ORPHA: 164736;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 12q13.3 | ?Advance sleep phase syndrome, familial, 4 | 620015 | Autosomal dominant | 3 | TIMELESS | 603887 |
A number sign (#) is used with this entry because of evidence that familial advance sleep phase syndrome-4 (FASPS4) is caused by heterozygous mutation in the TIMELESS gene (603887) on chromosome 12q13. One such family has been reported.
Familial advanced sleep phase syndrome-4 (FASPS4) is an autosomal dominant condition in which individuals wake and sleep early (summary by Kurien et al., 2019).
For a discussion of genetic heterogeneity of advanced sleep phase syndrome, see FASPS1 (604348).
Kurien et al. (2019) reported a 54-year-old male proband and his 80-year-old mother who were both categorized as having definite advanced sleep phase syndrome based on their score on a Horne-Ostberg morningness-eveningness questionnaire. The authors used actigraphy to determine activity onset and offset and EEG recordings to determine sleep onset and offset and documented early sleep and activity onset and offset in both family members.
The transmission pattern of FASPS4 in the family reported by Kurien et al. (2019) was consistent with autosomal dominant inheritance.
By screening 25 circadian clock-relevant candidate genes and performing whole-exome sequencing in a man and his mother from a small family (K5602) with FASPS4, Kurien et al. (2019) identified a nonsense mutation in the TIMELESS gene (R1081X; 603887.0001). The mutation segregated with the phenotype in the family and was not found in public variant databases.
Kurien et al. (2019) used CRISPR to generate mice with a heterozygous R1078X mutation in the Tim gene, corresponding to the human R1081X mutation (603887.0001). The mutant mice exhibited advanced sleep phase with altered sensitivity to light pulses but normal circadian period length.
Kurien, P., Hsu, P.-K., Leon, J., Wu, D., McMahon, T., Shi, G., Xu, Y., Lipzen, A., Pennacchio, L. A., Jones, C. R., Fu, Y.-H., Ptacek, L. J. TIMELESS mutation alters phase responsiveness and causes advanced sleep phase. Proc. Nat. Acad. Sci. 116: 12045-12053, 2019. [PubMed: 31138685] [Full Text: https://doi.org/10.1073/pnas.1819110116]