P09.084C - Strong interest of exome sequencing in progressive neurological diseases

Abstract

International audienceIntroduction: Neurogenetics represents a vast, complex, ever changing discipline whose diagnosis currently remains challenging, since clinical and/or imaging features frequently appear very unspecific, especially early in the evolution (cerebellar ataxia, tremor, dystonia...). In molecular diagnosis, current strategies usually include sequential investigations that may lead to long, tedious, expensive and disappointing patients care. Exome sequencing (ES) appears a promising approach for neurogenetics, apart from when nucleotide motif expansion disorders can be suspected. Materials and Methods: We recruited 48 individuals without cognitive development impairment, referred to our center for suspected neurogenetic disease: 20 cerebellar ataxia (42%), 12 neuromuscular diseases (25%), 8 spastic paraplegia (17%), 2 abnormal movements (4%) and 6 others (12%) for whom the phenotype could not be labelled under a usual neurological syndrome. ES was interpreted in a solo-based strategy (94%) or in trio with parental pool (6%). Results: ES identified a causal diagnosis in 4/8 individuals with spastic paraplegia (50%), 3/6 “other” (50%), 1/2 with abnormal movements (50%), 5/12 with neuromuscular diseases (42%), 4/11 with isolated cerebellar ataxia (37%) and 2/9 with spinocerebellar ataxia (22%). Overall diagnostic yield was of 40 %. Conclusions: With such overall diagnostic yield, this study reinforces the diagnostic interest of ES in neurogenetics, in all its fields, as this diagnostic yield ranges from 22% in spinocerebellar ataxia (which is higher than current yield of gene panels) to 50% in spastic paraplegia. It also includes situations in which clinical displays may be complex and hard to systematize. First-tier implementation would significantly improve diagnostic yield in neurogenetics