Background: Advanced sleep-wake phase disorder (ASWPD) is a circadian rhythm disorder characterized by early sleep onset and wake times. Although rare in the pediatric population, genetic factors, particularly mutations in core clock genes, may play a key role in its pathogenesis. Case Presentation: We report the case of a 4-year-old girl with early awakenings and excessive daytime sleepiness since infancy. Actigraphy, polysomnography, and salivary melatonin profiling confirmed the diagnosis of ASWPD. Whole exome sequencing identified two heterozygous variants in circadian genes: PER2 (c.2950C>T, p.Arg984Cys) and CSNK1D (c.538G>A, p.Ala180Thr). Parental segregation analysis revealed paternal inheritance of the PER2 variant, allowing reclassification of the CSNK1D variant as likely pathogenic. The patient underwent chronotherapy with bright light exposure and prolonged-release melatonin, resulting in improved sleep-wake patterns and daytime functioning. Conclusions: This case highlights a novel de novo variant in CSNK1D associated with paediatric-onset ASWPD, emphasizing the importance of genetic evaluation in early-onset circadian rhythm disorders. It contributes to the understanding of clock gene regulation and supports targeted chronotherapeutic interventions to improve clinical outcomes.
Pisanò, G., Gnazzo, M., Miranda, M., Palombo, F., Gordijn, M., La Morgia, C., et al. (2025). A novel CSNK1Dvariant in pediatric advanced sleep-wake phase syndrome. SLEEP MEDICINE, 131, 106524-106524 [10.1016/j.sleep.2025.106524].
A novel CSNK1Dvariant in pediatric advanced sleep-wake phase syndrome
La Morgia C.;Pizza F.;
2025
Abstract
Background: Advanced sleep-wake phase disorder (ASWPD) is a circadian rhythm disorder characterized by early sleep onset and wake times. Although rare in the pediatric population, genetic factors, particularly mutations in core clock genes, may play a key role in its pathogenesis. Case Presentation: We report the case of a 4-year-old girl with early awakenings and excessive daytime sleepiness since infancy. Actigraphy, polysomnography, and salivary melatonin profiling confirmed the diagnosis of ASWPD. Whole exome sequencing identified two heterozygous variants in circadian genes: PER2 (c.2950C>T, p.Arg984Cys) and CSNK1D (c.538G>A, p.Ala180Thr). Parental segregation analysis revealed paternal inheritance of the PER2 variant, allowing reclassification of the CSNK1D variant as likely pathogenic. The patient underwent chronotherapy with bright light exposure and prolonged-release melatonin, resulting in improved sleep-wake patterns and daytime functioning. Conclusions: This case highlights a novel de novo variant in CSNK1D associated with paediatric-onset ASWPD, emphasizing the importance of genetic evaluation in early-onset circadian rhythm disorders. It contributes to the understanding of clock gene regulation and supports targeted chronotherapeutic interventions to improve clinical outcomes.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
