Abstract
The p.D91A is one of the most common ALS-causing SOD1 mutations and is known to be either recessive or dominant. The homozygous phenotype is characterized by prolonged survival and slow progression of disease, whereas the affected heterozygous phenotypes can vary. To date, no genetic protective factors located close to SOD1 have been associated with the mild progressive homozygous phenotype. Using Next Generation Sequencing (NGS), we characterized a small cohort of sporadic and familial p.D91A-SOD1 heterozygous (n = 2) or homozygous (n = 5) ALS patients, to reveal any additional contributing variant in 39 ALS-related genes. We detected unique sets of non-synonymous variants, four of which were of uncertain significance and several in untranslated regions of ALS-related genes. Our results supported an individual oligogenic background underlying both sporadic and familial p.D91A cases irrespective of their p.D91A mutant alleles. We suggest that a comprehensive genomic view of p.D91A-SOD1 ALS patients may be useful in identifying emerging variants and improving disease diagnosis as well as guiding precision medicine.
Highlights
Amyotrophic lateral sclerosis (ALS) represents the third most common neurodegenerative disease, characterized by the progressive adult-onset degeneration of upper and lower motor neurons [1]
Sanger sequencing analysis performed in 997 ALS patients from southern Italy by our research group, revealed that 2% of patients had superoxide dismutase 1 (SOD1) mutations [33]
Previous reports demonstrated the absence of a neuroprotective factor in the genomic region near SOD1 in p.D91A-homozygous ALS patients, suggesting the existence of a putative protective factor modulating the phenotype located elsewhere in the genome [31]
Summary
Amyotrophic lateral sclerosis (ALS) represents the third most common neurodegenerative disease, characterized by the progressive adult-onset degeneration of upper and lower motor neurons [1]. There are two main forms of ALS, familial (FALS) and apparently sporadic (SALS) accounting for about 10% and 90% of cases, respectively [2] This complex disease is caused by the interplay of causative genetic factors (monogenic or oligogenic) and risk factors (genetic and non-genetic) [3]. Prevalence of p.D91A in ALS cases varies globally and is distinctly absent in some populations (https://gnomad.broadinstitute.org/, accessed on 22 October 2021) This is the most prevalent variant in Europe [5]. An updated literature search for previously reported p.D91A SOD1-related phenotypes [20] revealed the presence of at least three groups of patients with differences in disease progression rate and survival time, without fully identifying potential genetic modifiers or contributing variants in addition to the p.D91A zygosity (Table 1)
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