Individual Oligogenic Background in p.D91A-SOD1 Amyotrophic Lateral Sclerosis Patients

Gentile, Giulia; Perrone, Benedetta; Morello, Giovanna; Simone, Isabella Laura; Andò, Sebastiano; Cavallaro, Sebastiano; Conforti, Francesca Luisa

doi:10.3390/genes12121843

Cited by 5 publications

(3 citation statements)

References 66 publications

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“…We have reported p.Gly141Ala mutation in the SOD1 gene associated with incomplete penetrance (Dong et al 2020). Description of compound heterozygous and recessive SOD1 mutations suggests that oligogenic inheritance may account for incomplete penetrance (Gentile et al 2021;Kuuluvainen et al 2019). Subsequently, a series of studies have reported the coexistence of multiple variants in ALS causal genes in both sALS and fALS patients (Cady et al 2015;Dols-Icardo et al 2018;Giannoccaro et al 2017;McCann et al 2020;Morgan et al 2017;Naruse et al 2019;Pang et al 2017;Scarlino et al 2020;Shepheard et al 2021).…”

Section: Introductionmentioning

confidence: 83%

Presence of Rare Variants is Associated with Poorer Survival in Chinese Patients with Amyotrophic Lateral Sclerosis

et al. 2023

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with phenotypic and genetic heterogeneity. Recent studies have suggested an oligogenic basis of ALS, in which the co-occurrence of two or more genetic variants has additive or synergistic deleterious effects. To assess the contribution of possible oligogenic inheritance, we profiled a panel of 43 relevant genes in 57 sporadic ALS (sALS) patients and eight familial ALS (fALS) patients from five pedigrees in east China. We filtered rare variants using the combination of the Exome Aggregation Consortium, the 1000 Genomes and the HuaBiao Project. We analyzed patients with multiple rare variants in 43 known ALS causative genes and the genotype-phenotype correlation. Overall, we detected 30 rare variants in 16 different genes and found that 16 of the sALS patients and all the fALS patients examined harbored at least one variant in the investigated genes, among which two sALS and four fALS patients harbored two or more variants. Of note, the sALS patients with one or more variants in ALS genes had worse survival than the patients with no variants. Typically, in one fALS pedigree with three variants, the family member with three variants (Superoxide dismutase 1 (SOD1) p.V48A, Optineurin (OPTN) p.A433V and TANK binding kinase 1 (TBK1) p.R573H) exhibited much more severe disease phenotype than the member carrying one variant (TBK1 p.R573H). Our findings suggest that rare variants could exert a negative prognostic effect, thereby supporting the oligogenic inheritance of ALS.

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Section: Introductionmentioning

confidence: 83%

Presence of Rare Variants is Associated with Poorer Survival in Chinese Patients with Amyotrophic Lateral Sclerosis

et al. 2023

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“…In addition to the monogenic inheritance pattern, an oligogenic inheritance model of ALS has been proposed [186,187], which may account for the observed clinical heterogeneity. Gentile et al characterized a small cohort of ALS patients carrying the D91A variant and discovered that all 7 patients also harbored variants of other ALS-related genes [188]. Further studies are needed to unravel the multifaceted interplay of genetic and environmental factors, protein aggregation, and cellular dysfunction that together drive ALS onset and progression.…”

Section: Discussionmentioning

confidence: 99%

Variability in SOD1-associated amyotrophic lateral sclerosis: geographic patterns, clinical heterogeneity, molecular alterations, and therapeutic implications

Huang,

Liu,

Yao

et al. 2024

Transl Neurodegener

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of motor neurons, resulting in global health burden and limited post-diagnosis life expectancy. Although primarily sporadic, familial ALS (fALS) cases suggest a genetic basis. This review focuses on SOD1, the first gene found to be associated with fALS, which has been more recently confirmed by genome sequencing. While informative, databases such as ALSoD and STRENGTH exhibit regional biases. Through a systematic global examination of SOD1 mutations from 1993 to 2023, we found different geographic distributions and clinical presentations. Even though different SOD1 variants are expressed at different protein levels and have different half-lives and dismutase activities, these alterations lead to loss of function that is not consistently correlated with disease severity. Gain of function of toxic aggregates of SOD1 resulting from mutated SOD1 has emerged as one of the key contributors to ALS. Therapeutic interventions specifically targeting toxic gain of function of mutant SOD1, including RNA interference and antibodies, show promise, but a cure remains elusive. This review provides a comprehensive perspective on SOD1-associated ALS and describes molecular features and the complex genetic landscape of SOD1, highlighting its importance in determining diverse clinical manifestations observed in ALS patients and emphasizing the need for personalized therapeutic strategies.

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“…To date, over 200 SOD1 variants have been identified. Most are present in heterozygosity [ 14 ], confirming the autosomal dominant inheritance of the gene in this motor neuron disease [ 15 ], while others represent an exception, such as the recessive variant D91A (p.Asp91Ala) that shows frequent homozygosity in Scandinavian populations and Nordic countries [ 16 ] and the compound heterozygous variant D97N (p.Asp97Asn) [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

SOD-1 Variants in Amyotrophic Lateral Sclerosis: Systematic Re-Evaluation According to ACMG-AMP Guidelines

Ruffo

Perrone

Conforti

2022

Genes

Self Cite

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Amyotrophic lateral sclerosis (ALS) is the most common type of motor neuron disease whose causes are unclear. The first ALS gene associated with the autosomal dominant form of the disease was SOD1. This gene has a high rate of rare variants, and an appropriate classification is essential for a correct ALS diagnosis. In this study, we re-evaluated the classification of all previously reported SOD1 variants (n = 202) from ALSoD, project MinE, and in-house databases by applying the ACMG-AMP criteria to ALS. New bioinformatics analysis, frequency rating, and a thorough search for functional studies were performed. We also proposed adjusting criteria strength describing how to apply them to SOD1 variants. Most of the previously reported variants have been reclassified as likely pathogenic and pathogenic based on the modified weight of the PS3 criterion, highlighting how in vivo or in vitro functional studies are determining their interpretation and classification. Furthermore, this study reveals the concordance and discordance of annotations between open databases, indicating the need for expert review to adapt the study of variants to a specific disease. Indeed, in complex diseases, such as ALS, the oligogenic inheritance, the presence of genes that act as risk factors and the reduced penetration must be considered. Overall, the diagnosis of ALS remains clinical, and improving variant classification could support genetic data as diagnostic criteria.

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Individual Oligogenic Background in p.D91A-SOD1 Amyotrophic Lateral Sclerosis Patients

Cited by 5 publications

References 66 publications

Presence of Rare Variants is Associated with Poorer Survival in Chinese Patients with Amyotrophic Lateral Sclerosis

Presence of Rare Variants is Associated with Poorer Survival in Chinese Patients with Amyotrophic Lateral Sclerosis

Variability in SOD1-associated amyotrophic lateral sclerosis: geographic patterns, clinical heterogeneity, molecular alterations, and therapeutic implications

SOD-1 Variants in Amyotrophic Lateral Sclerosis: Systematic Re-Evaluation According to ACMG-AMP Guidelines

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