Burden of rare variants in causative genes for amyotrophic lateral sclerosis (ALS) accelerates age at onset of ALS

Naruse, Hiroya; Ishiura, Hiroyuki; Mitsui, Jun; Takahashi, Yūji; Matsukawa, Takashi; Tanaka, Masaki; Doi, Kouki; Yoshimura, Junichi; Morishita, Shinichi; Goto, Jun; Toda, Tatsushi; Tsuji, Shoji

doi:10.1136/jnnp-2018-318568

Cited by 33 publications

(43 citation statements)

References 30 publications

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“…It is important to note that the percentage of co-occurrence of gene variants estimated by our study is higher as compared with most of the previous studies, including a recent large-scale study, identifying oligogenity in 1% of ALS patients [75]. The reported frequencies of patients with multiple variants in ALS are indeed varied, having been estimated in previous studies as 1.6% [15], 1.3% [76], 1.4% [72], 3.8% [8], 7.9% [73], 18.8% [17], and 19.5% [71]. These differences reflect a number of methodological issues such as the number and selection of sequenced genes (i.e., gene size effect or genetic variability of studied genes), presence of controls, and criteria adopted for filtering and, most importantly, for predicting the pathogenicity of identified variants.…”

Section: Discussioncontrasting

confidence: 64%

“…In our cohort, about 15% of patients were harboring variants in at least two of the investigated genes, confirming the findings of previous studies and supporting the hypothesis that rare variant burden can play a role in the multistep model of disease. Such a model would be inclusive of patients with mutations in major ALS genes [8,15,17,57,[71][72][73], even if for such genes as C9orf72, SOD1, TARDBP and FUS a reduced number of pathogenetic steps has been recently suggested [74]. It is important to note that the percentage of co-occurrence of gene variants estimated by our study is higher as compared with most of the previous studies, including a recent large-scale study, identifying oligogenity in 1% of ALS patients [75].…”

Section: Discussionmentioning

confidence: 62%

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Burden of Rare Variants in ALS and Axonal Hereditary Neuropathy Genes Influence Survival in ALS: Insights from a Next Generation Sequencing Study of an Italian ALS Cohort

Scarlino¹,

Domi²,

Pozzi³

et al. 2020

IJMS

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Although the genetic architecture of amyotrophic lateral sclerosis (ALS) is incompletely understood, recent findings suggest a complex model of inheritance in ALS, which is consistent with a multistep pathogenetic process. Therefore, the aim of our work is to further explore the architecture of ALS using targeted next generation sequencing (NGS) analysis, enriched in motor neuron diseases (MND)-associated genes which are also implicated in axonal hereditary motor neuropathy (HMN), in order to investigate if disease expression, including the progression rate, could be influenced by the combination of multiple rare gene variants. We analyzed 29 genes in an Italian cohort of 83 patients with both familial and sporadic ALS. Overall, we detected 43 rare variants in 17 different genes and found that 43.4% of the ALS patients harbored a variant in at least one of the investigated genes. Of note, 27.9% of the variants were identified in other MND- and HMN-associated genes. Moreover, multiple gene variants were identified in 17% of the patients. The burden of rare variants is associated with reduced survival and with the time to reach King stage 4, i.e., the time to reach the need for percutaneous endoscopic gastrostomy (PEG) positioning or non-invasive mechanical ventilation (NIMV) initiation, independently of known negative prognostic factors. Our data contribute to a better understanding of the molecular basis of ALS supporting the hypothesis that rare variant burden could play a role in the multistep model of disease and could exert a negative prognostic effect. Moreover, we further extend the genetic landscape of ALS to other MND-associated genes traditionally implicated in degenerative diseases of peripheral axons, such as HMN and CMT2.

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Section: Discussioncontrasting

confidence: 64%

Section: Discussionmentioning

confidence: 62%

Burden of Rare Variants in ALS and Axonal Hereditary Neuropathy Genes Influence Survival in ALS: Insights from a Next Generation Sequencing Study of an Italian ALS Cohort

Scarlino¹,

Domi²,

Pozzi³

et al. 2020

IJMS

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“…It means that pathogenic variants in different genes may be needed to fully express the disease. The burden of rare variants could modify the phenotype [ 159 ], influencing the age at onset, which is anticipated in patients with multiple variants [ 160 , 161 ] and could have an impact on survival [ 162 ].…”

Section: The Complex Genetic Architecture Of Als and The Challengementioning

confidence: 99%

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

Lattante

Marangi

Doronzio

et al. 2020

Genes

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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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“…Additionally, discrete ALS phenotypes such as flail arm or flail leg demonstrate a slower disease course compared to classic "Charcot"-like forms [6]. Large-scale whole-exome sequencing studies showed that the age of onset or survival in ALS patients might be influenced by several genetic variants [7,8]. A general assumption is that the disease results from a complex interplay between genetic and environmental factors, with involved genes clustering into three major categories, namely protein homeostasis, RNA homeostasis/processing, and cytoskeletal dynamics, and immune dysregulation having a major role in determining disease onset and progression [9,10].…”

Section: Introductionmentioning

confidence: 99%

Neurofilaments in motor neuron disorders: towards promising diagnostic and prognostic biomarkers

Zucchi

Bonetto

Sorarù

et al. 2020

Mol Neurodegeneration

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Motor neuron diseases (MNDs) are etiologically and biologically heterogeneous diseases. The pathobiology of motor neuron degeneration is still largely unknown, and no effective therapy is available. Heterogeneity and lack of specific disease biomarkers have been appointed as leading reasons for past clinical trial failure, and biomarker discovery is pivotal in today’s MND research agenda. In the last decade, neurofilaments (NFs) have emerged as promising biomarkers for the clinical assessment of neurodegeneration. NFs are scaffolding proteins with predominant structural functions contributing to the axonal cytoskeleton of myelinated axons. NFs are released in CSF and peripheral blood as a consequence of axonal degeneration, irrespective of the primary causal event. Due to the current availability of highly-sensitive automated technologies capable of precisely quantify proteins in biofluids in the femtomolar range, it is now possible to reliably measure NFs not only in CSF but also in blood. In this review, we will discuss how NFs are impacting research and clinical management in ALS and other MNDs. Besides contributing to the diagnosis at early stages by differentiating between MNDs with different clinical evolution and severity, NFs may provide a useful tool for the early enrolment of patients in clinical trials. Due to their stability across the disease, NFs convey prognostic information and, on a larger scale, help to stratify patients in homogenous groups. Shortcomings of NFs assessment in biofluids will also be discussed according to the available literature in the attempt to predict the most appropriate use of the biomarker in the MND clinic.

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Burden of rare variants in causative genes for amyotrophic lateral sclerosis (ALS) accelerates age at onset of ALS

Cited by 33 publications

References 30 publications

Burden of Rare Variants in ALS and Axonal Hereditary Neuropathy Genes Influence Survival in ALS: Insights from a Next Generation Sequencing Study of an Italian ALS Cohort

Burden of Rare Variants in ALS and Axonal Hereditary Neuropathy Genes Influence Survival in ALS: Insights from a Next Generation Sequencing Study of an Italian ALS Cohort

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

Neurofilaments in motor neuron disorders: towards promising diagnostic and prognostic biomarkers

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