Enter Note Done


Keywords: Diagnostics; Exome sequencing; Rare variants; Neurodegeneration; Neurogenetics

Q. Thomas 1,2,3; A. Vitobello 1,4; F. Tran Mau-Them 1,4; A. Fromont 5; M. Giroud 3; B. Daubail 3; A. Jacquin-Piques 3; M. Hervieu-Begue 3; T. Moreau 5; G.-V. Osseby 3; S. Nambot 1,2; A.-L. Bruel 1,4; A. Sorlin 1,2,4; P. Callier 1,2,4; A.-S. Denomme-Pichon 1,4; L. Faivre 1,2; Y. Béjot 3,6; C. Philippe 1,4; C. Thauvin-Robinet 1,2,4; S. Moutton 1,2

1) Inserm UMR1231 team GAD, University of Burgundy and Franche-Comté, F-21000 Dijon, France; 2) Genetics Center, FHU-TRANSLAD, Dijon Bourgogne University Hospital, F-21000 Dijon, France; 3) Neurology, Dijon Burgundy University Hospital, Dijon, Burgungy, France; 4) Functional Unity of innovative diagnosis for rare disease, Dijon Bourgogne University Hospital, F-21000 Dijon, France; 5) Service de Pathologies Inflammatoires du système nerveux central, Neurologie Général, Dijon University Hospital; 6) Dijon Stroke Registry, EA7460, Pathophysiology and Epidemiology of Cerebro-Cardiovascular Diseases (PEC2), University Hospital of Dijon, University of Burgundy, Dijon, France

Most neurogenetic pathologies share two major characteristics: first, within a given framework their clinical presentations are highly uniform and non-specific e.g. gait disorders and limb incoordination for cerebellar ataxias. Second, their molecular bases are quite vast with large genetic and multiple modes of inheritance, making them difficult for physicians to choose between countless syndromes and genes.
After years of clinical classifications, the last decades have been marked by the clinical implementation of massive parallel sequencing technologies including exome sequencing (ES). Its implementation in neurogenetics led to the discovery of numerous new genes, phenotypes expansion and markedly increased diagnostic yield.

We performed ES as a first- or second-tier test in a cohort of 52 patients with neurodegenerative diseases: 13 cerebellar ataxia, 12 neuromuscular disorders, 10 spinocerebellar ataxia, 8 spastic paraplegia, 2 movement disorders and 7 labelled “others” in regard of complex clinical features. This study revealed a 42% overall diagnostic yield with 6 interesting atypical findings.

In a 13 year-old girl, with suspicion of mitochondrial cytopathy for years because of isolated cerebellar ataxia subsequently associated with psychomotor regression, cerebellar atrophy, hearing impairment, extensive leukoencephalopathy and gradient-echo sequences hyposignal of the basal ganglia, ES identified a homozygous CRAT missense variant inherited from related parents in favor of Neurodegeneration with Brain Iron Accumulation.
In an 11 year-old girl referred for the diagnosis of a cerebellar ataxia with basal ganglia and midbrain hypersignal, ES with a dedicated pipeline analysis allowed to identify a mitochondrial DNA missense variant in the MT-ATP6 gene.
In a family referred for familial gait disorder (spastic paresis of lower limbs in a 46 year-old man and hypotonic cerebellar ataxia in his daughter), ES identified a causal BSCL2 missense variant in the father while his daughter, who inherited this variant, also carried an additional missense variant in the MT-ATP6 gene leading to a mitochondrial defect explaining her current symptoms.

ES is a powerful tool for diagnosing neurodegenerative diseases, allowing not to be restricted to a given panel and thus to identify molecular bases of very interesting findings such as differential diagnosis, expansion of clinical spectrum, multiple diagnosis within a given family and even a given patient.