Targeted massively parallel sequencing of autism spectrum disorder-associated genes in a case control cohort reveals rare loss-of-function risk variants

The 14-3-3 protein family are molecular chaperones involved in several biological functions and neurological diseases. We previously pinpointed YWHAZ (encoding 14-3-3ζ) as a candidate gene for autism spectrum disorder (ASD) through a whole-exome sequencing study, which identified a frameshift variant within the gene (c.659-660insT, p.L220Ffs*18). Here, we explored the contribution of the seven human 14-3-3 family members in ASD and other psychiatric disorders by investigating the: (i) functional impact of the 14-3-3ζ mutation p.L220Ffs*18 by assessing solubility, target binding and dimerization; (ii) contribution of common risk variants in 14-3-3 genes to ASD and additional psychiatric disorders; (iii) burden of rare variants in ASD and schizophrenia; and iv) 14-3-3 gene expression using ASD and schizophrenia transcriptomic data. We found that the mutant 14-3-3ζ protein had decreased solubility and lost its ability to form heterodimers and bind to its target tyrosine hydroxylase. Gene-based analyses using publicly available datasets revealed that common variants in YWHAE contribute to schizophrenia (p = 6.6 × 10−7), whereas ultra-rare variants were found enriched in ASD across the 14-3-3 genes (p = 0.017) and in schizophrenia for YWHAZ (meta-p = 0.017). Furthermore, expression of 14-3-3 genes was altered in post-mortem brains of ASD and schizophrenia patients. Our study supports a role for the 14-3-3 family in ASD and schizophrenia.

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Comparing sleep patterns between children with autism spectrum disorder and children with typical development: A matched case–control study

Autism ◽

10.1177/1362361320936827 ◽

2020 ◽

Vol 24 (8) ◽

pp. 2298-2303

Author(s):

Andy CY Tse ◽

CCW Yu ◽

Paul H Lee

Keyword(s):

Body Mass Index ◽

Autism Spectrum Disorder ◽

Body Mass ◽

Sleep Onset ◽

Children With Autism ◽

Autism Spectrum ◽

Case Control ◽

Spectrum Disorder ◽

Typical Development ◽

Matched Case

Children with autism spectrum disorder are often reported to have more sleep deficits and poorer sleep quality compared with children with typical development. However, most previous studies have serious methodological limitations, such as varying sample sizes in the comparison groups, wide age range of participants, and body mass index not matched between participants. This study investigated whether sleep patterns differed between children with autism spectrum disorder and those with typical development using a carefully matched case–control design and incorporating both actigraphy and sleep log assessments. A total of 78 children diagnosed with autism spectrum disorder were matched with 78 typical development controls in this study. The matched variables included age, gender, and body mass index. The results showed that children with autism spectrum disorder had shorter sleep duration, reduced sleep efficiency, longer sleep-onset latency, and longer wake after sleep onset than children with typical development ( ps < 0.05). Further studies are needed to explore the mechanisms underlying these sleep deficits in children with autism spectrum disorder. Lay abstract This study compared the sleep pattern between children with autism spectrum disorders and children with typical development using a matched case–control design (matched age, gender, and body mass index). Significant differences were found in night-time sleep duration (total amount of sleep at night), sleep efficiency (percentage of time spent asleep), sleep-onset latency (length of time that it takes to transit from awake to asleep), and wake after sleep onset (total amount of time spent awake after defined sleep onset). Findings showed that children with autism spectrum disorder had poorer sleep quality than children with typical development. Mechanisms underlying the differences should be further explored in order to develop an effective treatment intervention.

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