Variants in the circadian clock genes PER2 and PER3 associate with familial sleep phase disorders

Plavc, Laura (author), Skubic, Cene (author), Dolenc-Grošelj, Leja (author), Rozman, Damjana (author)

Delayed sleep phase disorder and advanced sleep phase disorder cause disruption of the circadian clock and present with extreme morning/evening chronotype with unclear role of the genetic etiology, especially for delayed sleep phase disorder. To assess if genotyping can aid in clinical diagnosis, we examined the presence of genetic variants in circadian clock genes previously linked to both sleep disorders in Slovenian patient cohort. Based on Morning-evening questionnaire, we found 15 patients with extreme chronotypes, 13 evening and 2 morning, and 28 controls. Sanger sequencing was used to determine the presence of carefully selected candidate SNPs in regions of the CSNK1D, PER2/3 and CRY1 genes. In a patient with an extreme morning chronotype and a family history of circadian sleep disorder we identified two heterozygous missense variants in PER3 gene, c.1243C>G (NM_001377275.1 (p.Pro415Ala)) and c.1250A>G (NM_001377275.1 (p.His417Arg)). The variants were significantly linked to Advanced sleep phase disorder and were also found in proband’s father with extreme morningness. Additionally, a rare SNP was found in PER2 gene in a patient with clinical picture of Delayed sleep phase disorder. The novel variant in PER2 (NM_022817.3):c.1901–218 G>T was found in proband’s parent with eveningness, indicating an autosomal dominant inheritance. We identified a family with autosomal dominant inheritance of two PER3 heterozygous variants that can be linked to Advanced sleep phase disorder. We revealed also a rare hereditary form of Delayed sleep phase disorder with a new PER2 variant with autosomal dominant inheritance, shedding the light into the genetic causality.

• Language: English
• Keywords: circadian clock, genetics, PER2, sleep phase disorders, genotyping, PER3
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: MF - Faculty of Medicine
• Publication status: Published
• Publication version: Version of Record
• Year: 2024
• Number of pages: Str. 757-766
• Numbering: Vol. 41, iss. 5
• PID: 20.500.12556/RUL-158206
• UDC: 616.8
• ISSN on article: 0742-0528
• DOI: 10.1080/07420528.2024.2348016
• COBISS.SI-ID: 196658691
• Publication date in RUL: 29.05.2024

PLAVC, Laura, SKUBIC, Cene, DOLENC-GROŠELJ, Leja and ROZMAN, Damjana, 2024, Variants in the circadian clock genes PER2 and PER3 associate with familial sleep phase disorders. Chronobiology international [online]. 2024. Vol. 41, no. 5, p. 757–766. [Accessed 14 April 2025]. DOI 10.1080/07420528.2024.2348016. Retrieved from: https://repozitorij.uni-lj.si/IzpisGradiva.php?lang=eng&id=158206

Record is a part of a journal

• Title: Chronobiology international
• Shortened title: Chronobiol. int.
• Publisher: Taylor & Francis
• ISSN: 0742-0528
• COBISS.SI-ID: 27499264

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• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.