Novel Rare Missense Variations and Risk of Autism Spectrum Disorder: Whole-Exome Sequencing in Two Families with Affected Siblings and a Two-Stage Follow-Up Study in a Japanese Population

Egawa, Jun; Watanabe, Yuichiro; Wang, Chenyao; Inoue, Emiko; Sugimoto, Atsunori; Sugiyama, Toshiro; Igeta, Hirofumi; Nunokawa, Ayako; Shibuya, Masako; Kushima, Itaru; Orime, Naoki; Hayashi, Taketsugu; Okada, Takashi; Uno, Yuichi; Ozaki, Norio; Someya, Toshiyuki

doi:10.1371/journal.pone.0119413

Cited by 14 publications

(20 citation statements)

References 17 publications

(21 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Therefore, it was likely that sequencing these three individuals would enable the efficient identification of risk‐associated variants. WES was performed at the Dragon Genomics Center of Takara Bio Inc., Mie, Japan, as previously described [Egawa et al, ,; Inoue et al, ; Watanabe et al, ]. In brief, exome libraries were prepared using the SureSelect Human All Exon V4 Kit (Agilent, Santa Clara, CA) and sequenced using the HiSeq2000 system (Illumina, San Diego, CA).…”

Section: Methodsmentioning

confidence: 99%

Rare UNC13B variations and risk of schizophrenia: Whole‐exome sequencing in a multiplex family and follow‐up resequencing and a case–control study

Egawa

Hoya

Watanabe

et al. 2016

American J of Med Genetics Pt B

Self Cite

View full text Add to dashboard Cite

Rare genomic variations inherited in multiplex schizophrenia families are suggested to play a role in the genetic etiology of the disease. To identify rare variations with large effects on the risk of developing schizophrenia, we performed whole-exome sequencing (WES) in two affected and one unaffected individual of a multiplex family with 10 affected individuals. We also performed follow-up resequencing of the unc-13 homolog B (Caenorhabditis elegans) (UNC13B) gene, a potential risk gene identified by WES, in the multiplex family and undertook a case-control study to investigate association between UNC13B and schizophrenia. UNC13B coding regions (39 exons) from 15 individuals of the multiplex family and 111 affected offspring for whom parental DNA samples were available were resequenced. Rare missense UNC13B variations identified by resequencing were further tested for association with schizophrenia in two independent case-control populations comprising a total of 1,753 patients and 1,602 controls. A rare missense variation (V1525M) in UNC13B was identified by WES in the multiplex family; this variation was present in five of six affected individuals, but not in eight unaffected individuals or one individual of unknown disease status. Resequencing UNC13B coding regions identified five rare missense variations (T103M, M813T, P1349T, I1362T, and V1525M). In the case-control study, there was no significant association between rare missense UNC13B variations and schizophrenia, although single-variant meta-analysis indicated that M813T was nominally associated with schizophrenia. These results do not support a contribution of rare missense UNC13B variations to the genetic etiology of schizophrenia in the Japanese population. © 2016 Wiley Periodicals, Inc.

show abstract

Section: Methodsmentioning

confidence: 99%

Rare UNC13B variations and risk of schizophrenia: Whole‐exome sequencing in a multiplex family and follow‐up resequencing and a case–control study

Egawa

Hoya

Watanabe

et al. 2016

American J of Med Genetics Pt B

Self Cite

View full text Add to dashboard Cite

show abstract

“…The sample included 241 patients and 667 controls involved in the study by Egawa et al . [ 3 ]. Patient and control groups were not sex- or age-matched.…”

Section: Methodsmentioning

confidence: 99%

“…Our recent whole-exome sequencing (WES) study in two families with affected siblings ( S1 Fig ) and a follow-up study identified ceroid-lipofuscinosis, neuronal 8 (epilepsy, progressive with mental retardation) ( CLN8 ) as a potential genetic risk factor for ASD [ 3 ]. In one family, a rare heterozygous missense variation, R24H, was transmitted from an affected father to three affected sons and thus co-segregated with ASD.…”

Section: Introductionmentioning

confidence: 99%

Resequencing and Association Analysis of CLN8 with Autism Spectrum Disorder in a Japanese Population

et al. 2015

Self Cite

View full text Add to dashboard Cite

Rare variations contribute substantially to autism spectrum disorder (ASD) liability. We recently performed whole-exome sequencing in two families with affected siblings and then carried out a follow-up study and identified ceroid-lipofuscinosis neuronal 8 (epilepsy, progressive with mental retardation) (CLN8) as a potential genetic risk factor for ASD. To further investigate the role of CLN8 in the genetic etiology of ASD, we performed resequencing and association analysis of CLN8 with ASD in a Japanese population. Resequencing the CLN8 coding region in 256 ASD patients identified five rare missense variations: g.1719291G>A (R24H), rs201670636 (F39L), rs116605307 (R97H), rs143701028 (T108M) and rs138581191 (N152S). These variations were genotyped in 568 patients (including the resequenced 256 patients) and 1017 controls. However, no significant association between these variations and ASD was identified. This study does not support a contribution of rare missense CLN8 variations to ASD susceptibility in the Japanese population.

show abstract

“…On the other hand, WES of affected and unaffected individuals has proven to be a powerful approach and has already led to the identification of more than 150 novel candidate genes for ASD . Compared to GWAS, WES provides new opportunities for sporadic cases and has the capacity to detect de novo mutations and variations with incomplete penetrance.…”

Section: Research Approachesmentioning

confidence: 99%

Autism genetics – an overview

Yin

Schaaf

2016

Prenatal Diagnosis

View full text Add to dashboard Cite

Autism spectrum disorder (ASD) is a highly heritable, clinically diverse group of neurodevelopmental disorders. Its genetic heterogeneity is remarkable, with more than 800 ASD predisposition genes identified to date. They are involved in various biological processes, including chromatin remodeling and gene transcription regulation, cell growth and proliferation, ubiquitination, and neuronal-specific processes, such as synaptic organization and activity, dendritic morphology, and axonogenesis. This review aims to discuss basic autism genetics, explicate ways to investigate ASD in model systems, highlight some key genes and their molecular pathways, and introduce novel theories of ASD pathogenesis, such as imbalance of excitatory and inhibitory brain activity, oligogenic heterozygosity, and the female protective model. © 2016 John Wiley & Sons, Ltd.

show abstract

Novel Rare Missense Variations and Risk of Autism Spectrum Disorder: Whole-Exome Sequencing in Two Families with Affected Siblings and a Two-Stage Follow-Up Study in a Japanese Population

Cited by 14 publications

References 17 publications

Rare UNC13B variations and risk of schizophrenia: Whole‐exome sequencing in a multiplex family and follow‐up resequencing and a case–control study

Rare UNC13B variations and risk of schizophrenia: Whole‐exome sequencing in a multiplex family and follow‐up resequencing and a case–control study

Resequencing and Association Analysis of CLN8 with Autism Spectrum Disorder in a Japanese Population

Autism genetics – an overview

Contact Info

Product

Resources

About