Delayed Sleep Phase Disorder, Susceptibility To

A number sign (#) is used with this entry because of evidence that susceptibility to delayed sleep phase disorder (DSPD) is conferred by heterozygous mutation in the CRY1 gene (601933) on chromosome 12q23.

Description

Delayed sleep phase syndrome is a circadian rhythm sleep disorder characterized by sleep-onset insomnia and difficulty in awakening at the desired time. Patients with DSPD have chronic difficulty in adjusting their sleep-onset and wake-up times to occupational, school, and social activities. Although psychosocial and environmental factors sometimes induce this kind of disorder, most patients with DSPD appear to have an abnormal circadian pacemaker and/or an abnormal entrainment system (summary by Hohjoh et al., 2003).

Clinical Features

Shibui et al. (1999) found that the melatonin rhythms in patients with delayed sleep phase syndrome are delayed compared with those in normal individuals.

Hohjoh et al. (2003) studied 50 Japanese outpatients with DSPD. All had chronic symptoms of sleep-onset insomnia and difficulty waking at the desired time, which did not appear to be caused by environmental factors. All of the cases were sporadic.

Patke et al. (2017) reported over 40 patients from 7 unrelated families with delayed sleep phase disorder confirmed by genetic analysis. The proband of 1 family (TAUX), 46-year-old female,underwent special sleep studies. She showed several intrinsic circadian rhythm abnormalities consistent with sleep phase delay, including a dim light melatonin onset well after the normal time and a longer sleep/wake rhythm cycle compared to controls. She also showed abnormal core body temperature oscillation patterns with diminished amplitudes compared to controls. Six additional families, all of Turkish descent, were subsequently found to have a similar disorder. Affected individuals had variable sleep disturbances, including late onset of sleep and fragmented sleep patterns. In some cases, the fragmented sleep was augmented by early rising due to cultural or social obligations. One mutation carrier who reported conventional sleep times was subject to work-imposed strong light exposure, suggesting that CRY1-mediated disposition can be modifiable given adequate environmental conditions.

Inheritance

The transmission pattern of DSPD in the families reported by Patke et al. (2017) was consistent with autosomal dominant inheritance.

Molecular Genetics

In affected members of 7 unrelated families, mostly of Turkish origin, with DSPD, Patke et al. (2017) identified a splice site mutation in the CRY1 gene (601933.0001). Analysis of cells from 1 patient confirmed that the mutation resulted in deletion of exon 11 with an in-frame deletion of 24 residues in the C-terminal region. The mutation in the first family was found by a combination of candidate gene and whole-exome sequencing. The mutation segregated with the disorder in all families; there were 31 heterozygous carriers and 8 homozygous carriers, and there were no phenotypic differences between heterozygous and homozygous carriers. The variant was found at a frequency of 0.6% in databases of human genetic variation: minor allele frequency of 0.0012 in the 1000 Genomes Project and 0.004335 in the ExAC databases; this frequency lies within the reported range of DSPD prevalence in the general population. In vitro functional expression studies in mouse embryonic fibroblasts showed that mutant CRY1 increased the circadian period by approximately half an hour compared to wildtype, which was similar to the human phenotype. The mutant protein showed increased localization to the nucleus compared to wildtype, and it had increased interaction with its target transcription factors CLOCK (601851) and ARNTL (602550), resulting in increased transcriptional inhibition consistent with a gain of function. Chromatin immunoprecipitation studies indicated that the CRY1 mutation displaced the CLOCK and ARNTL transcription factor from chromatin at their target gene promoters, resulting in decreased expression of these target genes.

Associations Pending Confirmation

For discussion of a possible association between susceptibility to delayed sleep phase syndrome and mutation in the AANAT gene on chromosome 17q25, see 600950.0001.