Coexistence of variants in TBK1 and in other ALS-related genes elucidates an oligogenic model of pathogenesis in sporadic ALS

Lattante, Serena; Doronzio, Paolo Niccolò; Marangi, Giuseppe; Conte, Amelia; Bisogni, Giulia; Bernardo, Daniela; Russo, Tommaso; Lamberti, Dante; Patrizi, Sara; Apollo, F.; Lunetta, Christian; Scarlino, Stefania; Pozzi, Laura; Zollino, Marcella; Riva, Nilo; Sabatelli, Mario

doi:10.1016/j.neurobiolaging.2019.03.010

Cited by 24 publications

(21 citation statements)

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“…In agreement with several studies that have shown an oligogenic basis of ALS [12,53,57,[98][99][100] as the number of patients with multiple ALS-associated variants is higher than what can be expected by chance, based on the individual mutation frequencies of the respective genes, we also found three patients carrying two potential disease-causing variants. Thus, certain variants alone may not cause disease and the simultaneous analysis of disease genes is highly important [59].…”

Section: Discussionsupporting

confidence: 92%

Targeted next-generation sequencing study in familial ALS-FTD Portuguese patients negative for C9orf72 HRE

et al. 2020

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with clinical and etiological heterogeneity and a complex genetic contribution. Clinical, neuropathological, and genetic evidence revealed that ALS and frontotemporal dementia (FTD) are in part of a single disease continuum. Genetic causes have been identified in sporadic (SALS) and familial patients (FALS) and the recurrent genetic factor underlying ALS and FTD is the C9orf72 hexanucleotide repeat expansion (HRE). However, in our population, the concomitance of ALS and FTD cannot be explained by C9orf72 HRE in many FALS and SALS cases. Our aim is to further understand the genetic basis of ALS in Portuguese patients. 34 patients with FALS or SALS-FTD, negative for C9orf72 HRE, were screened for rare variants in a panel of 29 relevant genes by next-generation sequencing. We detected 15 variants in 11 genes, one classified as pathogenic in TARDBP, two as likely pathogenic in TARDBP and PRPH, and the others as variants of unknown significance (VUS). Gene variants, including VUS, were found in 41.2% FALS patients and 40% SALS-FTD. In most patients, no potential pathogenic variants were found. Our results emphasize the need to enhance the efforts to unravel the genetic architecture of ALS-FTD.

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Section: Discussionsupporting

confidence: 92%

Targeted next-generation sequencing study in familial ALS-FTD Portuguese patients negative for C9orf72 HRE

et al. 2020

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“…The mechanism underlying TBK1 pathogenesis can be considered the same for nonsense and missense variants, especially when located in critical domains. Additionally, we tested TBK1 mRNA and protein levels in fibroblasts from ALS patients carrying novel variants, to confirm that loss-of-function is a consistent mechanism [ 144 ]. Results of in vivo and in vitro experiments need to be carefully evaluated because of the indirect correlation to the phenotype observed.…”

Section: Applying the Acmg Standards And Guidelines For The Interpmentioning

confidence: 99%

High-Throughput Genetic Testing in ALS: The Challenging Path of Variant Classification Considering the ACMG Guidelines

Lattante

Marangi

Doronzio

et al. 2020

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The development of high-throughput sequencing technologies and screening of big patient cohorts with familial and sporadic amyotrophic lateral sclerosis (ALS) led to the identification of a significant number of genetic variants, which are sometimes difficult to interpret. The American College of Medical Genetics and Genomics (ACMG) provided guidelines to help molecular geneticists and pathologists to interpret variants found in laboratory testing. We assessed the application of the ACMG criteria to ALS-related variants, combining data from literature with our experience. We analyzed a cohort of 498 ALS patients using massive parallel sequencing of ALS-associated genes and identified 280 variants with a minor allele frequency < 1%. Examining all variants using the ACMG criteria, thus considering the type of variant, inheritance, familial segregation, and possible functional studies, we classified 20 variants as “pathogenic”. In conclusion, ALS’s genetic complexity, such as oligogenic inheritance, presence of genes acting as risk factors, and reduced penetrance, needs to be considered when interpreting variants. The goal of this work is to provide helpful suggestions to geneticists and clinicians dealing with ALS.

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“…TBK1 codes the TBK1 (TANK-binding kinase 1) protein, a kinase which binds and phosphorylates proteins involved in innate immunity ( Pilli et al, 2012 ), autophagy ( Korac et al, 2013 ), and mitophagy ( Heo et al, 2015 ). Protein targets include optineurin ( OPTN ) (ALS12) and p62 ( SQSTM1 ) (FTDALS3), two ALS-FTD associated genes ( Maruyama et al, 2010 ; Rea et al, 2014 ) and mutations in both of these genes have been found along with TBK1 mutations in patients ( Pottier et al, 2015 ; Borghero et al, 2016 ; Dols-Icardo et al, 2018 ; Lattante et al, 2019 ).…”

Section: Als-ftd Genesmentioning

confidence: 99%

“…TBK1 mutations have also been identified alongside the C9orf72 expansion ( Gijselinck et al, 2015 ; van der Zee et al, 2017 ), and mutations in FUS ( Lattante et al, 2019 ), TARDBP ( Freischmidt et al, 2015 ; de Majo et al, 2018 ), or DCTN1 and FUS together ( Muller et al, 2018 ). Interestingly, those harboring TBK1 and TARDBP ( de Majo et al, 2018 ) or TBK1 and FUS ( Freischmidt et al, 2015 ) mutations, showed earlier disease onset than those with TBK1 alone ( Freischmidt et al, 2015 ; Pozzi et al, 2017 ).…”

Section: Als-ftd Genesmentioning

confidence: 99%

Multifaceted Genes in Amyotrophic Lateral Sclerosis-Frontotemporal Dementia

et al. 2020

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Coexistence of variants in TBK1 and in other ALS-related genes elucidates an oligogenic model of pathogenesis in sporadic ALS

Cited by 24 publications

References 34 publications

Targeted next-generation sequencing study in familial ALS-FTD Portuguese patients negative for C9orf72 HRE

Targeted next-generation sequencing study in familial ALS-FTD Portuguese patients negative for C9orf72 HRE

High-Throughput Genetic Testing in ALS: The Challenging Path of Variant Classification Considering the ACMG Guidelines

Multifaceted Genes in Amyotrophic Lateral Sclerosis-Frontotemporal Dementia

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