_N[patient number]-[initial of last name]-[initial of first name] Example: Pierre MARTIN, 15th enrolled patient → CARTOGEN_N[15]-[M]-[P]
入排标准
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients presenting with at least two congenital anomalies, with or without intellectual disability, and weighing more than 5 kg.
- •Whole-genome sequencing performed by the AURAGEN laboratory deemed non-contributive (absence of class 4 or 5 variants, or identification of a VUS, or identification of only one variant in the context of a recessive disorder).
- •Patient covered by a social security scheme.
- •Patient able to understand and to oppose participation in the study.
- •Written informed consent for genetic analyses, signed either by the patient or by their legal representatives (for minors), after clear and fair information about the study has been provided.
- •Non-Inclusion Criteria
- •Patients for whom a non-genetic cause (infectious, environmental, or toxic) has been previously identified.
- •Inability to obtain a compliant sample.
- •Patient or holder of parental authority under guardianship or legal protection, deprived of liberty, or placed under court-ordered protection.
排除标准
- 未提供
研究组 & 干预措施
single arm of patients with congenital malformations
干预措施: blood sample (Genetic)
结局指标
主要结局
diagnostic yield of optical genome mapping (OGM) in multiple congenital anomalies with or without intellectual disability when whole-genome sequencing (WGS) is non-contributive
时间窗: day 1 (inclusion and blood collection)
Assessing the diagnostic yield of optical genome mapping (OGM) in multiple congenital anomalies with or without intellectual disability when whole-genome sequencing (WGS) is non-contributive (absence of causal genetic variation or detection of a variant of uncertain significance (VUS) or a single variant in a recessive disorder).
次要结局
- Number of reclassified variants intially considered as VUS (Variants of Uncertain/Unknown Signification)(day 1 (inclusion and blood collection))
- Number of patients in whom a new candidate gene/pathogenic mechanism is identified(day 1 (inclusion and blood collection))
- Evaluation of the feasibility (duration) of the technique in current practice in 1st-line, 2nd-line (after routine tests such as chromosomal microarray, exome sequencing…), or 3rd-line in the case of non-contributive WGS based on several criteria(day 1 (inclusion and blood collection))
- Evaluation of the feasibility of the technique (failure) in current practice in 1st-line, 2nd-line (after routine tests such as chromosomal microarray, exome sequencing…), or 3rd-line in the case of non-contributive WGS based on several criteria(day 1 (inclusion and blood collection))
- Evaluation of the feasibility of the technique (reprocessing) in current practice in 1st-line, 2nd-line (after routine tests such as chromosomal microarray, exome sequencing…), or 3rd-line in the case of non-contributive WGS based on several criteria(day 1 (inclusion and blood collection))
- Evaluation of the feasibility of the technique (interpretation) in current practice in 1st-line, 2nd-line (after routine tests such as chromosomal microarray, exome sequencing…), or 3rd-line in the case of non-contributive WGS based on several criteria(day 1 (inclusion and blood collection))
- Assess the impact of using these new technologies on patient management.(day 1 (inclusion and blood collection))
研究者
Céline PEBREL-RICHARD
Dr
University Hospital, Clermont-Ferrand