Combined genotype of HCRTR2 and CLOCK variants in a large family of cluster headache with familial periodicity phenotype.

purposeCluster headache (CH) is a debilitating condition with severe and recurrent headaches characterized by circannual and circadian rhythms. A genetic contingent was suggested, and several loci were described in large cohorts. However, no variant associated with CH for multiplex families has been described. The purpose of our study was to examine candidate genes and new genetic variants in a multigenerational family of cluster headaches in which two members have original chronobiological characteristics that we have called the phenomenon of "family periodicity". METHODS AND

resultsWe performed a whole genome sequencing in four patients in a large multigenerational family of cluster headache to identify additional loci associated with CH. This allowed us to replicate the genomic association of HCRTR2 and CLOCK as candidate genes. In two family members with the same phenotypic circadian pattern (familial periodicity) the association of polymorphism NM_001526.4:c.922G > A was shown in the HCRTR2 gene, and NM_004898.4:c.213T > C in the CLOCK gene.

interpretationThis whole genome sequencing reproduced two genetic risk loci for CH already involved in its pathogenicity. This is the first time that the combination of HCRTR2 and CLOCK gene variants is identified in a multigenerational family of CH with striking periodicity characteristics. Our study supports the hypothesis that the combination of HCRTR2 and CLOCK gene variants can contribute to the risk of cluster headache and offer the prospect of a new area of research on the molecular circadian clock.