Rare homozygosity in amyotrophic lateral sclerosis suggests the contribution of recessive variants to disease genetics

Objective: to determine the occurrence of homozygous rare, in-silico damaging variants in a genetically relatively homogenous group of amyotrophic lateral sclerosis (ALS) patients. Methods: Whole-exome-sequencing of 43 ALS patients of North-Africa Jewish origin was performed. Data were filtered to identify very rare homozygous recessive in-silico damaging variants, in genes annotated to ALS-associated cellular pathways. Results: We identified a rare missense homozygous variant, p.Arg663Cys in MFN2, predicted to be damaging, in a patient with an early age at disease onset (36 years) and fast progression. An additional ALS patient carried the mutation and together established its association to ALS (p =.01). Additional homozygous variants were identified, including the risk allele p.Arg261His in NEK1, as well as variants in genes known to be associated with other neurodegenerative diseases, such as HIT (Huntington's disease), ATM (Ataxia-Telangiectasia), and ZFYVE26 (SPG15), and variants in genes previously reported as upregulated (LZTS3) or downregulated (ARMCO, CFAP54, and MTHFSD) in ALS patients. Altogether, 13 patients (30%) carried at least one homozygous rare in-silico damaging variant, of them 10 carried either another rare homozygous variant and/or a variant in a known ALS gene, which is categorized as pathogenic, likely-pathogenic or variant of uncertain significance. Conclusions: Our results suggest the contribution of recessive alleles to ALS and the possibility of burden of mutations, emphasizing the complexity of ALS genetics.