GenIDA

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Coordinateur

Participants

Keywords

santé 4P, génétique, déficience intellectuelle, autisme, réseau social

Summary

Intellectual disability (ID) is a mental disorder that constitutes a major health and social problem, which has been comparatively neglected until recently in medical research. It affects 1-2% of the population and shows a large overlap with autism. A genetic cause may be implicated in a majority of patients. ID is characterized by an extreme genetic heterogeneity that underlies a phenotypic heterogeneity in severity and in associated medical problems, with causes that can be chromosomal, notably including recurrent Copy Number Variants (CNVs), or single gene mutations. Progress in genome analysis has allowed the identification of more than 300-400 genes associated to monogenic forms of ID/autism, that can be associated or not to other medically significant manifestations. Each of these recurrent CNVs or mutated genes corresponds thus to a unique form of rare disease. Thanks to the striking technical progresses in genome analysis (CGH array, and now high-throughput sequencing), an increased number of genetic diagnoses are made in individuals with ID. Although this is useful for genetic counselling, the extraordinary genetic heterogeneity of ID will render extremely difficult the determination, for each specific cause (recurrent CNV or mutated gene), of genotype-phenotype correlations and natural history, the estimation of penetrance and variability of clinical expression. Symptomatic treatments for co-morbidities such as attention deficit, aggressive behavior or epilepsy will be proposed, with limited opportunities to assess their efficacies or potential serious adverse effects that may depend on the specific genetic cause of ID. And if for a given gene the specific pathomechanisms involved suggest a therapeutic strategy using an available drug, it will be very difficult to recruit enough patients sharing a defect in the same gene for a clinical trial, except for the most common causes. While the need for clinical databases allowing longitudinal follow-ups is well recognized, it is difficult to motivate physicians and costly to establish and maintain the large number of individual databases that would be required for such studies, and longitudinal information is often not available. We wish to develop an alternative database model for specific genetic causes of ID, organized in a social network format, whereby most clinical information would be entered by the family of the patient, based on wide range questionnaires established by professionals, but understandable by lay persons (and translated in several languages, to allow international participation). In particular we wish to gain relevant information for individualized medical care on risk of developing specific pathological complications and of possible serious adverse events linked to symptomatic medications. Recent examples show that medical information entered by patients can be the basis of useful research. Contacts between families affected by the same genetic cause could then be established in an initially anonymous way, creating gene or CNV specific social-networks to which interested professionals could be associated, akin to disease specific patients associations. Anonymized data could be accessible to professionals for specific projects approved by a comity composed of health or research professionals, of representatives of families or patients associations and of bioethicists. Concerned families could then decide to take part or not in such projects, and would also be informed of prospective clinical trials specific for the cognate gene. This proposal is based on the prior identification in a patient of causal mutations or highly penetrant CNV, and does not apply to individuals for whom the cause of ID is unknown or may result from oligogenic or multifactorial inheritances. The database could however be useful to recruit gene specific cohorts to estimate (from further familial segregation studies) the penetrance of mutations in a given gene.


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