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. 2024 Jul 27;81(1):316.
doi: 10.1007/s00018-024-05335-8.

Increased copy-number variant load of associated risk genes in sporadic cases of amyotrophic lateral sclerosis

Maria Guarnaccia  1 , Giovanna Morello  1 , Valentina La Cognata  1 , Vincenzo La Bella  2 , Francesca Luisa Conforti  3 , Sebastiano Cavallaro  4
Affiliations

Increased copy-number variant load of associated risk genes in sporadic cases of amyotrophic lateral sclerosis

Maria Guarnaccia et al. Cell Mol Life Sci. .

Abstract

Amyotrophic lateral sclerosis (ALS) is an age-related neurodegenerative disease characterized by selective loss of motor neurons in the brainstem and spinal cord. Several genetic factors have been associated to ALS, ranging from causal genes and potential risk factors to disease modifiers. The search for pathogenic variants in these genes has mostly focused on single nucleotide variants (SNVs) while relatively understudied and not fully elucidated is the contribution of structural variants, such as copy number variations (CNVs). Here, we applied an exon-centric aCGH method to investigate, in sporadic ALS patients, the load of CNVs in 131 genes previously associated to ALS. Our approach revealed that CNV load, defined as the total number of CNVs or their size, was significantly higher in ALS cases than controls. About 87% of patients harbored multiple CNVs in ALS-related genes, and 75% structural variants compromised genes directly implicated in ALS pathogenesis (C9orf72, CHCHD10, EPHA4, FUS, HNRNPA1, KIF5A, NEK1, OPTN, PFN1, SOD1, TARDBP, TBK1, UBQLN2, UNC13A, VAPB, VCP). CNV load was also associated to higher onset age and disease progression rate. Although the contribution of individual CNVs in ALS is still unknown, their extensive load in disease-related genes may have relevant implications for the diagnostic, prognostic and therapeutical management of this devastating disorder.

Keywords: Amyotrophic lateral sclerosis; CNVs load; Copy number variant; Customized aCGH; Diagnostics.

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Conflict of interest statement

Authors declare that there are any competing interests in relation to the work described.

Figures

Fig. 1
Fig. 1
Quality control of aCGH analysis. The following parameters were used to monitor quality of aCGH analysis in each sample: signal-to-noise ratio (SignalToNoise), signal intensity (SignalIntensity), background noise (BGNoise), derivative of log2 ratio spread (DLRSpread), and Reproducibility. Distributions of quality metrics, detected as excellent, good, or poor, are reported as box plots
Fig. 2
Fig. 2
ALS-related genes including CNVs. ALS related genes are highlighted as Definitive, Moderate, Strong, Tenues or Clinical Modifier according to AlsOD database
Fig. 3
Fig. 3
Classification of CNVs in ALS related genes. ALS related genes are categorized as Definitive, Moderate, Strong, Tenues or Clinical Modifier according to ALSoD database. The graph shows the number of ALS related genes including CNVs in our patient’s cohort
Fig. 4
Fig. 4
Load of CNVs in sALS patients compared to neurological control samples. Panel A: sALS patients show a higher load of CNVs in ALS-related genes (Definitive, Moderate, Strong and Clinical Modifier) compared to controls (p-value = 0,02, unpaired t-test two tailed); Panel B: sALS patients show a higher load of CNVs in Definitive ALS genes compared to controls (p-value = 0,03, unpaired t-test two tailed); Panel C: sALS patients show a higher total length of CNVs in Definitive ALS genes compared to controls (p-value = 0,03, unpaired t-test two tailed)
Fig. 5
Fig. 5
Classification of CNVs based on type and their frequency in sALS patient and control samples; Gain (blue), Loss (red) or Deletion (grey); genes are subdivided based on the classification reported on AlsOD: A = Definitive; B = Moderate; C = Clinical Modifier; D= Strong
Fig. 6
Fig. 6
Distribution of large-scale gain and losses, and small-scale (intragenic) copy number aberration in ALS related genes. Gain of exon 1 is the most frequent small-scale (intragenic) CNVs found in 5 Definitive ALS genes (C9orf72, CHCHD10, SOD1, TBK1, VCP), 7 Moderate ALS genes and 1 Strong ALS gene in 46% of patients
Fig. 7
Fig. 7
Genomic distribution of CNVRs and their frequency in our cohort. The CNVRs were obtained after merging overlapping CNVs from multiple individuals of our population. CNVR are distributed across all chromosomes. CNVR are listed by CNV type (Loss and Gain)
Fig. 8
Fig. 8
Correlation analysis of identified CNVs with ALS age of onset and disease progression. Panel A: correlation plot between the number of CNVs in ALS genes classified as Definitive and age of onset (p = 0.02 by unpaired two tailed t-test); Panel B: correlation plot between disease progression score (AFS) and the number of CNVs in ALS genes classified as Definitive (p = 0,0048 by One-way ANOVA)
Fig. 9
Fig. 9
Effects of CNVs load on survival. Kaplan-Meyer analysis showed as patients with low CNVs load had a higher average overall survival (average 47.1), while patients with high CNVs load had a lower average overall survival (average 33.1)
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