Study coordinator: Vincent CANTAGREL, Lydie BURGLE
Developmental anomalies of the cerebellum and brainstem are responsible for a wide range of disabilities evident from birth or early childhood, involving motor disorders (such as balance and coordination problems) and often learning difficulties or intellectual disability.
Most of these anomalies are of genetic origin, and many different genes can be implicated. It is important to identify the precise cause to provide parents and families with genetic counselling (such as the risk of having another child with the same condition) and, in some cases, to consider treatment options. Significant progress has been made in recent years thanks to advances in genetic techniques (high‑throughput sequencing), and the cause is found in approximately 60% of cases when using technology developed in hospital laboratories.
Patients with a developmental anomaly of the cerebellum who do not receive a diagnosis following these analyses may benefit from whole genome sequencing on the high‑throughput platforms SeqOIA and Auragen as part of the PFMG2025 plan. Experience from the Reference Centre for Cerebellar Malformations and Congenital Diseases (2M2C) over the last two years, based on 51 patients analyzed on the SeqOIA platform, shows that the genetic cause is identified in about 40‑50% of these undiagnosed patients.
Thus, half of the patients explored by whole genome sequencing with the very efficient informatics tool provided by the platform remain undiagnosed, even though these patients have a neurodevelopmental disorder highly likely to be genetic in origin. It is therefore necessary to initiate a project aimed at identifying these as‑yet unrecognised genetic causes. The main objective here is to re‑analyse the whole genome sequence data generated under the PFMG2025 plan for patients without a genetic diagnosis or for whom the diagnosis does not explain the cerebellar symptoms.
New bioinformatics tools will be used to identify genes or genetic mechanisms not previously known to be involved in these conditions. These new genes and mechanisms may be located in coding regions of genes or in regions of the genome whose analysis is more complex. This project will improve the genetic knowledge of these pathologies and builds on ongoing work recruiting patients at Trousseau Hospital, Necker Hospital, and the National Reference Centre for Malformations and Congenital Diseases of the Cerebellum.