Phenotype‐to‐genotype approach reveals head‐circumference‐associated genes in an autism spectrum disorder cohort

Wu, Huidan; Li, Honghui; Bai, Ting; Lin, Han; Ou, Jianjun; Xun, Guanglei; Zhang, Yu; Wang, Yazhe; Duan, Guiqin; Zhao, Ningxia; Chen, Biyuan; Du, Xiaogang; Yao, Meiling; Zou, Xiaobing; Zhao, Jingping; Hu, Zhengmao; Eichler, Evan E.; Guo, Hui; Xia, Kun

doi:10.1111/cge.13665

Cited by 35 publications

(44 citation statements)

References 40 publications

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“…In addition to CNTNAP5, damaging missense variants were identified in four other mutation intolerant genes, previously implicated in ASD: TANC2, ERBIN, SYNE1 and HERC2. [40][41][42][43][44][45][46][47][48][49][50] Finally, the proband did not carry any pathogenic mutation in her mtDNA. However, we found five variants with low-level heteroplasmy (ranging from 0.2% to 0.7%) that were absent in the mother, and two maternally inherited variants, which increased their heteroplasmic load in the proband as compared to the mother.…”

Section: Ta B L E 1 Summary Of Clinical Datamentioning

confidence: 89%

An increased burden of rare exonic variants in NRXN1 microdeletion carriers is likely to enhance the penetrance for autism spectrum disorder

Cameli

Viggiano

Rochat

et al. 2021

J Cellular Molecular Medi

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Autism spectrum disorder (ASD) is characterized by a complex polygenic background, but with the unique feature of a subset of cases (~15%‐30%) presenting a rare large‐effect variant. However, clinical interpretation in these cases is often complicated by incomplete penetrance, variable expressivity and different neurodevelopmental trajectories. NRXN1 intragenic deletions represent the prototype of such ASD‐associated susceptibility variants. From chromosomal microarrays analysis of 104 ASD individuals, we identified an inherited NRXN1 deletion in a trio family. We carried out whole‐exome sequencing and deep sequencing of mitochondrial DNA (mtDNA) in this family, to evaluate the burden of rare variants which may contribute to the phenotypic outcome in NRXN1 deletion carriers. We identified an increased burden of exonic rare variants in the ASD child compared to the unaffected NRXN1 deletion‐transmitting mother, which remains significant if we restrict the analysis to potentially deleterious rare variants only (P = 6.07 × 10−5). We also detected significant interaction enrichment among genes with damaging variants in the proband, suggesting that additional rare variants in interacting genes collectively contribute to cross the liability threshold for ASD. Finally, the proband's mtDNA presented five low‐level heteroplasmic mtDNA variants that were absent in the mother, and two maternally inherited variants with increased heteroplasmic load. This study underlines the importance of a comprehensive assessment of the genomic background in carriers of large‐effect variants, as penetrance modulation by additional interacting rare variants to might represent a widespread mechanism in neurodevelopmental disorders.

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Section: Ta B L E 1 Summary Of Clinical Datamentioning

confidence: 89%

An increased burden of rare exonic variants in NRXN1 microdeletion carriers is likely to enhance the penetrance for autism spectrum disorder

Cameli

Viggiano

Rochat

et al. 2021

J Cellular Molecular Medi

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“…However, the literature indicates that both male and female ASD cases with CHD8 mutations demonstrate consistent clinical phenotypes, including macrocephaly (An et al, 2020;Barnard et al, 2015;Beighley et al, 2020;Bernier et al, 2014;Douzgou et al, 2019;Li et al, 2017;T. Wang et al, 2016;Wu et al, 2020). Additionally, publications of Chd8 mouse models, including earlier work on this line, reported relevant phenotypes in both males and females (Gompers et al, 2017;Suetterlin et al, 2018;Zhao et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

“…Despite the clinical and genetic heterogeneity that typifies ASD, some anatomical features appear to be either present in many cases or so dramatically altered in some that their presence is now reasonably well replicated as characteristic of ASD among a subset of cases across a number of studies. One such finding is the tendency towards increased size of the brain during the early postnatal period causing macrocephaly (Albores-Gallo et al, 2017;Amaral et al, 2017;Bernier et al, 2014Bernier et al, , 2016Donovan & Basson, 2017;Li et al, 2017;Libero et al, 2016;Nordahl et al, 2011;Woodbury-Smith et al, 2017;Wu et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Increased cortical volume without increased neuron number in heterozygousChd8mutant mouse cortex

Canales

Frank

Bennett

et al. 2021

Preprint

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De novo mutations in the chromatin-remodeling factor CHD8 (Chromodomain-Helicase DNA-binding protein 8) have emerged as a key genetic risk factor for Autism Spectrum Disorder (ASD) and, more generally, neurodevelopmental disorders. Individuals with heterozygous mutations in CHD8 typically present hallmarks of ASD with comorbid cognitive disability and macrocephaly. Knockdown or haploinsufficiency of Chd8 in animal models has recapitulated phenotypes observed in patients, including increased head circumference and brain size. Here, we aimed to determine whether increased neuron numbers or soma size drives increased cortical volume. We performed design-based stereological analyses of cortical structure in adult male and female heterozygous Chd8 mice and wild-type littermate controls. Chd8 haploinsufficient male mice displayed a ~8-12% increase in cortical volume, no differences in cortical neuron number and comparable neuronal soma size. Our study reproduced previous reports of increased brain size associated with CHD8 mutation in humans and mice and are consistent with reported sex-specific impacts of Chd8 mutations in mice and increased burden of CHD8 mutations in human males with ASD. These findings suggest that the nature of the cortical enlargement due to Chd8 haploinsufficiency is complex and appears to be due to a factor other than an increased neuron number or soma size.Lay SummaryWe measured the size and neuron number in the neocortex in mice with heterozygous Chd8 mutation, a model relevant to Autism Spectrum Disorder. We found an increased cortical volume in male mutants, which was not accompanied by increased neuron number or soma size. Our results indicate that the enlarged brain in Chd8 mutant mice is complex, more evident here in males, and is due to factors other than increased neuron number.

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“…57 Additional support comes from genetic studies suggesting that HC is highly heritable 58 and that genetic variations associated with HC are also associated with risk of ASD. 59 Another indication of a familial link between abnormal fetal head growth and risk of ASD lies in some maternal endocrine functions during pregnancy that have been associated with both of these traits. 60,61 Interestingly, fetuses of our TDS group demonstrated accelerated head growth during late gestation to compensate for their relatively smaller heads, a finding consistent with previous study demonstrating slightly faster growth rate among TDS compared to TDP.…”

Section: Discussionmentioning

confidence: 99%

Association between Abnormal Fetal Head Growth and Autism Spectrum Disorder

Regev

Cohen

Hadar

et al. 2020

Preprint

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Background: Despite evidence for the prenatal onset of abnormal head growth in ASD children, studies on fetal ultrasound data in ASD are limited and controversial. Methods: A longitudinal matched case-sibling-control study on prenatal ultrasound biometric measures of ASD children was conducted. Children with ASD were matched to two control groups: (1) typically developed sibling (TDS) and (2) typically developed population (TDP). The cohort comprised 528 children (72.7% males): 174 ASD, 178 TDS, and 176 TDP. Results: Second-trimester ASD and TDS fetuses had significantly smaller biparietal diameter (BPD) than TDP fetuses (aORzBPD=0.685, 95%CI=0.527−0.890 and aORzBPD=0.587, 95%CI=0.459−0.751, respectively). However, these differences became statistically indistinguishable in the third trimester. Head biometric measures were associated with the sex of the fetus, with males having larger heads than females within and across groups. A linear mixed-effect model assessing the effects of sex and group assignment on fetal longitudinal head growth indicated faster BPD growth in TDS vs both ASD and TDP in males (β=0.084 and β=0.100 respectively; p<0.001) but not in females, suggesting an ASD−sex interaction in head growth during gestation. Fetal head shape showed sex-specific characteristics, and head growth was inversely correlated with ASD severity in males and females, thus further supporting the sex effect on the association between fetal head growth and ASD. Conclusions: Our findings suggest that abnormal fetal head growth is a familial trait of ASD, which is modulated by sex and is associated with the severity of the disorder. Thus, it could serve as an early biomarker for ASD.

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Phenotype‐to‐genotype approach reveals head‐circumference‐associated genes in an autism spectrum disorder cohort

Cited by 35 publications

References 40 publications

An increased burden of rare exonic variants in NRXN1 microdeletion carriers is likely to enhance the penetrance for autism spectrum disorder

An increased burden of rare exonic variants in NRXN1 microdeletion carriers is likely to enhance the penetrance for autism spectrum disorder

Increased cortical volume without increased neuron number in heterozygousChd8mutant mouse cortex

Association between Abnormal Fetal Head Growth and Autism Spectrum Disorder

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