Abstract
BackgroundWe studied a family including two half-siblings, sharing the same mother, affected by slowly progressive, adult-onset neurological syndromes. In spite of the diversity of the clinical features, characterized by a mild movement disorder with cognitive impairment in the elder patient, and severe motor-neuron disease (MND) in her half-brother, the brain Magnetic Resonance Imaging (MRI) features were compatible with adult-onset Alexander’s disease (AOAD), suggesting different expression of the same, genetically determined, condition.MethodsSince mutations in the alpha isoform of glial fibrillary acidic protein, GFAP-α, the only cause so far known of AOAD, were excluded, we applied exome Next Generation Sequencing (NGS) to identify gene variants, which were then functionally validated by molecular characterization of recombinant and patient-derived cells.ResultsExome-NGS revealed a mutation in a previously neglected GFAP isoform, GFAP-ϵ, which disrupts the GFAP-associated filamentous cytoskeletal meshwork of astrocytoma cells. To shed light on the different clinical features in the two patients, we sought for variants in other genes. The male patient had a mutation, absent in his half-sister, in X-linked histone deacetylase 6, a candidate MND susceptibility gene.ConclusionsExome-NGS is an unbiased approach that not only helps identify new disease genes, but may also contribute to elucidate phenotypic expression.
Highlights
We studied a family including two half-siblings, sharing the same mother, affected by slowly progressive, adult-onset neurological syndromes
The Magnetic Resonance Imaging (MRI) features were consistent with adult-onset Alexander’s disease (AOAD), but no mutation was detected in the nine exons encoding the prevalent isoform of GFAP (GFAP-α, NP_002046.1; Figure 2A)
exon 7A (Ex7A) is part of the transcript encoding the GFAP-ε isoform (NP_001124491.1), which differs from GFAP-α in the last 35 amino acids
Summary
We studied a family including two half-siblings, sharing the same mother, affected by slowly progressive, adult-onset neurological syndromes. In spite of the diversity of the clinical features, characterized by a mild movement disorder with cognitive impairment in the elder patient, and severe motor-neuron disease (MND) in her half-brother, the brain Magnetic Resonance Imaging (MRI) features were compatible with adult-onset Alexander’s disease (AOAD), suggesting different expression of the same, genetically determined, condition. GFAP mutations frequently occur de novo, in infantile cases, We here report the results of exome next-generation DNA sequencing (NGS) conducted on a family with two maternal half-siblings, affected by two distinct adultonset neurological syndromes: mild cognitive deterioration and movement disorder in a female patient, motor-neuron disease (MND) in her half-brother. Standard sequence analysis of the nine canonical exons encoding the predominant isoform, GFAP-α, had previously ruled out mutations in both patients
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