- Laurence Hubert
- Arnold Munnich
- Sylvain Hanein
- Céline Vidal
- Marie Faoucher
- Erwan Mercier
Poirier K, Hubert L, Viot G, Rio M, Billuart P, Besmond C, Bienvenu T. CSNK2B splice site mutations in patients cause intellectual disability with or without myoclonic epilepsy. Hum Mutat. 2017 38(8):932-941.
Xu M Mutations in the Spliceosome Component CWC27 Cause Retinal Degeneration with or without Additional Developmental Anomalies. Am J Hum Genet. 2017 100(4):592-604.
CarrÃ© A. Mutations in BOREALIN cause thyroid dysgenesis. Hum Mol Genet. 2017 26(3):599-610.
Cavallin M Recurrent KIF5C mutation leading to frontal pachygyria without microcephaly. Neurogenetics. 2016 17(1):79-82.
Metodiev MD, Mutations in the tricarboxylic acid cycle enzyme, aconitase 2, cause either isolated or syndromic optic neuropathy with encephalopathy and cerebellar atrophy. J Med Genet. 2014 51:834-8
The Translational Genetics Platform offers genotyping/exome sequencing to uninvestigated cases of “orphan” diseases. It was created by INSERM in 2012.
Rare genetics diseases are the first cause of referral of in- and outpatients at the Necker-Enfants Malades hospital. While a significant fraction of cases are investigated by the research teams of the Imagine Institute, a great number of cases remain hitherto unaddressed and not even investigated. It is also the case for patients showing complex clinical presentation for which putative or known have been searched for without success by others clinical or research groups.
Our goal is to identify the genetic cause of such diseases which remained, often for years, genetically uncharacterized.
The decision to direct a case to the Translational Genetics Platform is taken collectively during multidisciplinary meetings with various specialists at the Department of Genetics. The Translational Genetics Platform operates at the interface between clinical units of the IHU, the onsite Reference Centers for Rare diseases, the service laboratories, the research teams and others research groups in France and EU. DNA samples are taken and stored in the DNA repository of the IHU. Clinical and genotypic data are available to physicians in charge of the patients. They monitor on-site and external cooperation for a given patient. Following genotyping, it is managed that those unique observations are either taken over by the research teams of the Institute, or re-directed toward external research teams.
Our strategy is based on high-throughput approaches such as exome or genome screenings at our on-site Genomics Platform. Alignment and variants annotation is performed by our common with University Paris Descartes Bioinformatics Platform. The data are then available to us for analysis via an in situ software interface designed by the bioinformatics platform.
For the last four years, we investigated about fifty patients and their families per year. When a family is larger than a trio, in order to give more power to our research, we include when possible all the samples from the sibship whether they are affected or not.
Our elucidating rate is around fifty per cent and remains constant over the years. It should be noted that one must be open minded when carrying such analysis, thus exploring all possible modes of inheritance neglecting no candidate gene whatever protein it is coding for. Such genes are searched for all available data regarding their function including animal models, pathways or networks. Correlation based on strong functional points is then tentatively established with the clinical presentation of the patient.
Results are then presented in details before a multidisciplinary panel composed of scientists and clinicians. When fully agreed, the identified gene and variant are presented to the patient’s family by the concerned clinician and made publicly available. On the societal side, our work allowed fourteen families to carry on their project thus giving birth to children free of genetic disease.
As of today, we have identified thirty five genes that were not known to be related to any genetic disease. They usually are unique cases and databases such as Decipher Or GeneMatcher among others are screened for second case worldwide so that it can be published. Over the years, a fair number of those genes have been published by other groups, thus confirming our initial results.
We are also engaged in several ongoing collaborative works with groups familiar with the functions of the proteins encoded by theses genes. This approach is beneficial to both parties since most of the functional studies, including animal models, have already been performed and therefore available for studying the incidence of the deleterious variants we identified in patients.
In summary, the translational genetics platform generate genotypic informations on unusually rare genetic diseases not taken over by research teams and provide them with a genomic signature. This approach proved to be beneficial to all three parties, patients, clinicians and research laboratories.