Table 1.

Clinical studies on circadian rhythmicity and autism spectrum disorder in children.

Authors (Ref.) country	Study design	Sample size	ASD assessment	Sleep–wake cycle assessment	Results	Major limitations
Takase, Taira and Sasaki (57) Japan	Cross-sectional study	89 autistic children (3–20 years).	Clinical diagnoses.	Actigraphy Total sleep time (TST) was calculated from their sleep logs.	One autistic girl showed a tendency of non-24-h sleep–wake syndrome. The others did not. Most subjects showed a large variation in TST.	No diagnostic criteria for diagnosis, no control group.
Nicholas et al. (25) Autism Genetic Resource Exchange	Cross-sectional study	110 autistic subjects and their parents.	ADI-R, ADOS-G94, DSM-IV diagnostic criteria.	Analysis of the single-nucleotide polymorphisms (SNPs) in 11 clock/clock-related genes.	A significant allelic association was detected for PER1 and NPAS2.	Predominant high-functioning subjects.
Giannotti et al. (58) Rome, Italy	Case–control study	104 children with autism; 162 TD children.	DSM-IV-TR diagnostic criteria; ADI-R; ADOS-G; CARS.	CSHQ; Parental report sleep diary for 4 weeks; 21 channel EEG recordings.	Regressed group showed higher incidence of circadian rhythm disorders than non-regressed ones. The regressed group showed higher CSHQ bedtime resistance, sleep onset delay, sleep duration and night awakening scores.	No evaluation of sleep parameters by standardized measures.
Mullegama et al. (59) Richmond, VA, USA	Cross-sectional study	19 children with a molecular diagnosis of del 2q23.1 (9 months to 11 years).	Molecular diagnosis of del 2q23.1	Parent sleep questionnaire; The expression of four circadian genes, NR1D2, PER1, PER2, and PER3, in 2q23.1 deletion syndrome lymphoblastoid cell lines (LCLs).	Molecular analysis of the circadian deficits associated with haploinsufficiency of MBD5 in which circadian gene mRNA levels of NR1D2, PER1, PER2, and PER3 were altered in del 2q23.1 of LCLs; haploinsufficiency of MBD5 can result in dysregulation of circadian rhythm gene expression. Circadian and mTOR signaling pathways were associated with sleep disturbance.	Small sample size; no objective sleep measures.
Yang et al. (26) Tochigi, Japan	Case–control study	28 ASD patients 23 controls of Japanese descent.	DSM IV-TR diagnostic criteria	The coding regions of 18 canonical clock genes and clock-controlled genes were sequenced.	The mutations p.S20R in NR1D1, p.H542R in CLOCK, p.L473S in ARNTL2, p.A325T in TIMELESS, p.S13T in ARNTL, and p.G24E in PER2 were diagnosed in ASD. Mutations in circadian-relevant genes affecting gene function were more frequent in patients with ASD than in controls.	Small sample size; no objective sleep measures.
Goto et al. (60) Nagoya, Japan	Case–control study	111 Caucasian 87 Japanese patients with ASD; 158 Caucasian and 133 Japanese TD children.	DSM IV-TR and DSM-5 diagnostic criteria.	The patients, their siblings, and parents were tested for mutations in all exons of NR1D1 (also known as Rev-Erbα).	They detected single-base changes with an amino acid substitution in the coding region of NR1D1 in 4 individuals. Not detected in controls. c.1012C were identified as the rare SNPs. A (p.R500H) mutation (AU1098302) had typical features of ASD and no difficulty in sleep induction; he showed strong anxiety and little sociability without verbal communication with others.	No objective sleep measures.
Van der Heijden et al. (61) The Netherlands	Case–control study	44 children with ADHD; 67 children with ASD; 243 TD children (8–12 years).	Parent report CBCL.	Sleep Disturbance Scale for Children parental report questionnaire; Chronotype of the children was assessed with Children’s Chronotype Questionnaire; Sleep hygiene was assessed using the Children’s Sleep Hygiene Scale	Children with ADHD and ASD showed more sleep problems (63.6 and 64.7%, vs. 25.1% in TD) and shorter sleep duration than controls, while differences between ADHD and ASD were not significant. Evening types were associated with sleep problems in ADHD and ASD. Associations of greater anxiety/depression with sleep problems were shown in ADHD and TD.	No objective sleep measures.

DSM, Diagnostic and Statistical Manual; TD, typically development; NDD, neurodevelopment disorder; CSHQ, Children’s Sleep Habits Questionnaire; ICD-10, International Classification of Diseases-10; ASD, autism spectrum disorder; ADI_R, Autism Diagnostic Interview-Revised; ADOS, Autism Diagnostic Observation Schedules; PSG, polysomnography; CBCL, child behavior checklist; ADHD, attention-deficit hyperactivity disorder; PER1, Period Circadian Regulator 1; NPAS2, Neuronal PAS domain protein 2; NR1D1-2, nuclear receptor subfamily 1 group D member 1–2; MBD5, methyl-CpG binding domain protein 5.