Two de novo variations identified by massively parallel sequencing in 13 Chinese families with children diagnosed with autism spectrum disorder

Li, Shijun; Yu, Shanshan; Luo, Haitao; Li, Xin; Rao, Bin; Wang, Yi; Li, Zhenzhen; Liu, Gang; Zou, Li‐Ping; Zhang, Jishui; Chen, Feng; Liu, Jing; Liu, Jianwei; Hu, Nan; Chen, Xiaoqiao; Yu, Shengyuan; Li, Ké; He, Mianwang; Yu, Xin; Wang, Jun; Guo, Sheng-Li; Chen, Zhiye; Ma, Lin

doi:10.1016/j.cca.2018.01.025

Cited by 7 publications

(9 citation statements)

References 22 publications

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“…Additionally, the canonical donor splice site 3′ of c.664 was also found to be repeatedly affected. 17 We show in our study that c.664+1G>T causes skipping of exon 4, producing an in-frame deletion in the SAND domain that results in abnormal transcriptional activity mimicking the effect of other missense variants on DEAF1 protein activity.…”

Section: Discussionmentioning

confidence: 59%

“…Moreover, variants have been found recurrently affecting the same residues, namely p.Gly212, p.Leu214, p.Lys216, p.Ile228, p.Arg254, p.Gln264, and p.Ala276 (refs. 1,[12][13][14][15][16][17][18][19][20]. Additionally, the canonical donor splice site 3′ of c.664 was also found to be repeatedly affected.…”

Section: Discussionmentioning

confidence: 94%

“…7 Biallelic disruption of Deaf1 in mice results in neural tube defects, 10 and biallelic Drosophila Deaf1 loss-of-function mutants show early embryonic arrest. 11 Pathogenic variants in the DEAF1 gene have been reported to lead to two clinically distinct intellectual disability (ID) syndromes: autosomal dominant mental retardation 24 (MRD24; MIM 615828) caused by de novo variants, 1,[12][13][14][15][16][17] and the recessively inherited dyskinesia, seizures, and intellectual developmental disorder syndrome (DYSEIDD; MIM 617171) (refs. 16,[18][19][20].…”

Section: Introductionmentioning

confidence: 99%

“…To date, nine different de novo pathogenic variants have been described in ten individuals, p.(Gln264Pro) (n =3) [1;13;16] p.(Leu272Ser) p.(Ala276Pro) (n =2) p.(Pro293Leu) p.(Lys305del) [16] p.(Gly212Ser) (n =3) [16] p.(Gly225Glu) p.(lle228Ser) [1;12] p.(Trp234Arg) [15] p.(Ser236Gly) p.(Lys253Glu) p.(Arg246Thr) [14] p.(Arg254Ser) [ [17] p.(Arg224Trp [1] p.(Gly292Profs*) (n =3) [ ZnF NLS NES MYND 301306 453 476 504 540 565 12 11 10 9 8 7 6 5 4 3 2 1 who manifested moderate to severe ID with severely affected expressive speech and mild motor delay. 1,[12][13][14][15][16][17] Epilepsy was described in half of the individuals. 16 Behavioral problems consisted of hyperactive, compulsive, and/or aggressive behavior; fascination with water; and striking mood swings.…”

Section: Introductionmentioning

confidence: 99%

“…1 All but one of the de novo pathogenic DEAF1 variants occurred in the SAND domain, including seven missense variants and one splice-site variant. 1,[12][13][14][15][16][17] One in-frame deletion of three base pairs was reported in the NLS domain. 16 These de novo pathogenic DEAF1 variants impair the DEAF1 transcriptional activity, DNA-binding, and/or alter subcellular localization.…”

Section: Introductionmentioning

confidence: 99%

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De novo and biallelic DEAF1 variants cause a phenotypic spectrum

Sá

Jensik

McGee

et al. 2019

Genetics in Medicine

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Purpose: To investigate the effect of different DEAF1 variants on the phenotype of patients with autosomal dominant and recessive inheritance patterns and on DEAF1 activity in vitro. Methods: We assembled a cohort of 23 patients with de novo and biallelic DEAF1 variants, described the genotype-phenotype correlation, and investigated the differential effect of de novo and recessive variants on transcription assays using DEAF1 and Eif4g3 promoter luciferase constructs. Results: The proportion of the most prevalent phenotypic features, including intellectual disability, speech delay, motor delay, autism, sleep disturbances, and a high pain threshold, were not significantly different in patients with biallelic and pathogenic de novo DEAF1 variants. However, microcephaly was exclusively observed in patients with recessive variants (p < 0.0001). Conclusion: We propose that different variants in the DEAF1 gene result in a phenotypic spectrum centered around neurodevelopmental delay. While a pathogenic de novo dominant variant would also incapacitate the product of the wild-type allele and result in a dominant-negative effect, a combination of two recessive variants would result in a partial loss of function. Because the clinical picture can be nonspecific, detailed phenotype information, segregation, and functional analysis are fundamental to determine the pathogenicity of novel variants and to improve the care of these patients.

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Section: Discussionmentioning

confidence: 59%

Section: Discussionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

De novo and biallelic DEAF1 variants cause a phenotypic spectrum

Sá

Jensik

McGee

et al. 2019

Genetics in Medicine

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De novo variants of DEAF1 cause intellectual disability in six Chinese patients

Chen

Deng

Xiong

et al. 2021

Clinica Chimica Acta

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Expression analysis of selected genes involved in tryptophan metabolic pathways in Egyptian children with Autism Spectrum Disorder and learning disabilities

Higazi

Kamel

Abd-Elnaeem

et al. 2021

Sci Rep

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Autism Spectrum Disorder (ASD) and learning disabilities are neurodevelopmental disabilities characterized by dramatically increasing incidence rates, yet the exact etiology for these disabilities is not identified. Impairment in tryptophan metabolism has been suggested to participate in the pathogenesis of ASD, however, further validation of its involvement is required. Additionally, its role in learning disabilities is still uninvestigated. Our objective was to evaluate some aspects of tryptophan metabolism in ASD children (N = 45) compared to children with learning disabilities (N = 44) and healthy controls (N = 40) by measuring the expression levels of the MAOA, HAAO and AADAT genes using real-time RT-qPCR. We also aimed to correlate the expression patterns of these genes with parental ages at the time of childbirth, levels of serum iron, and vitamin D3 and zinc/copper ratio, as possible risk factors for ASD. Results demonstrated a significant decrease in the expression of the selected genes within ASD children (p < 0.001) relative to children with learning disabilities and healthy controls, which significantly associated with the levels of our targeted risk factors (p < 0.05) and negatively correlated to ASD scoring (p < 0.001). In conclusion, this study suggests that the expression of the MAOA, HAAO and AADAT genes may underpin the pathophysiology of ASD.

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Two de novo variations identified by massively parallel sequencing in 13 Chinese families with children diagnosed with autism spectrum disorder

Cited by 7 publications

References 22 publications

De novo and biallelic DEAF1 variants cause a phenotypic spectrum

De novo and biallelic DEAF1 variants cause a phenotypic spectrum

De novo variants of DEAF1 cause intellectual disability in six Chinese patients

Expression analysis of selected genes involved in tryptophan metabolic pathways in Egyptian children with Autism Spectrum Disorder and learning disabilities

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