TABLE 2.
Clock gene polymorphisms in ASD.
| Clock genes | Chr | Location | SFARI gene and score | Findings | References |
| NPAS2 | 2 | NC_000002.12 (100820139..100996829) | Yes, Score 3 | Association analysis in an AGRE cohort revealed two Npas2 significant selected markers. Rs1811399 C > A (p = 0.018), and NPAS2-X3-C-T T > C (p = 0.028) | Nicholas et al., 2007 |
| PER1 | 17 | NC_000017.11 (8140470..8156360, complement) | Yes, Score 3 | Association analysis in an AGRE cohort revealed two Per1 significant selected markers. Rs885747 C > G (p = 0.047), and rs6416892 C > A (p = 0.042) | Nicholas et al., 2007 |
| PER2 | 2 | NC_000002.12 (238244038..238290102, complement) | Yes, Score 2 | A de novo loss-of-function variant in the PER2 gene was observed in an ASD proband from the Simons Simplex Collection in Iossifov et al. (2014). Yuen et al. (2017) identified additional PER2 variants by whole genome sequencing in four ASD families, including a de novo LoF variant in a simplex family from the ASD: Genomes to Outcome Study cohort. | Iossifov et al., 2014 Yuen et al., 2017 |
| PER3 | 1 | NC_000001.11 (7784285..7845181) | No | Base change c.1361G > A causing amino acid change p.R366Q considered disease causing in 1/28 ASD individuals with sleep disturbance. | Yang et al., 2016 |
| ClOCK | 4 | Chromosome 4, NC_000004.12 (55427903..55547138, complement) | No | Base change c.2551A > G causing amino acid change p.H542R considered disease causing in 1/28 ASD individuals with sleep disturbance. SNP number = rs3762836 | Yang et al., 2016 |
| ARNTL | 11 | NC_000011.10 (13276552..13387268) | No | Base change c.38G > C causing amino acid change p.S13T considered disease causing in 1/28 ASD individuals without sleep disturbance | Yang et al., 2016 |
| ARNTL2 | 12 | NC_000012.12 (27332836..27425813) | No | Base change c.1418T > C causing amino acid change p.L473S considered disease causing in 1/28 ASD individuals without sleep disturbance | Yang et al., 2016 |
| NR1D1 | 17 | NC_000017.11 (40092793..40100589, complement) | Yes, Score 3 | Base change c.58A > C, c.1031 A > C, c.1499G > A causing amino acid change p.S20R, p.N344T, p.R500H, respectively, considered disease causing in ASD individuals | Yang et al., 2016; Goto et al., 2017 |
| RORA | 15 | NC_000015.10 (60488284..61229302, complement) | Yes, Score S | Allele frequencies of rs4774388 showed significant overrepresentation of T allele in patients compared with controls in Sayad et al. (2017). Increased DNA methylation and decreased gene expression of Rora in autistic co-twin than undiagnosed co-twin and unaffected controls in Nguyen et al. | Sayad et al., 2017 Nguyen et al., 2010 |
| RORB | 9 | NC_000009.12 (74497335..74693177) | Yes, Score 1 | A de novo missense variant in the RORB gene has been identified in an ASD proband from the Simons Simplex Collection by Iossifov et al. (2014) Rudolf et al. (2016) found that two individuals from patients with de novo mutations involving RORB also presented with autism spectrum disorder. Boudry-Labis et al. (2013) found that RORB was one of four genes within the minimal region of overlap in 9q21.13 microdeletion syndrome, a disorder characterized by autistic features | Iossifov et al., 2014 Rudolf et al., 2016 Boudry-Labis et al., 2013 |
| CSNK1E | 22 | NC_000022.11 (38290691..38318084, complement) | Yes, Score 3 | Two de novo missense variants that were predicted in silico to be damaging were identified in the CSNK1E gene in ASD probands from the Autism Sequencing Consortium in De Rubeis et al. (2014). Base change c.2551A > G causing amino acid change p.H542R considered disease causing by Mutation Taster analysis in three ASD individuals. SNP number = rs77945315 TADA-Denovo analysis using a combined dataset of previously published cohorts from the Simons Simplex Collection and the Autism Sequencing Consortium, as well as a novel cohort of 262 Japanese ASD trios, in Takata et al. (2018) identified CSNK1E as a gene significantly enriched in damaging de novo mutations in ASD cases | De Rubeis et al., 2014; Yang et al., 2016; Takata et al., 2018 |
| TIMELESS | 12 | NC_000012.12 (56416363..56449426, complement) | No | Base changes c.1493T > C causing amino acid changes p.F498S considered disease causing in 1/28 ASD individuals with sleep disturbance | Yang et al., 2016 |