Clinical Research Directory

FARD (RaDiCo Cohort) (RaDiCo-FARD)

The goal of this observational study is to conduct a prospective assessment of the individual Burden of 9 rare skin diseases to assess disability in the broadest sense of the term (psychological, social, economic and physical) for patients and/or families. Two types of indicators will be used to reach this objective : 1. an individual burden score calculated based on a burden questionnaire created specifically, approved and designed to understand the tendency to changes in care and lifestyles. The burden questionnaire should be used by patients and/or their family themselves in self-assessment. 2. a descriptive analysis of all resources (medical and non-medical) used by the family unit to manage the disease.

Implementation of Long-read Sequencing for the Diagnosis of Rare Diseases.

Following on from the third national plan for rare diseases (PNMR3), the main objectives of the PNMR4 are to reduce diagnostic uncertainty and dead ends and to strengthen translational research to promote diagnosis and the development of new treatments in the field of rare diseases. To this end, the French Genomic Medicine Plan 2025 (PFMG2025) is organizing the rollout of whole genome sequencing (WGS) for diagnostic purposes. This technological milestone, covering regions outside the coding regions, has recently enabled the identification of variations in the RNU4-2 gene as a major cause of Intellectual Developmental Disorder (IDD), accounting for approximately 0.4% of cases. RNU4-2 is a gene encoding a small nuclear RNA (snRNA), which is not translated into protein, and whose variations are not accessible to exome sequencing techniques. However, based on current knowledge, these techniques are based on short-read sequencing technology and can diagnose up to 50% of patients. It is therefore necessary to develop new techniques to detect variations not identified by these techniques. In this context, the development of third-generation sequencing, particularly using Nanopore technology, now makes it possible to combine genomic and post-genomic approaches through long-read whole genome sequencing coupled with the detection of methylated cytosines on native DNA. This new approach therefore enables the simultaneous detection of point or structural genomic variants, methylation abnormalities, and haplotype reconstruction. Numerous studies have shown that this strategy improves the diagnosis rate of rare diseases and could become a first-line genetic test. DNA methylation is an epigenetic modification that does not cause changes in the genomic sequence but regulates the transcription (RNA synthesis) of genes and therefore their expression. Methylation studies are performed either to establish an episignature or to search for methylation abnormalities. An episignature is the result of a variation in a gene known to regulate methylation marks. Methylation abnormalities are already known and sought after in targeted analysis for certain diseases such as Prader-Willi/Angelman syndromes and Beckwith-Wiedemann/Silver-Russell syndromes. The contribution of methylation analysis to the diagnosis of other diseases has recently been demonstrated. For example, in methylmalonic aciduria and homocystinuria type cblC associated with the autosomal recessive gene MMACHC, promoter methylation analysis revealed hypermethylation linked to the presence of an intronic variant of the PRDX1 gene. This intronic variant leads to the synthesis of an aberrant antisense RNA overlapping the promoter of the MMACHC gene, causing its hypermethylation. In 2024, combined whole-genome and methylation analysis in patients with porokeratosis led to the discovery of the FDFT1 gene. In general, the study of methylation profiles has shown its value in reducing diagnostic uncertainty in patients with rare diseases who have not been diagnosed after genome analysis. The search for methylation abnormalities (or epimutation) at the pan-genomic level in the context of molecular diagnosis of rare diseases remains largely inaccessible and poorly described in the literature. The techniques routinely used for their detection are most often based on bisulfite treatment and PCR amplification. The disadvantages of bisulfite treatment are that it degrades DNA, preventing long-read applications, that it does not distinguish between 5mC and 5hmC methylation, and that failure to treat unmethylated cytosines can lead to false positives . In addition, phase determination with a genomic variant identified in short reads requires complementary techniques such as SNP arrays. This approach therefore appears to be a major technological advance in the fight against diagnostic uncertainty in rare diseases and is part of the move towards precision medicine for patients. As part of our Reference Center for Developmental Anomalies and Malformation Syndromes of Southwest Occitanie Réunion (CRMR ADSOOR) at Bordeaux University Hospital, we have developed clinical and molecular expertise, particularly in the field of developmental anomalies with intellectual development disorders (particularly chromatinopathies and Rubinstein Taybi syndrome and albinism. In 2024, 2,300 consultations were carried out at the CRMR. In addition, 243 and 228 genome or exome analyses were interpreted in our molecular biology laboratory for albinism and intellectual development disorder and malformation syndrome, respectively. Our expertise in these two areas therefore represents the best starting point for the development of this pilot project using this innovative approach at Bordeaux University Hospital.

National Ophthalmic Genotyping and Phenotyping Network (eyeGENE (Registered Trademark)), Stage 3 - Expansion of DNA and Data Repositories for Rare Inherited Ophthalmic Diseases

Background: The eyeGENE (Registered Trademark) program is a research resource for inherited eye conditions which includes genotypic and phenotypic data, imaging, and a corresponding biobank of DNA samples from people with a variety of eye diseases. Since 2007 this registry has been helping researchers learn more about the genetic sources for many inherited eye diseases. These findings helped them create better treatments. Now researchers want to expand eyeGENE (Registered Trademark) to include more people for certain eye diseases. Objective: To collect information and DNA samples for the study of eye diseases. * Primary objective --To expand the current eyeGENE (Registered Trademark) data repository with targeted participant accrual * Secondary objectives * To enhance recruitment for clinical trials and investigations in inherited eye diseases * To establish genotype-phenotype correlations for rare eye diseases Eligibility: People of any age with certain eye diseases. These can include aniridia; Best disease; blue-cone monochromacy; corneal dystrophy; and disorders of pigmentation, such as albinism. Relatives unaffected by the eye disease of interest may also be needed. Design: Researchers will select participants based on their diagnosis. The data may include images and test results from eye exams. Participants will provide a sample of saliva. They will receive a kit with written instructions. They will spit in a tube and mail it to the NIH. Participants may be asked to provide a blood sample. The blood may be drawn at the NIH or at a local clinic. The eyeGENE (Registered Trademark) repository will offer researchers data about the participants eye conditions. The data may include pictures of their eyes, results of the genetic testing, and history of other diseases. Researchers will be able to see data such as age and gender, but they will not see names, dates of birth, or contact information.

Qualitative Study in Patients With Genodermatoses and Healthcare Professionals on Reproductive Counselling

The goal of this observational study is to understand the perspectives and needs of patients with genodermatoses and their partners who wish to have children, regarding their decision-making process and their consideration of reproductive options. Additionally, the investigators aim to investigate the level of knowledge and perspectives of healthcare professionals (such as clinical geneticists, dermatologists and other clinicians involved), and want to explore to what extent patients and their partners are well informed about these reproductive options. To achieve this, the investigators will conduct individual semi-structured qualitative interviews with participants affected by genodermatoses (and their partners) and with healthcare professionals.

Reproductive Options in Inherited Skin Diseases

The goal of this observational study is to learn about the indications for prenatal diagnostics and preimplantation genetic testing for patients/couples affected by an inherited skin disease, and evaluate the clinical outcomes of these reproductive options. By providing a complete overview, the investigators aim to improve reproductive counselling for these patients/couples with a desire to have children. To achieve this, the investigators aim to retrospectively collect data from a cohort of patiens/couples affected by an inherited skin disease on a national level (in the Netherlands) and also an international level from various countries in Europe.