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Genomic Portrait of a Sporadic Amyotrophic Lateral Sclerosis Case in a Large Spinocerebellar Ataxia Type 1 Family

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Genomic Portrait of a Sporadic Amyotrophic Lateral Sclerosis Case in a Large Spinocerebellar Ataxia Type 1 Family Journal of Personalized Medicine Article Genomic Portrait of a Sporadic Amyotrophic Lateral Sclerosis Case in a Large Spinocerebellar Ataxia Type 1 Family Giovanna Morello 1,2, Giulia Gentile 1 , Rossella Spataro 3, Antonio Gianmaria Spampinato 1,4, 1 2 3 5, , Maria Guarnaccia , Salvatore Salomone , Vincenzo La Bella , Francesca Luisa Conforti * y 1, , and Sebastiano Cavallaro * y 1 Institute for Research and Biomedical Innovation (IRIB), Italian National Research Council (CNR), Via Paolo Gaifami, 18, 95125 Catania, Italy; [email protected] (G.M.); [email protected] (G.G.); [email protected] (A.G.S.); [email protected] (M.G.) 2 Department of Biomedical and Biotechnological Sciences, Section of Pharmacology, University of Catania, 95123 Catania, Italy; [email protected] 3 ALS Clinical Research Center and Neurochemistry Laboratory, BioNeC, University of Palermo, 90127 Palermo, Italy; [email protected] (R.S.); [email protected] (V.L.B.) 4 Department of Mathematics and Computer Science, University of Catania, 95123 Catania, Italy 5 Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, 87036 Rende, Italy * Correspondence: [email protected] (F.L.C.); [email protected] (S.C.); Tel.: +39-0984-496204 (F.L.C.); +39-095-7338111 (S.C.); Fax: +39-0984-496203 (F.L.C.); +39-095-7338110 (S.C.) F.L.C. and S.C. are co-last authors on this work. y Received: 6 November 2020; Accepted: 30 November 2020; Published: 2 December 2020 Abstract: Background: Repeat expansions in the spinocerebellar ataxia type 1 (SCA1) gene ATXN1 increases the risk for amyotrophic lateral sclerosis (ALS), supporting a relationship between these disorders. We recently reported the co-existence, in a large SCA1 family, of a clinically definite ALS individual bearing an intermediate ATXN1 expansion and SCA1 patients with a full expansion, some of which manifested signs of lower motor neuron involvement. Methods: In this study, we employed a systems biology approach that integrated multiple genomic analyses of the ALS patient and some SCA1 family members. Results: Our analysis identified common and distinctive candidate genes/variants and related biological processes that, in addition to or in combination with ATXN1, may contribute to motor neuron degeneration phenotype. Among these, we distinguished ALS-specific likely pathogenic variants in TAF15 and C9ORF72, two ALS-linked genes involved in the regulation of RNA metabolism, similarly to ATXN1, suggesting a selective role for this pathway in ALS pathogenesis. Conclusions: Overall, our work supports the utility to apply personal genomic information for characterizing complex disease phenotypes. Keywords: spinocerebellar ataxia; amyotrophic lateral sclerosis; SCA1-MN; NGS; customized aCGH; multi-omics; pathway; network 1. Introduction Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by severe muscle weakness with atrophy caused by the loss of motor neurons (MNs) in the motor cortex, brainstem, and spinal cord [1]. The genetic and molecular architecture of ALS is complex as the disease is associated with a multitude of causative genes and biological pathways. A limited number J. Pers. Med. 2020, 10, 262; doi:10.3390/jpm10040262 www.mdpi.com/journal/jpm J.J. Pers.Pers. Med. 2020, 10,, x 262 FOR PEER REVIEW 2 of2 of18 18 number of genes, including Cu/Zn superoxide dismutase (SOD1), fused in sarcoma/translocated in of genes, including Cu/Zn superoxide dismutase (SOD1), fused in sarcoma/translocated in liposarcoma liposarcoma (FUS/TLS or FUS), transactive response DNA binding protein 43 kDa (TDP-43), and (FUS/TLS or FUS), transactive response DNA binding protein 43 kDa (TDP-43), and chromosome chromosome 9 open reading frame 72 (C9ORF72), are responsible for a significant percentage of both 9 open reading frame 72 (C9ORF72), are responsible for a significant percentage of both familial familial (FALS) and sporadic ALS (SALS) cases [2–4]. In addition to multiple disease-associated (FALS) and sporadic ALS (SALS) cases [2–4]. In addition to multiple disease-associated genetic genetic variants, there is evidence about putatively associated variants with a moderate or small effect variants, there is evidence about putatively associated variants with a moderate or small effect size size that may act as predisposing factors or modifiers of the disease phenotype [5–7]. Among the that may act as predisposing factors or modifiers of the disease phenotype [5–7]. Among the different different genetic risk factors for ALS is ataxin-1 (ATXN1), a gene involved in transcriptional ATXN1 geneticregulation risk that factors normally for ALS contains is ataxin-1 a segment ( of), 22–23 a gene CAG involved trinucleotide in transcriptional repeats, encoding regulation for that a normallypolyglutamine contains (polyQ) a segment tract. of Intermediate-length 22–23 CAG trinucleotide (~29–33 repeats, CAG) encodingrepeats are for consistently a polyglutamine associated (polyQ) tract.with increased Intermediate-length risk for ALS, (~29–33 while high CAG) poly-Q repeats repeat are consistently expansions (>34 associated CAG) withcause increased spinocerebellar risk for ALS,ataxia while type high1 (SCA1), poly-Q an repeat adult-onset expansions autosomal (>34 CAG) dominant cause spinocerebellarneurodegenerative ataxia disease type 1that (SCA1), is ancharacterized adult-onset by autosomal progressive dominant cerebellar neurodegenerative degeneration causing disease loss thatof motor is characterized coordination by and progressive balance cerebellar[8,9]. degeneration causing loss of motor coordination and balance [8,9]. InIn ourour previous work, work, we we described described a a large large SCA1 SCA1 family, family, in in which which one one non-SCA1 non-SCA1 member, member, bearingbearing an an intermediate intermediate ATXN1ATXN1 poly-Qpoly-Q expansion, expansion, was was instead instead affected affected by ALS by (10) ALS (Figure (10) (Figure 1). The1). Thecoexistence coexistence of ALS of ALSand SCA1 and SCA1 in the insame the family same family is very is rare very and rare supports and supports a role for a roleATXN1 for ATXN1in the inpathogenesis the pathogenesis of ALS of[10]. ALS Traditional [10]. Traditional genetic testing genetic for testing the ALS for patient the ALS did patientnot identify did notmutations identify mutationsin the ALS-causing in the ALS-causing genes SOD1, genes C9ORF72,SOD1 FUS,, C9ORF72 TARDPB, FUS, and, TARDPB ANG. The, and phenotypicANG. The variability phenotypic of variabilitythis family of is this further family complicated is further complicated by the presence by the presenceof a “central of a “centralbranch” branch”in the genealogical in the genealogical tree tree(termed (termed as MN-branch), as MN-branch), including including SCA1 SCA1 patients patients showing showing early earlysigns signsand symptoms and symptoms of lower of lowerMN MNinvolvement, involvement, reinforcing reinforcing a putative a putative pathogenic pathogenic link link between between SCA1 SCA1 and and other other degenerative degenerative MN MN diseases,diseases, including ALS (Figure 11).). Figure 1. SCA1-ALS family pedigree. Square indicates male; circle female; slash deceased; black symbols indicateFigure 1. patients SCA1-ALS affected family by SCA1;pedigree. blue Square symbol indicates indicates male; the patient circle female; affected slash by amyotrophic deceased; black lateral sclerosissymbols (ALS).indicate The patients red arrows affected indicate by SCA1; the patients blue insymbol whom indicates genomic the analyses patient were affected performed. by Theamyotrophic “central branch”lateral sclerosis of the genealogical (ALS). The red tree, arrows presenting indicate patients the patients showing in whom ataxic-spastic genomicphenotype analyses withwere lowerperformed. motor The neuron “central (MN) branch” signs or of symptoms the geneal isogical highlighted tree, presenting in yellow. patients showing ataxic- spastic phenotype with lower motor neuron (MN) signs or symptoms is highlighted in yellow. In this study, we employed a systems biology approach that integrated multiple genomic data (sequenceIn this and study, copy we number employed variations, a systems CNV) biology from approach the ALS that patient integrated along withmultiple some genomic SCA1 familydata members(sequence (withand copy or without number MNvariations, phenotype), CNV) tofrom fully the investigate ALS patient the along complex with some genetic SCA1 factors family and pathogenicmembers (with mechanisms or without that MN may phenotype), contribute toto motor fully neuroninvestigate dysfunctions. the complex genetic factors and pathogenic mechanisms that may contribute to motor neuron dysfunctions. J. Pers. Med. 2020, 10, 262 3 of 18 2. Materials and Methods 2.1. The SCA1 Family with a Member Affected by ALS Figure1 shows the large pedigree of the SCA1 family, spanning five generations [ 10]. The founder could not be identified. All patients belonging to the fourth-generation of this large family underwent an accurate clinical evaluation, which confirmed in all the presence of cerebellar ataxia [10]. Interestingly, patients belonging to a branch of the family, all descendants from the patient II-4, showed early signs and symptoms of lower MN involvement (this branch, termed as “MN-branch”, is highlighted in yellow in Figure1). The ALS patient, bearing an ATXN1 intermediate expansion, was in this branch
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