Medical Biology - Research Publications

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Author: Amor, David × Author: Bahlo, Melanie × Author: Delatycki, Martin × Author: Diakumis, Peter × Author: Lockhart, Paul × End date: 2019 × Start date: 2017 ×

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    Neuropathology of childhood-onset basal ganglia degeneration caused by mutation of VAC14
    Stutterd, C ; Diakumis, P ; Bahlo, M ; Fernandez, MF ; Leventer, RJ ; Delatycki, M ; Amor, D ; Chow, CW ; Stephenson, S ; Meisler, MH ; Mclean, C ; Lockhart, PJ (WILEY, 2017-12)
    OBJECTIVE: To characterize the clinical features and neuropathology associated with recessive VAC14 mutations. METHODS: Whole-exome sequencing was used to identify the genetic etiology of a rapidly progressive neurological disease presenting in early childhood in two deceased siblings with distinct neuropathological features on post mortem examination. RESULTS: We identified compound heterozygous variants in VAC14 in two deceased siblings with early childhood onset of severe, progressive dystonia, and neurodegeneration. Their clinical phenotype is consistent with the VAC14-related childhood-onset, striatonigral degeneration recently described in two unrelated children. Post mortem examination demonstrated prominent vacuolation associated with degenerating neurons in the caudate nucleus, putamen, and globus pallidus, similar to previously reported ex vivo vacuoles seen in the late-endosome/lysosome of VAC14-deficient neurons. We identified upregulation of ubiquitinated granules within the cell cytoplasm and lysosomal-associated membrane protein (LAMP2) around the vacuole edge to suggest a process of vacuolation of lysosomal structures associated with active autophagocytic-associated neuronal degeneration. INTERPRETATION: Our findings reveal a distinct clinicopathological phenotype associated with recessive VAC14 mutations.
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    Bioinformatics-Based Identification of Expanded Repeats: A Non-reference Intronic Pentamer Expansion in RFC1 Causes CANVAS
    Rafehi, H ; Szmulewicz, DJ ; Bennett, MF ; Sobreira, NLM ; Pope, K ; Smith, KR ; Gillies, G ; Diakumis, P ; Dolzhenko, E ; Eberle, MA ; Garcia Barcina, M ; Breen, DP ; Chancellor, AM ; Cremer, PD ; Delatycki, MB ; Fogel, BL ; Hackett, A ; Halmagyi, GM ; Kapetanovic, S ; Lang, A ; Mossman, S ; Mu, W ; Patrikios, P ; Perlman, SL ; Rosemergy, I ; Storey, E ; Watson, SRD ; Wilson, MA ; Zee, DS ; Valle, D ; Amor, DJ ; Bahlo, M ; Lockhart, PJ (CELL PRESS, 2019-07-03)
    Genomic technologies such as next-generation sequencing (NGS) are revolutionizing molecular diagnostics and clinical medicine. However, these approaches have proven inefficient at identifying pathogenic repeat expansions. Here, we apply a collection of bioinformatics tools that can be utilized to identify either known or novel expanded repeat sequences in NGS data. We performed genetic studies of a cohort of 35 individuals from 22 families with a clinical diagnosis of cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS). Analysis of whole-genome sequence (WGS) data with five independent algorithms identified a recessively inherited intronic repeat expansion [(AAGGG)exp] in the gene encoding Replication Factor C1 (RFC1). This motif, not reported in the reference sequence, localized to an Alu element and replaced the reference (AAAAG)11 short tandem repeat. Genetic analyses confirmed the pathogenic expansion in 18 of 22 CANVAS-affected families and identified a core ancestral haplotype, estimated to have arisen in Europe more than twenty-five thousand years ago. WGS of the four RFC1-negative CANVAS-affected families identified plausible variants in three, with genomic re-diagnosis of SCA3, spastic ataxia of the Charlevoix-Saguenay type, and SCA45. This study identified the genetic basis of CANVAS and demonstrated that these improved bioinformatics tools increase the diagnostic utility of WGS to determine the genetic basis of a heterogeneous group of clinically overlapping neurogenetic disorders.