Dados do Trabalho

Título

Whole-genome analysis of monozygotic twins discordant for type 1 narcolepsy

RESUMO

Narcolepsy type 1 (NT1) is a rare and chronic neurological disease characterized by sudden sleep attacks, overwhelming daytime drowsiness, and cataplexy. To contribute to the understanding of NT1 genetic basis, here we describe a whole-genome analysis of a monozygotic twin pair discordant for NT1. Our whole-genome analysis revealed that both twins have identical pathogenic mutations in NT1 associated genes (such as HLA-DQB1*06:02:01, HLA-DRB1*11:01:02/*15:03:01) and therefore the affected twin has the expected clinical manifestation while the unaffected twin has an unexpected phenotype. This suggests that the unaffected twin might have protective alleles outside the HLA complex. The unaffected twin has significantly more frameshift mutations as compared to the affected twin (108 versus 75) and mutations that affect stop codons (61 versus 5 in stop gain, 26 versus 2 in start lost). Frameshift mutations and stop codon mutations are generally associated with loss-of-function effects and protective alleles are almost always loss-of-function rare alleles. Also, overrepresentation analysis of genes containing variants with potential clinical relevance in the unaffected twin shows that most mutations are in genes related to immune regulation function, Golgi apparatus, MHC, and olfactory receptor. These results support the notion that NT1 has an immunological basis but that protective mutations in non-HLA alleles might interfere with the expression of the NT1 phenotype and consequently with the clinical manifestation of the disease. Discordant monozygotic twin studies provide a unique opportunity to observe the effects of very rare alleles that might not be picked up in populational studies.