Sleep phenotype of individuals with autism spectrum disorder bearing mutations in the PER2 circadian rhythm gene

Abstract

The Per family of genes functions as a primary circadian rhythm maintenance in the brain. Mutations in PER2 are associated with familial advanced sleep‐phase syndrome 1 (FASPS1), and recently suggested in delayed sleep phase syndrome and idiopathic hypersomnia. The detection of PER2 variants in individuals with autism spectrum disorder (ASD) and without reported sleep disorders, has suggested a role of circadian‐relevant genes in the pathophysiology of ASD. It remains unclear whether these individuals may have, in addition to ASD, an undiagnosed circadian rhythm sleep disorder. The MSSNG database was used to screen whole genome sequencing data of 5,102 individuals with ASD for putative mutations in PER2. Families identified were invited to complete sleep phenotyping consisting of a structured interview and two standardized sleep questionnaires: the Pittsburgh Sleep Quality Index and the Morningness‐Eveningness Questionnaire. From 5,102 individuals with ASD, two nonsense, one frameshift, and one de novo missense PER2 variants were identified (0.08%). Of these four, none had a diagnosed sleep disorder. Three reported either a history of, or ongoing sleep disturbances, and one had symptoms highly suggestive of FASPS1 (as did a mutation carrier father without ASD). The individual with the missense variant did not report sleep concerns. The ASD and cognitive profiles of these individuals varied in severity and symptoms. The results support a possible role of PER2‐related circadian rhythm disturbances in the dysregulation of sleep overall and sometimes FASPS1. The relationship between dysregulated sleep and the pathophysiology of ASD require further exploration.

Bioinformatics and next generation sequencing data analysis to identify key genes and pathways influencing in Parkinson’s disease

“…Signaling by NTRK1 (TRKA) [55], cardiac conduction [56], signaling by GPCR [57], immune system [58], cytokine signaling in immune system [59], interferon signaling [60] and toll-like receptor cascades [61] were responsible for development of PD. Recent studies have shown that EGR2 [62], WNT1 [63], ARC (activity regulated cytoskeleton associated protein) [64], CHRNA7 [65], SEZ6L2 [66], IL1RAPL2 [67], PER2 [68], PCDH19 [69], CNTNAP2 [70], SLC12A5 [71], CDK5 [72], ACTL6B [73], GABRD (gamma-aminobutyric acid type A receptor subunit delta) [74], CACNA1G [75], HTR2C [76], STX1A [77], ATP1A3 [78], RIMS3 [79], CNTNAP2 [80], CDH8 [81], SCAMP5 [82], SYNGR1 [83], ARHGEF9 [84], DLG3 [85], RBP4 [86], IL9 [87], S100A9 [88], HGF (hepatocyte growth factor) [89], C3 [90], FKBP5 [91], GABRE (gamma-aminobutyric acid type A receptor subunit epsilon) [92], NCKAP1L [93], PIK3CG [94], ITGB3 [95], ANXA1 [96], SYNE2 [97] and DBI (diazepam binding inhibitor, acyl-CoA binding protein) [98] were closely involved with the occurrence, development, and prognosis of autism spectrum disorder. EGR2 [99], ADCYAP1 [100], CHRNA7 [101], NRN1 [102], ETV5 [103], STXBP1 [104], CAMKK2 [105], VAMP2 [106], SYNGR1 [107], NOD2 [108], TLR2 [109], BRCA2 [110] and LEF1 [111] were previously reported to be critical for the development of bipolar disorder.…”

Genetic basis of sleep phenotypes and rare neurodevelopmental syndromes reveal shared molecular pathways

“…Using functional interaction networks from the set of intersect genes, we discuss critical nodes of coalescence between biological processes related to sleep and neurodevelopment. observed in NDD patients (Hoang et al, 2021). We thus sought to investigate the interplay between sleep and rare genetic syndromes.…”

The trilateral interactions between mammalian target of rapamycin (mTOR) signaling, the circadian clock, and psychiatric disorders: an emerging model

“…The functional mutations of NR1D1 were also detected in ASD subjects with and without sleep disorders [ 112 ]. A study by Hoang et al suggested a possible role of PER2 gene in the sleep dysregulation of ASD individuals [ 117 ]. Whole exome sequencing studies identified de novo loss-of-function variants in PER2 , RORB and CSNK1E [ 118 – 121 ].…”