Oligogenic background in SOD1 D91A south Italian ALS patients

What is it about?

One of the most common ALS-causing SOD1 mutations is the p.D91A, known to be either recessive or dominant. It is also known the presence of at least three p.D91A SOD1-related ALS phenotypes 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. Hypothesizing that genetic factors in other ALS-related genes, in combination with the p.D91A-SOD1 variant, may contribute to the different disease phenotypes in homozygous and heterozygous cases, we investigated 39 ALS-related genes by targeted NGS sequencing in a small cohort of ALS patients carrying the p.D91A-SOD1 heterozygous or homozygous mutation.

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Photo by National Cancer Institute on Unsplash

Photo by National Cancer Institute on Unsplash

Why is it important?

We detected unique sets of non-synonymous variants in seven south Italian ALS patients previously characterized as p.D91A carriers. In particular, 19 variants were exclusively found in patients and not in controls, four of which were of uncertain significance including one segregating with the genotype zygosity in two patients. This was the case of TUBA4A/TUBA4B rs45488900, shared by two p.D91A-homozygous SALS patients of our cohort. These results support an individual oligogenic background underlying sporadic and familial p.D91A cases irrespective of their p.D91A mutant alleles.

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