Advanced Sleep Phase Syndrome, Familial, 1

A number sign (#) is used with this entry because of evidence that familial advanced sleep phase syndrome-1 (FASPS1) is caused by heterozygous mutation in the PER2 (603426) gene on chromosome 2q37. One such family has been reported.

Description

Advanced sleep phase syndrome is characterized by very early sleep onset and offset (summary by Jones et al., 1999).

Genetic Heterogeneity of Advanced Sleep Phase Syndrome

See also FASPS2 (615224), caused by mutation in the CSNK1D gene (600864) on chromosome 17q25, and FASPS3 (616882), caused by mutation in the PER3 gene (603427) on chromosome 1p36.

Clinical Features

Advanced sleep phase syndrome is characterized by very early sleep onset and offset. Jones et al. (1999) stated that only 2 cases had been reported in young adults (Billiard et al., 1993; Singer and Lewy, 1989). Using strict classification criteria, they identified 29 individuals with familial advanced sleep phase syndrome (FASPS) and 46 unaffected individuals in 3 families. All 3 families were of northern European descent. The youngest affected subject was 8 years old. Six FASPS subjects and 6 unrelated sex- and age-matched controls were admitted for detailed studies. Polysomnographic measurements of sleep phase, plasma melatonin, and body core temperature rhythms were all phase-advanced by 3 to 4 hours in FASPS subjects compared with controls. The endogenous period of the circadian clock was shown to be very short (23.3 hours) in a 69-year-old FASPS subject compared to that (24.2 hours) in a sex- and age-matched control. The authors suggested that this familial circadian rhythm variant in humans will provide a unique opportunity for genetic analysis of human circadian physiology.

Inheritance

The transmission pattern of FASPS in the families reported by Jones et al. (1999) was consistent with autosomal dominant inheritance.

Mapping

In a large 4-generation pedigree with FASPS, Toh et al. (2001) found linkage of the phenotype to marker D2S395 on chromosome 2qter (maximum lod = 5.25 at theta = 0.00).

Molecular Genetics

In affected members of a family with FASPS mapping to chromosome 2q, Toh et al. (2001) identified a heterozygous mutation in the PER2 gene (S662G; 603426.0001). This mutation caused hypophosphorylation by casein kinase I-epsilon (CSNK1E; 600863) in vitro. Thus, a variant in human sleep behavior can be attributed to a missense mutation in a clock component, which alters the circadian period. One branch of the kindred studied by Toh et al. (2001) did not map to chromosome 2q, suggesting that even within this large family there is a phenocopy for FASPS that maps to another region.