Emerging genetics of sleep and circadian disorders.

PURPOSE OF REVIEW: Improved access to genetic testing is accelerating identification of variants underlying common sleep traits and rare Mendelian disorders. This review highlights advances over the past two years. RECENT FINDINGS: Family-based studies continue to uncover genes governing sleep timing and amount. Advanced sleep-wake phase disorder (ASWPD) is largely caused by molecular clock variants, but newly identified variants in CACNA1D instead affect light entrainment while leaving behavioral rhythms in constant conditions intact. Additionally, a SIK3 loss-of-function variant adds to a growing list of familial natural short sleep (FNSS) genes, including DEC2, NPSR1, ADRB1, and GRM1. Although decreased sleep typically predicts poor health outcomes, converging evidence suggests FNSS variants may promote healthy aging. Mapping causative genes from genome-wide association studies (GWAS) has been a challenge, but novel variant-to-gene approaches uncover variants affecting CADM2 as a driver of hypersomnia. Finally, we highlight consequences of variation in the molecular clock: ultrarare variants in BMAL1 cause a novel neurodevelopmental syndrome that includes variable sleep dysfunction. SUMMARY: The genetic landscape of sleep and circadian disorders is rapidly expanding, driven by family-based studies and GWAS coupled with variant-to-gene mapping. We conclude by hypothesizing that early, severe sleep or circadian dysfunction may itself drive neurodevelopmental disorders.