| Summary: | The p.D91A is one of the most common ALS-causing <i>SOD1</i> 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 <i>SOD1</i> 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-<i>SOD1</i> heterozygous (<i>n</i> = 2) or homozygous (<i>n</i> = 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-<i>SOD1</i> ALS patients may be useful in identifying emerging variants and improving disease diagnosis as well as guiding precision medicine.
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