Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases

Stessman, Holly A.F.; Xiong, Bo; Coe, Bradley P.; Wang, Tianyun; Hoekzema, Kendra; Fencková, Michaela; Kvarnung, Malin; Gerdts, Jennifer; Trinh, Sandy; Cosemans, Nele; Vives, Laura; Lin, Jyh Dong; Turner, Tychele N.; Santen, Gijs W.E.; Ruivenkamp, Claudia; Kriek, Marjolein; Haeringen, Arie van; Aten, Emmelien; Friend, Kathryn; Liebelt, Jan; Barnett, Christopher; Haan, Eric; Shaw, Marie; Gécz, Jozef; Anderlid, Britt Marie; Nordgren, Ann; Wedell, Anna; Schwartz, Charles E.; Kooy, R. Frank; Vandeweyer, Geert; Helsmoortel, Céline; Romano, Corrado; Alberti, Antonino; Vinci, Mirella; Avola, Emanuela; Giusto, Stefania; Courchesne, Eric; Pramparo, Tiziano; Pierce, Karen; Nalabolu, Srinivasa; Amaral, David G.; Scheffer, Ingrid E.; Delatycki, Martin B.; Lockhart, Paul J.; Hormozdiari, Fereydoun; Harich, Benjamin; Castells-Nobau, Anna; Xia, Kun; Peeters, Hilde; Nordenskjöld, Magnus; Schenck, Annette; Bernier, Raphael; Eichler, Evan E.

doi:10.1038/ng.3792

Cited by 471 publications

(449 citation statements)

References 123 publications

(152 reference statements)

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“…CNVs involving NRXN1 have been associated with intellectual disability, language delay, autism, and several psychiatric disorders, in particular, schizophrenia [Feng et al, 2006; Kim et al, 2008; Glessner et al, 2009; Rujescu et al, 2009; Ching et al, 2010; Gauthier et al, 2011; Liu et al, 2012; Gjørlund et al, 2012; Stessman et al, 2017], indicating a broad phenotypic spectrum for NRXN mutations. In the four previously reported pedigrees with NRXN3 deletion, the deletion carrying probands were all diagnosed with autism.…”

Section: Discussionmentioning

confidence: 99%

“…Neurexins are cell-surface receptors that bind neuroligins to form a Ca 2+ -dependent neurexin/neuroligin complex at synapses in the central nervous system; they are required for efficient neurotransmission and play key roles in synaptic contacts and function [Tabuchi and Sudhof, 2002; Reissner et al, 2008]. All three genes had been implicated in autism spectrum disorders (ASD) [Feng et al, 2006; Autism Genome Project Consortium et al, 2007; Kim et al, 2008; Glessner et al, 2009; Rujescu et al, 2009; Ching et al, 2010; Gauthier et al, 2011; Liu et al, 2012; Gjørlund et al, 2012; Stessman et al, 2017; Mohrmann et al, 2011; Dachtler et al, 2014; Born et al, 2015; Boyle et al, 2015; Vaags et al, 2012]. …”

Section: Introductionmentioning

confidence: 99%

“…Loss of function variants had been mostly identified in NRXN1 among patients with neurodevelopmental or neuropsychiatric disorders, supporting NRXN1 as a susceptibility gene for ASD, schizophrenia and intellectual disability [Feng et al, 2006; Szatmari et al, 2007; Kim et al, 2008; Glessner et al, 2009; Rujescu et al, 2009; Ching et al, 2010; Gauthier et al, 2011; Liu et al, 2012; Gjørlund et al, 2012; Stessman et al, 2017]. Variable expressivity and incomplete penetrance frequently were observed [Woodbury-Smith et al, 2017; Lowther et al, 2017].…”

Section: Introductionmentioning

confidence: 99%

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A rare exonic NRXN3 deletion segregating with neurodevelopmental and neuropsychiatric conditions in a three‐generation Chinese family

Yuan

Wang

Liu

et al. 2018

American J of Med Genetics Pt B

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Members of the neurexin gene family, neurexin 1 (NRXN1), neurexin 2 (NRXN2), and neurexin 3 (NRXN3) encode important components of synaptic function implicated in autism and other neurodevelopmental/neuropsychiatric disorders. Loss of function variants have been reported predominantly in NRXN1, with fewer such variants detected in NRXN2 and NRXN3. Evidence for segregating NRNX3 variants has particularly been lacking. Here, we report identification by chromosomal microarray analysis of a rare exonic deletion affecting the NRXN3 alpha isoform in a three-generation Chinese family. The proband, a 7-year-old boy, presented with motor and language delay and met the clinical diagnostic criteria for autism. He also presented with moderate intellectual disability, attention-deficit hyperactivity disorder and facial dysmorphic features. The mother and maternal grandfather, both deletion carriers, presented with variable degrees of language and communication difficulties, as well as neuropsychiatric problems such as schizophrenia and temper tantrums. A compilation of sporadic cases with deletions involving part or all of NRXN3 revealed that 9 of 23 individuals (39%) displayed features of autism. The evidence for cosegregation in our family further supports a role for NRXN3 in autism and neurodevelopmental/neuropsychiatric disorders but demonstrates intrafamily variable expressivity due to this NRXN3 deletion, with schizophrenia and facial dysmorphism being potential novel features of NRXN3 haploinsufficiency.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A rare exonic NRXN3 deletion segregating with neurodevelopmental and neuropsychiatric conditions in a three‐generation Chinese family

Yuan

Wang

Liu

et al. 2018

American J of Med Genetics Pt B

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“…Thus, future studies on multiple phenotypes across samples (rather than just only autism or ASD) would reveal the predictive biomarkers or modifier genes that lead to the disease. A recent study using targeted sequencing of 208 candidate genes from >11 730 cases and >2867 controls identified 91 genes related to neurodevelopmental‐disorder risks, including 25 genes showing bias towards autism …”

Section: Genetic Risk Factorsmentioning

confidence: 99%

Genetics and epigenetics of autism: A Review

Waye

Cheng

2017

Psychiatry Clin Neurosci

116

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Autism is a developmental disorder that starts before age 3 years, and children with autism have impairment in both social interaction and communication, and have restricted, repetitive, and stereotyped patterns of behavior, interests, and activities. There is a strong heritable component of autism and autism spectrum disorder (ASD) as studies have shown that parents who have a child with ASD have a 2-18% chance of having a second child with ASD. The prevalence of autism and ASD have been increasing during the last 3 decades and much research has been carried out to understand the etiology, so as to develop novel preventive and treatment strategies. This review aims at summarizing the latest research studies related to autism and ASD, focusing not only on the genetics but also some epigenetic findings of autism/ASD. Some promising areas of research using transgenic/knockout animals and some ideas related to potential novel treatment and prevention strategies will be discussed.

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“…http://dx.doi.org/10.1101/257758 doi: bioRxiv preprint first posted online Feb. 1, 2018; We used a modified de Vries scoring system for quantifying the number and severity of phenotypic abnormalities in affected children, which allows for a uniform assessment of developmental phenotypes from clinical records (Table S1) 6,37-40 . Originally used for characterizing phenotypes associated with subtelomeric and balanced chromosomal rearrangements, this method, used reliably in several studies, allows for a uniform assessment of developmental phenotypes from clinical records [38][39][40] . Using keyword searches for more than 50…”

Section: Cc-by-nd 40 International License Peer-reviewed) Is the Autmentioning

confidence: 99%

Rare variants in the genetic background modulate the expressivity of neurodevelopmental disorders

Pizzo

Jensen

Polyak

et al. 2018

Preprint

Self Cite

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Rare copy-number variants (CNVs) and gene-disruptive mutations associated with neurodevelopmental disease are characterized by phenotypic heterogeneity. When affected children inherit these mutations, they usually present more severe features than carrier parents, leading to challenges in diagnosis and management. To understand how the genetic background modulates phenotypes of these variants, we analyzed clinical and exome-sequencing data from 757 probands and 233 parents and siblings who carry disease-associated mutations. We found that the number of rare pathogenic secondary mutations in developmental genes (second-hits) modulates the expressivity of disease in probands with 16p12.1 deletion (n=26, p=0.014) and in autism probands with gene-disruptive mutations (n=184, p=0.031) when compared to their carrier family members. Probands with 16p12.1 deletion and a strong family history of neuropsychiatric disease were more likely to manifest multiple and more severe clinical features (p=0.035) and carry a higher burden of second-hits compared to those with mild or no family history (p=0.001). The amount of secondary variants determined the severity of cognitive impairment in 432 probands carrying pathogenic rare CNVs or de novo mutations in disease genes and negatively correlated with head size in 84 probands with 16p11.2 deletion, suggesting an effect of the genetic background across multiple phenotypic domains. These second-hits involved known disease genes, such as SETD5, AUTS2, and NRXN1, and novel candidate modifiers, such as CDH23, RYR3, and DNAH3, affecting core developmental processes. Our findings suggest that in the era of personalized medicine, accurate diagnosis will require complete evaluation of the genetic background even after a candidate gene mutation is identified.

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Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases

Cited by 471 publications

References 123 publications

A rare exonic NRXN3 deletion segregating with neurodevelopmental and neuropsychiatric conditions in a three‐generation Chinese family

A rare exonic NRXN3 deletion segregating with neurodevelopmental and neuropsychiatric conditions in a three‐generation Chinese family

Genetics and epigenetics of autism: A Review

Rare variants in the genetic background modulate the expressivity of neurodevelopmental disorders

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